2021/07/12 更新

写真a

オオハシ トシタカ
大橋 俊孝
OOHASHI Toshitaka
所属
医歯薬学域 教授
職名
教授
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プロフィール
神経特異的細胞外マトリックス(ECM)分子の発見から、その機能、神経糖鎖生物学に魅せられています。また、軟骨代謝、軟骨プロテオグリカンのイメージング、薬物送達技術にも興味をもっています。

学位

  • 博士(薬学) ( 岡山大学 )

研究キーワード

  • 分子生物学

  • マトリックス生物学

  • 生化学

研究分野

  • ライフサイエンス / 神経科学一般

  • ライフサイエンス / 医化学

  • ライフサイエンス / 耳鼻咽喉科学

  • ライフサイエンス / 形成外科学

  • ライフサイエンス / 生体材料学

  • ライフサイエンス / 生体医工学

  • ライフサイエンス / 整形外科学

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学歴

  • 岡山大学   Graduate School, Division of National Science and Technology  

    - 1992年

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  • 岡山大学    

    - 1992年

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    国名: 日本国

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  • 京都大学   Faculty of Pharmaceutical Science  

    - 1987年

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  • 京都大学   薬学部   製薬化学科

    - 1987年

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    国名: 日本国

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経歴

  • - Professor,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University

    2014年 - 現在

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  • - 岡山大学医歯薬学総合研究科 教授

    2014年 - 現在

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  • Associate Professor,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University

    2012年 - 2014年

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  • 岡山大学医歯薬学総合研究科 准教授

    2012年 - 2014年

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  • Max-Planck Research fellow,Max-Planck Institute of Biochemistry

    1997年2月 - 1997年9月

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  • マックスプランク 生化学研究所 マックスプランク研究員

    1997年2月 - 1997年9月

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  • Postdoctoral Fellowships of Japan Society for the Promotion of Science,Max-Planck Institute of Biochemistry

    1996年 - 1997年

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  • マックスプランク 生化学研究所 日本学術振興会特別研究員

    1996年 - 1997年

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所属学協会

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委員歴

  • 日本結合組織学会理事   理事  

    2018年   

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    団体区分:学協会

    日本結合組織学会理事

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  • 日本軟骨代謝学会理事   理事  

    2017年   

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    団体区分:学協会

    日本軟骨代謝学会理事

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  • 日本軟骨代謝学会 評議員   評議員  

    2014年   

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    団体区分:学協会

    日本軟骨代謝学会 評議員

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  • 日本生化学会   なし  

    1987年   

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    団体区分:学協会

    日本生化学会

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論文

  • The roles of perineuronal nets and the perinodal extracellular matrix in neuronal function. 査読 国際誌

    James W Fawcett, Toshitaka Oohashi, Tommaso Pizzorusso

    Nature reviews. Neuroscience   20 ( 8 )   451 - 465   2019年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Perineuronal nets (PNNs) are extracellular matrix (ECM) chondroitin sulfate proteoglycan (CSPG)-containing structures that surround the soma and dendrites of various mammalian neuronal cell types. PNNs appear during development around the time that the critical periods for developmental plasticity end and are important for both their onset and closure. A similar structure - the perinodal ECM - surrounds the axonal nodes of Ranvier and appears as myelination is completed, acting as an ion-diffusion barrier that affects axonal conduction speed. Recent work has revealed the importance of PNNs in controlling plasticity in the CNS. Digestion, blocking or removal of PNNs influences functional recovery after a variety of CNS lesions. PNNs have further been shown to be involved in the regulation of memory and have been implicated in a number of psychiatric disorders.

    DOI: 10.1038/s41583-019-0196-3

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  • Under the ECM Dome: The Physiological Role of the Perinodal Extracellular Matrix as an Ion Diffusion Barrier. 査読 国際誌

    Yoko Bekku, Toshitaka Oohashi

    Advances in experimental medicine and biology   1190   107 - 122   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Enriched Na+ channel clustering allows for rapid saltatory conduction at a specialized structure in myelinated axons, the node of Ranvier, where cations are exchanged across the axon membrane. In the extracellular matrix (ECM), highly negatively charged molecules accumulate and wrap around the nodal gaps creating an ECM dome, called the perinodal ECM. The perinodal ECM has different molecular compositions in the central nervous system (CNS) and peripheral nervous system (PNS). Chondroitin sulfate proteoglycans are abundant in the ECM at the CNS nodes, whereas heparan sulfate proteoglycans are abundant at the PNS nodes. The proteoglycans have glycosaminoglycan chains on their core proteins, which makes them electrostatically negative. They associate with other ECM molecules and form a huge stable ECM complex at the nodal gaps. The polyanionic molecular complexes have high affinity to cations and potentially contribute to preventing cation diffusion at the nodes.In this chapter, we describe the molecular composition of the perinodal ECM in the CNS and PNS, and discuss their physiological role at the node of Ranvier.

    DOI: 10.1007/978-981-32-9636-7_8

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  • Hapln4/Bral2 is a selective regulator for formation and transmission of GABAergic synapses between Purkinje and deep cerebellar nuclei neurons. 査読 国際誌

    Midori Edamatsu, Rinako Miyano, Atsushi Fujikawa, Fuminari Fujii, Tetsuya Hori, Takeshi Sakaba, Toshitaka Oohashi

    Journal of neurochemistry   147 ( 6 )   748 - 763   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Purkinje cells (PCs) convey the sole output of the cerebellar cortex to the deep cerebellar nuclei (DCN). DCN neurons are enwrapped in densely organized extracellular matrix structures, known as perineuronal nets (PNNs). PNNs are typically found around fast-spiking GABAergic interneurons expressing parvalbumin but interestingly also exist surrounding other neurons, such as the neurons in the DCN and medial nucleus of the trapezoid body, which are the post-synaptic neurons of large axo-somatic synapses adapted for fast signaling. This characteristic localization prompted the hypothesis that PNNs might play a role in the maintenance and formation of large fast-signaling synapses. To elucidate the role of the PNN at these synapses, we investigated the electrophysiological and morphological properties of DCN synapses in hyaluronan and proteoglycan binding link protein 4 (Hapln4/Bral2) knockout (KO) mice around postnatal day (P)14. Hapln4/Bral2 is important for PNN structure, as it stabilizes the interaction between hyaluronan and proteoglycan. Here, using immunohistochemistry we show that Hapln4/Bral2 localized closely with GABAergic terminals. In DCN neurons of Hapln4/Bral2 KO mice, inhibitory synaptic strengths were reduced as compared to those in wild-type mice, whereas the properties of excitatory synapses were unaffected. The reduced IPSC amplitudes were mainly because of reduced numbers of releasable vesicles. Moreover, Hapln4/Bral2 deficiency reduced the number of PC GABAergic terminals in the DCN. These results demonstrate that Hapln4/Bral2 is a PNN component that selectively contributes to formation and transmission of PC-DCN synapses in the cerebellum. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

    DOI: 10.1111/jnc.14571

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  • Distinct Osteogenic Potentials of BMP-2 and FGF-2 in Extramedullary and Medullary Microenvironments. 国際誌

    Shuji Nosho, Ikue Tosa, Mitsuaki Ono, Emilio Satoshi Hara, Kei Ishibashi, Akihiro Mikai, Yukie Tanaka, Aya Kimura-Ono, Taishi Komori, Kenji Maekawa, Takuo Kuboki, Toshitaka Oohashi

    International journal of molecular sciences   21 ( 21 )   2020年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Bone morphogenetic protein-2 (BMP-2) and fibroblast growth factor-2 (FGF-2) have been regarded as the major cytokines promoting bone formation, however, several studies have reported unexpected results with failure of bone formation or bone resorption of these growth factors. In this study, BMP-2 and FGF-2 adsorbed into atellocollagen sponges were transplanted into bone defects in the bone marrow-scarce calvaria (extramedullary environment) and bone marrow-abundant femur (medullary environment) for analysis of their in vivo effects not only on osteoblasts, osteoclasts but also on bone marrow cells. The results showed that BMP-2 induced high bone formation in the bone marrow-scarce calvaria, but induced bone resorption in the bone marrow-abundant femurs. On the other hand, FGF-2 showed opposite effects compared to those of BMP-2. Analysis of cellular dynamics revealed numerous osteoblasts and osteoclasts present in the newly-formed bone induced by BMP-2 in calvaria, but none were seen in either control or FGF-2-transplanted groups. On the other hand, in the femur, numerous osteoclasts were observed in the vicinity of the BMP-2 pellet, while a great number of osteoblasts were seen near the FGF-2 pellets or in the control group. Of note, FCM analysis showed that both BMP-2 and FGF-2 administrated in the femur did not significantly affect the hematopoietic cell population, indicating a relatively safe application of the two growth factors. Together, these results indicate that BMP-2 could be suitable for application in extramedullary bone regeneration, whereas FGF-2 could be suitable for application in medullary bone regeneration.

    DOI: 10.3390/ijms21217967

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  • BMP-2/β-TCP Local Delivery for Bone Regeneration in MRONJ-Like Mouse Model. 査読

    Mikai A, Ono M, Tosa I, Nguyen HTT, Hara ES, Nosho S, Kimura-Ono A, Nawachi K, Takarada T, Kuboki T, Oohashi T

    Int J Mol Sci.   21 ( 19 )   E7028   2020年9月

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    担当区分:最終著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • The Effect of Hapln4 Link Protein Deficiency on Extracellular Space Diffusion Parameters and Perineuronal Nets in the Auditory System During Aging. 査読 国際誌

    Petra Sucha, Martina Chmelova, Monika Kamenicka, Marcel Bochin, Toshitaka Oohashi, Lydia Vargova

    Neurochemical research   45 ( 1 )   68 - 82   2020年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hapln4 is a link protein which stabilizes the binding between lecticans and hyaluronan in perineuronal nets (PNNs) in specific brain regions, including the medial nucleus of the trapezoid body (MNTB). The aim of this study was: (1) to reveal possible age-related alterations in the extracellular matrix composition in the MNTB and inferior colliculus, which was devoid of Hapln4 and served as a negative control, (2) to determine the impact of the Hapln4 deletion on the values of the ECS diffusion parameters in young and aged animals and (3) to verify that PNNs moderate age-related changes in the ECS diffusion, and that Hapln4-brevican complex is indispensable for the correct protective function of the PNNs. To achieve this, we evaluated the ECS diffusion parameters using the real-time iontophoretic method in the selected region in young adult (3 to 6-months-old) and aged (12 to 18-months-old) wild type and Hapln4 knock-out (KO) mice. The results were correlated with an immunohistochemical analysis of the ECM composition and astrocyte morphology. We report that the ECM composition is altered in the aged MNTB and aging is a critical point, revealing the effect of Hapln4 deficiency on the ECS diffusion. All of our findings support the hypothesis that the ECM changes in the MNTB of aged KO animals affect the ECS parameters indirectly, via morphological changes of astrocytes, which are in direct contact with synapses and can be influenced by the ongoing synaptic transmission altered by shifts in the ECM composition.

    DOI: 10.1007/s11064-019-02894-2

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  • Mechanical strain attenuates cytokine-induced ADAMTS9 expression via transient receptor potential vanilloid type 1. 査読 国際誌

    Takashi Ohtsuki, Akira Shinaoka, Kanae Kumagishi-Shinaoka, Keiichi Asano, Omer Faruk Hatipoglu, Junko Inagaki, Ken Takahashi, Toshitaka Oohashi, Keiichiro Nishida, Keiji Naruse, Satoshi Hirohata

    Experimental cell research   383 ( 2 )   111556 - 111556   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The synovial fluids of patients with osteoarthritis (OA) contain elevated levels of inflammatory cytokines, which induce the expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and of the matrix metalloproteinase (MMP) in chondrocytes. Mechanical strain has varying effects on organisms depending on the strength, cycle, and duration of the stressor; however, it is unclear under inflammatory stimulation how mechanical strain act on. Here, we show that mechanical strain attenuates inflammatory cytokine-induced expression of matrix-degrading enzymes. Cyclic tensile strain (CTS), as a mechanical stressor, attenuated interleukin (IL)-1β and tumor necrosis factor (TNF)-α-induced mRNA expression of ADAMTS4, ADAMTS9, and MMP-13 in normal chondrocytes (NHAC-kn) and in a chondrocytic cell line (OUMS-27). This effect was abolished by treating cells with mechano-gated channel inhibitors, such as gadolinium, transient receptor potential (TRP) family inhibitor, ruthenium red, and with pharmacological and small interfering RNA-mediated TRPV1 inhibition. Furthermore, nuclear factor κB (NF-κB) translocation from the cytoplasm to the nucleus resulting from cytokine stimulation was also abolished by CTS. These findings suggest that mechanosensors such as the TRPV protein are potential therapeutic targets in treating OA.

    DOI: 10.1016/j.yexcr.2019.111556

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  • Type XVIII Collagen Modulates Keratohyalin Granule Formation and Keratinization in Oral Mucosa. 査読 国際誌

    Ha Thi Thu Nguyen, Mitsuaki Ono, Emilio Satoshi Hara, Taishi Komori, Midori Edamatsu, Tomoko Yonezawa, Aya Kimura-Ono, Kenji Maekawa, Takuo Kuboki, Toshitaka Oohashi

    International journal of molecular sciences   20 ( 19 )   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Epithelial keratinization involves complex cellular modifications that provide protection against pathogens and chemical and mechanical injuries. In the oral cavity, keratinized mucosa is also crucial to maintain healthy periodontal or peri-implant tissues. In this study, we investigated the roles of type XVIII collagen, a collagen-glycosaminoglycan featuring an extracellular matrix component present in the basement membrane, in oral mucosal keratinization. Histological analysis of keratinized and non-keratinized oral mucosa showed that type XVIII collagen was highly expressed in keratinized mucosa. Additionally, a 3D culture system using human squamous carcinoma cells (TR146) was used to evaluate and correlate the changes in the expression of type XVIII collagen gene, COL18A1, and epithelial keratinization-related markers, e.g., keratin 1 (KRT1) and 10 (KRT10). The results showed that the increase in COL18A1 expression followed the increase in KRT1 and KRT10 mRNA levels. Additionally, loss-of-function analyses using silencing RNA targeting COL18A1 mRNA and a Col18-knockout (KO) mouse revealed that the absence of type XVIII collagen induces a dramatic decrease in KRT10 expression as well as in the number and size of keratohyalin granules. Together, the results of this study demonstrate the importance of type XVIII collagen in oral mucosal keratinization.

    DOI: 10.3390/ijms20194739

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  • Postnatal Runx2 deletion leads to low bone mass and adipocyte accumulation in mice bone tissues. 査読 国際誌

    Ikue Tosa, Daisuke Yamada, Misa Yasumatsu, Eiichi Hinoi, Mitsuaki Ono, Toshitaka Oohashi, Takuo Kuboki, Takeshi Takarada

    Biochemical and biophysical research communications   516 ( 4 )   1229 - 1233   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Global gene deletion studies have established that Runt-related transcription factor-2 (Runx2) is essential during skeletogenesis for osteoblastic differentiation in both intramembranous and endochondral ossification processes. However, the postnatal significance of Runx2 in vivo is poorly understood because a global Runx2 deletion causes perinatal lethality. In this study, we generated tamoxifen-induced Runx2 global deficient mice by crossing Runx2flox mice with ROSA26-CreERT2 mice (Rosa26-CreERT2; Runx2flox/flox). Four-week-old mice were intraperitoneally treated with tamoxifen for five consecutive days, sacrificed, and analyzed six weeks after tamoxifen administration. Deletion of Runx2 led to low bone mass, which is associated with decreased bone formation and bone resorption as well as excessive bone marrow adiposity. Collectively, postnatal Runx2 absolutely plays an important role in maintaining the homeostasis of bone tissues not only in bone mass, but also in the bone marrow environment.

    DOI: 10.1016/j.bbrc.2019.07.014

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  • Collagen XVIII Deposition in the Basement Membrane Zone beneath the Newly Forming Epidermis during Wound Healing in Mice. 査読

    Takahiro Maeba, Tomoko Yonezawa, Mitsuaki Ono, Yasuko Tomono, Ritva Heljasvaara, Taina Pihlajaniemi, Kiichi Inagawa, Toshitaka Oohashi

    Acta medica Okayama   73 ( 2 )   135 - 146   2019年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The basement membrane (BM) is composed of various extracellular molecules and regulates tissue regeneration and maintenance. Here, we demonstrate that collagen XVIII was spatiotemporally expressed in the BM during skin wound healing in a mouse excisional wound-splinting model. Re-epithelialization was detected at days 3 and 6 post-wounding. The ultrastructure of epidermal BM was discontinuous at day 3, whereas on day 6 a continuous BM was observed in the region proximal to the wound edge. Immunohistochemistry demonstrated that collagen XVIII was deposited in the BM zone beneath newly forming epidermis in day 3 and 6 wounds. Laminin-332, known to be the earliest BM component appearing in wounds, was colocalized with collagen XVIII in the epidermal BM zone at days 3 and 6. The deposition of α1(IV) collagen and nidogen-1 in the epidermal BM zone occurred later than that of collagen XVIII. We also observed the short isoform of collagen XVIII in the epidermal BM zone at day 3 post-wounding. Collectively, our results suggested that collagen XVIII plays a role in the formation of the dermal-epidermal junction during re-epithelialization, and that it is the short isoform that is involved in the early phase of re-epithelialization.

    DOI: 10.18926/AMO/56649

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  • Acidic Pre-Conditioning Enhances the Stem Cell Phenotype of Human Bone Marrow Stem/Progenitor Cells. 査読 国際誌

    Yuri Hazehara-Kunitomo, Emilio Satoshi Hara, Mitsuaki Ono, Kyaw Thu Aung, Keiko Komi, Hai Thanh Pham, Kentaro Akiyama, Masahiro Okada, Toshitaka Oohashi, Takuya Matsumoto, Takuo Kuboki

    International journal of molecular sciences   20 ( 5 )   2019年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A deeper understanding of the detailed mechanism of in vivo tissue healing is necessary for the development of novel regenerative therapies. Among several external factors, environmental pH is one of the crucial parameters that greatly affects enzyme activity and cellular biochemical reactions involving tissue repair and homeostasis. In this study, in order to analyze the microenvironmental conditions during bone healing, we first measured the pH in vivo at the bone healing site using a high-resolution fiber optic pH microsensor directly in femur defects and tooth extraction sockets. The pH was shown to decrease from physiological 7.4 to 6.8 during the initial two days of healing (inflammatory phase). In the same initial stages of the inflammatory phase of the bone healing process, mesenchymal stem cells (MSCs) are known to migrate to the healing site to contribute to tissue repair. Therefore, we investigated the effect of a short-term acidic (pH 6.8) pre-treatment on the stemness of bone marrow-derived MSCs (BMSCs). Interestingly, the results showed that pre-treatment of BMSCs with acidic pH enhances the expression of stem cell markers (OCT-4, NANOG, SSEA-4), as well as cell viability and proliferation. On the other hand, acidic pH decreased BMSC migration ability. These results indicate that acidic pH during the initial stages of bone healing is important to enhance the stem cell properties of BMSCs. These findings may enable the development of novel methods for optimization of stem cell function towards tissue engineering or regenerative medicine.

    DOI: 10.3390/ijms20051097

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  • Bone Marrow Cells Inhibit BMP-2-Induced Osteoblast Activity in the Marrow Environment. 査読 国際誌

    Ha Thi Nguyen, Mitsuaki Ono, Yasutaka Oida, Emilio Satoshi Hara, Taishi Komori, Kentaro Akiyama, Ha Thi Thu Nguyen, Kyaw Thu Aung, Hai Thanh Pham, Ikue Tosa, Takeshi Takarada, Koichi Matsuo, Toshihide Mizoguchi, Toshitaka Oohashi, Takuo Kuboki

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research   34 ( 2 )   327 - 332   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Bone morphogenetic protein 2 (BMP-2) is widely known as a potent growth factor that promotes bone formation. However, an increasing number of studies have demonstrated side effects of BMP-2 therapy. A deeper understanding of the effect of BMP-2 on cells other than those involved directly in bone remodeling is of fundamental importance to promote a more effective delivery of BMP-2 to patients. In this study, we aimed to investigate the effect of BMP-2 in the marrow environment. First, BMP-2 adsorbed onto titanium implants was delivered at the tooth extraction socket (marrow-absent site) or in the mandible marrow of beagle dogs. BMP-2 could induce marked bone formation around the implant at the tooth extraction socket. Surprisingly, however, no bone formation was observed in the BMP-2-coated titanium implants inserted in the mandible marrow. In C57BL/6 mice, BMP-2 adsorbed in freeze-dried collagen pellets could induce bone formation in marrow-absent calvarial bone. However, similar to the canine model, BMP-2 could not induce bone formation in the femur marrow. Analysis of osteoblast differentiation using Col1a1(2.3)-GFP transgenic mice revealed a scarce number of osteoblasts in BMP-2-treated femurs, whereas in the control group, osteoblasts were abundant. Ablation of femur marrow recovered the BMP-2 ability to induce bone formation. In vitro experiments analyzing luciferase activity of C2C12 cells with the BMP-responsive element and alkaline phosphatase activity of MC3T3-E1 osteoblasts further revealed that bone marrow cells inhibit the BMP-2 effect on osteoblasts by direct cell-cell contact. Collectively, these results showed that the effect of BMP-2 in inducing bone formation is remarkably repressed by marrow cells via direct cell-cell contact with osteoblasts; this opens new perspectives on the clarification of the side-effects associated with BMP-2 application. © 2018 American Society for Bone and Mineral Research.

    DOI: 10.1002/jbmr.3598

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  • DNA Methylation-Based Regulation of Human Bone Marrow-Derived Mesenchymal Stem/Progenitor Cell Chondrogenic Differentiation. 査読 国際誌

    Yu Nomura, Emilio Satoshi Hara, Yuya Yoshioka, Há Thi Nguyen, Shuji Nosho, Taishi Komori, Kei Ishibashi, Toshitaka Oohashi, Mitsuaki Ono, Takuo Kuboki

    Cells, tissues, organs   207 ( 3-4 )   115 - 126   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Stem cells have essential applications in in vitro tissue engineering or regenerative medicine. However, there is still a need to understand more deeply the mechanisms of stem cell differentiation and to optimize the methods to control stem cell function. In this study, we first investigated the activity of DNA methyltransferases (DNMTs) during chondrogenic differentiation of human bone marrow-derived mesenchymal stem/progenitor cells (hBMSCs) and found that DNMT3A and DNMT3B were markedly upregulated during hBMSC chondrogenic differentiation. In an attempt to understand the effect of DNMT3A and DNMT3B on the chondrogenic differentiation of hBMSCs, we transiently transfected the cells with expression vectors for the two enzymes. Interestingly, DNMT3A overexpression strongly enhanced the chondrogenesis of hBMSCs, by increasing the gene expression of the mature chondrocyte marker, collagen type II, more than 200-fold. Analysis of the methylation condition in the cells revealed that DNMT3A and DNMT3B methylated the promoter sequence of early stem cell markers, NANOG and POU5F1(OCT-4). Conversely, the suppression of chondrogenic differentiation and the increase in stem cell markers of hBMSCs were obtained by chemical stimulation with the demethylating agent, 5-azacitidine. Loss-of-function assays with siRNAs targeting DNMT3A also significantly suppressed the chondrogenic differentiation of hBMSCs. Together, these results not only show the critical roles of DNMTs in regulating the chondrogenic differentiation of hBMSCs, but also suggest that manipulation of DNMT activity can be important tools to enhance the differentiation of hBMSCs towards chondrogenesis for potential application in cartilage tissue engineering or cartilage regeneration.

    DOI: 10.1159/000502885

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  • Inhibition of the glutamine transporter SNAT1 confers neuroprotection in mice by modulating the mTOR-autophagy system. 査読 国際誌

    Daisuke Yamada, Kenji Kawabe, Ikue Tosa, Shunpei Tsukamoto, Ryota Nakazato, Miki Kou, Koichi Fujikawa, Saki Nakamura, Mitsuaki Ono, Toshitaka Oohashi, Mari Kaneko, Shioi Go, Eiichi Hinoi, Yukio Yoneda, Takeshi Takarada

    Communications biology   2   346 - 346   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The pathophysiological role of mammalian target of rapamycin complex 1 (mTORC1) in neurodegenerative diseases is established, but possible therapeutic targets responsible for its activation in neurons must be explored. Here we identified solute carrier family 38a member 1 (SNAT1, Slc38a1) as a positive regulator of mTORC1 in neurons. Slc38a1
    flox/flox
    and Synapsin I-Cre mice were crossed to generate mutant mice in which Slc38a1 was selectively deleted in neurons. Measurement of 2,3,5-triphenyltetrazolium chloride (TTC) or the MAP2-negative area in a mouse model of middle cerebral artery occlusion (MCAO) revealed that Slc38a1 deficiency decreased infarct size. We found a transient increase in the phosphorylation of p70S6k1 (pp70S6k1) and a suppressive effect of rapamycin on infarct size in MCAO mice. Autophagy inhibitors completely mitigated the suppressive effect of SNAT1 deficiency on neuronal cell death under in vitro stroke culture conditions. These results demonstrate that SNAT1 promoted ischemic brain damage via mTOR-autophagy system.

    DOI: 10.1038/s42003-019-0582-4

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  • Unripe peach (Prunus persica) extract ameliorates damage from UV irradiation and improved collagen XVIII expression in 3D skin model. 査読 国際誌

    Tomoko Yonezawa, Ryusuke Momota, Hideki Iwano, Steven Zhao, Tomohiro Hakozaki, Chieko Soh, Shigetoyo Sawaki, Kazumi Toyama, Toshitaka Oohashi

    Journal of cosmetic dermatology   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    INTRODUCTION: Collagen type XVIII regulates cellular activities of adjacent cells at the dermal-epidermal junction (DEJ). To investigate its possible changes during aging, we compared its mRNA levels and protein localization in skin samples from female participants aged 20-70 years old. In addition, we evaluated the beneficial effects of unripe peach extracts in a 3D skin model. METHODS: Sun-exposed or sun-protected female skin samples were compared by DNA array or by immunohistochemistry for basement membrane components. To evaluate protective effects of fresh unripe peach extract, UV-B irradiated human 3D skin models were incubated in the presence or absence of the extract, followed by measurements of mRNA levels by real-time PCR, or by immunohistochemistry. RESULTS: In aged skin samples, COL18A1 mRNA levels were lower and the protein localization exhibited less intensive signal by anti-collagen type XVIII immunostaining. As observed in the skin tissues, collagen type XVIII exists at the DEJ in the 3D skin model. Fresh unripe peach extract significantly improved mRNA levels and partially localizations of collagen type XVIII, suggesting that fresh unripe peach extract ameliorates DEJ damages caused by UV-B irradiation. CONCLUSION: Collagen type XVIII and fresh unripe peach extract can be promising protective cosmetic strategies against skin aging.

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  • High molecular weight hyaluronan protects cartilage from degradation by inhibiting aggrecanase expression. 査読 国際誌

    Takashi Ohtsuki, Keiichi Asano, Junko Inagaki, Akira Shinaoka, Kanae Kumagishi-Shinaoka, Mehmet Z Cilek, Omer F Hatipoglu, Toshitaka Oohashi, Keiichiro Nishida, Issei Komatsubara, Satoshi Hirohata

    Journal of orthopaedic research : official publication of the Orthopaedic Research Society   36 ( 12 )   3247 - 3255   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hyaluronan (HA) is an extracellular matrix (ECM) component of articular cartilage and has been used to treat patients with osteoarthritis (OA). A disintegrin and metalloproteinases with thrombospondin motifs (ADAMTSs) play an important role in cartilage degradation in OA. We have previously reported that ADAMTS4 and ADAMTS9 were induced by cytokine stimulation. However, the effect of HA on the cytokine-inducible ADAMTS9 has never been investigated. Moreover, it is unclear whether HA protects cartilage by suppressing aggrecan degradation. Here, we examined the effects of HA on ADAMTS expression in vitro and on cartilage degradation in vivo. ADAMTS9 expression was higher than that of the other aggrecanases (ADAMTS4 and 5) in human chondrocytes, chondrocytic cells, and rat cartilage. ADAMTS4 and 9 mRNA levels were upregulated in cytokine-stimulated chondrocytes and chondrocytic cells. Pre-incubation with HA significantly inhibited ADAMTS9 mRNA expression in cytokine-stimulated cells. In a rat OA model, Adamts5 and 9 mRNA levels were transiently increased after surgery; intra-articular HA injections attenuated the induction of Adamts5 and 9 mRNA. HA also blocked aggrecan cleavage by aggrecanase in OA rats in a molecular size-dependent manner. These results demonstrate that HA attenuates induced aggrecanases expression in OA and thereby protects articular cartilage degradation by this enzyme. Our findings provide insight into the molecular basis for the beneficial effects of HA in OA. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 36:3247-3255, 2018.

    DOI: 10.1002/jor.24126

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  • Host-produced ADAMTS4 Inhibits Early-Stage Tumor Growth. 査読

    Keiichi Asano, Midori Edamatsu, Omer F Hatipoglu, Junko Inagaki, Mitsuaki Ono, Takashi Ohtsuki, Toshitaka Oohashi, Satoshi Hirohata

    Acta medica Okayama   72 ( 3 )   257 - 266   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Several research groups demonstrated that 'a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs (ADAMTS)'-family proteases play roles in cancer progression. However, the origins and contributions of these proteases are not known. Here, we demonstrate an association between host-produced ADAMTS4 and early-stage tumor growth. Murine Lewis lung carcinoma (LLC) tumors showed marked expressions of Adamts4 and Adamts5. We examined the contributions and distributions of host-derived Adamts4 and Adamts5 on tumor growth, using Adamts4LacZ/LacZ and Adamts5LacZ/LacZ knockout mice. Interestingly, the Adamts4LacZ/LacZ mice showed enhanced tumor growth compared to wild-type mice at 5-, 10- and 12-days post-inoculation, whereas the Adamts5LacZ/LacZ mice did not show significant differences in tumor growth. We next examined LacZ distribution in LLC tumor-bearing Adamts4LacZ/LacZ mice by β-galactosidase (β-gal) staining. We found that the β-gal-positive signals were strictly localized at the interior areas of the tumor at 10 days post-inoculation. Multiple staining demonstrated that most of the β-gal-positive cells were localized at the tumor vasculature in Adamts4LacZ/LacZ mice. Interestingly, β-gal-positive signals were not co-localized with biglycan after 10 days post-inoculation, excluding the biglycan cleavage by host-derived ADAMTS4. Taken together, these findings illustrate that host-derived ADAMTS4 was expressed at the tumor vessels and was associated with early-stage tumor growth.

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  • Physiological role of urothelial cancer-associated one long noncoding RNA in human skeletogenic cell differentiation. 査読 国際誌

    Takanori Ishikawa, Takashi Nishida, Mitsuaki Ono, Takeshi Takarada, Ha Thi Nguyen, Shinnosuke Kurihara, Takayuki Furumatsu, Yurika Murase, Masaharu Takigawa, Toshitaka Oohashi, Hiroshi Kamioka, Satoshi Kubota

    Journal of cellular physiology   233 ( 6 )   4825 - 4840   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A vast number of long-noncoding RNAs (lncRNA) are found expressed in human cells, which RNAs have been developed along with human evolution. However, the physiological functions of these lncRNAs remain mostly unknown. In the present study, we for the first time uncovered the fact that one of such lncRNAs plays a significant role in the differentiation of chondrocytes and, possibly, of osteoblasts differentiated from mesenchymal stem cells, which cells eventually construct the human skeleton. The urothelial cancer-associated 1 (UCA1) lncRNA is known to be associated with several human malignancies. Firstly, we confirmed that UCA1 was expressed in normal human chondrocytes, as well as in a human chondrocytic cell line; whereas it was not detected in human bone marrow mesenchymal stem cells (hBMSCs). Of note, although UCA1 expression was undetectable in hBMSCs, it was markedly induced along with the differentiation toward chondrocytes, suggesting its critical role in chondrogenesis. Consistent with this finding, silencing of the UCA1 gene significantly repressed the expression of chondrogenic genes in human chondrocytic cells. UCA1 gene silencing and hyper-expression also had a significant impact on the osteoblastic phenotype in a human cell line. Finally, forced expression of UCA1 in a murine chondrocyte precursor, which did not possess a UCA1 gene, overdrove its differentiation into chondrocytes. These results indicate a physiological and important role of this lncRNA in the skeletal development of humans, who require more sustained endochondral ossification and osteogenesis than do smaller vertebrates.

    DOI: 10.1002/jcp.26285

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  • Type IV collagen α6 chain is a regulator of keratin 10 in keratinization of oral mucosal epithelium. 査読 国際誌

    Komori T, Ono M, Hara ES, Ueda J, Nguyen HTT, Nguyen HT, Yonezawa T, Maeba T, Kimura-Ono A, Takarada T, Momota R, Maekawa K, Kuboki T, Oohashi T

    Scientific reports   8 ( 1 )   2612 - 2612   2018年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s41598-018-21000-0

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  • A deficiency of the link protein Bral2 affects the size of the extracellular space in the thalamus of aged mice. 査読 国際誌

    Michal Cicanic, Midori Edamatsu, Yoko Bekku, Ivan Vorisek, Toshitaka Oohashi, Lydia Vargova

    Journal of neuroscience research   96 ( 2 )   313 - 327   2018年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Bral2 is a link protein stabilizing the binding between lecticans and hyaluronan in perineuronal nets and axonal coats (ACs) in specific brain regions. Using the real-time iontophoretic method and diffusion-weighted magnetic resonance, we determined the extracellular space (ECS) volume fraction (α), tortuosity (λ), and apparent diffusion coefficient of water (ADCW ) in the thalamic ventral posteromedial nucleus (VPM) and sensorimotor cortex of young adult (3-6 months) and aged (14-20 months) Bral2-deficient (Bral2-/- ) mice and age-matched wild-type (wt) controls. The results were correlated with an analysis of extracellular matrix composition. In the cortex, no changes between wt and Bral2-/- were detected, either in the young or aged mice. In the VPM of aged but not in young Bral2-/- mice, we observed a significant decrease in α and ADCW in comparison with age-matched controls. Bral2 deficiency led to a reduction of both aggrecan- and brevican-associated perineuronal nets and a complete disruption of brevican-based ACs in young as well as aged VPM. Our data suggest that aging is a critical point that reveals the effect of Bral2 deficiency on VPM diffusion. This effect is probably mediated through the enhanced age-related damage of neurons lacking protective ACs, or the exhausting of compensatory mechanisms maintaining unchanged diffusion parameters in young Bral2-/- animals. A decreased ECS volume in aged Bral2-/- mice may influence the diffusion of neuroactive substances, and thus extrasynaptic and also indirectly synaptic transmission in this important nucleus of the somatosensory pathway.

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  • Stromal Versican Regulates Tumor Growth by Promoting Angiogenesis 査読

    Keiichi Asano, Courtney M. Nelson, Sumeda Nandadasa, Noriko Aramaki-Hattori, Daniel J. Lindner, Tyler Alban, Junko Inagaki, Takashi Ohtsuki, Toshitaka Oohashi, Suneel S. Apte, Satoshi Hirohata

    SCIENTIFIC REPORTS   7   2017年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    The proteoglycan versican is implicated in growth and metastases of several cancers. Here we investigated a potential contribution of stromal versican to tumor growth and angiogenesis. We initially determined versican expression by several cancer cell lines. Among these, MDA-MB231 and B16F10 had none to minimal expression in contrast to Lewis lung carcinoma (LLC). Notably, tumors arising from these cell lines had higher versican levels than the cell lines themselves suggesting a contribution from the host-derived tumor stroma. In LLC-derived tumors, both the tumor and stroma expressed versican at high levels. Thus, tumor stroma can make a significant contribution to tumor versican content. Versican localized preferentially to the vicinity of tumor vasculature and macrophages in the tumor. However, an ADAMTS protease-generated versican fragment uniquely localized to vascular endothelium. To specifically determine the impact of host/stroma-derived versican we therefore compared growth of tumors from B16F10 cells, which produced littleversican, in Vcan(hdf/+) mice and wild-type littermates. Tumors in Vcan(hdf/+) mice had reduced growth with a lower capillary density and accumulation of capillaries at the tumor periphery. These findings illustrate the variability of tumor cell line expression of versican, and demonstrate that versican is consistently contributed by the stromal tissue, where it contributes to tumor angiogenesis.

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  • Monoclonal Suncus Antibodies: Generation of Fusion Partners to Produce Suncus-Suncus Hybridomas. 査読

    Yoshikazu Sado, Satoko Inoue, Yasuko Tomono, Makoto Matsuyama, Masaki Fukushima, Toshitaka Oohashi, Takamichi Jogahara, Sen-Ichi Oda

    Acta histochemica et cytochemica   50 ( 2 )   71 - 84   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We used suncus (Suncus murinus; house musk shrew) to generate partner cells for cell fusion to produce suncus monoclonal antibodies. Suncus are insectivores that are genetically distant to rodents, and recognize antigens and epitopes that are not immunogenic in mice and rats, which are the animals most commonly used in basic life science research and from which monoclonal antibodies are usually produced. To date, monoclonal antibodies from suncus have not been generated due to the lack of a plasmacytoma fusion partner. To obtain suncus plasmacytoma cell lines suitable as a cell fusion partner, we injected suncus at both sides of the tail base with antigen emulsion, collected the lymph nodes and spleens, and cultured the cells to obtain immortalized lymphoid cell lines visually resembling mouse SP2/0-Ag14 myeloma cells. Three suncus immunized with the antigen provided 4 cell lines of suncus plasmacytoma, but they did not secrete immunoglobulins. Antibody-producing hybrid cells were generated from these cell lines using a cell fusion technique. Using one of the cell lines as a fusion partner, we obtained six lines of immunoglobulin-producing hybrid cells which secreted an unidentified monoclonal IgG. When these 6 lines were used as new fusion partners, we obtained several hybrid cell lines which secreted immunogen-specific monoclonal antibodies. These hybrid cells can be cloned and cryopreserved. We also obtained another good fusion partner which initially secreted antibody but later stopped doing so. These suncus-suncus hybrid cell lines will be useful for the production of suncus monoclonal antibodies.

    DOI: 10.1267/ahc.17007

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  • Modifications of perineuronal nets and remodelling of excitatory and inhibitory afferents during vestibular compensation in the adult mouse. 査読 国際誌

    Alessio Faralli, Federico Dagna, Andrea Albera, Yoko Bekku, Toshitaka Oohashi, Roberto Albera, Ferdinando Rossi, Daniela Carulli

    Brain structure & function   221 ( 6 )   3193 - 209   2016年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Perineuronal nets (PNNs) are aggregates of extracellular matrix molecules surrounding several types of neurons in the adult CNS, which contribute to stabilising neuronal connections. Interestingly, a reduction of PNN number and staining intensity has been observed in conditions associated with plasticity in the adult brain. However, it is not known whether spontaneous PNN changes are functional to plasticity and repair after injury. To address this issue, we investigated PNN expression in the vestibular nuclei of the adult mouse during vestibular compensation, namely the resolution of motor deficits resulting from a unilateral peripheral vestibular lesion. After unilateral labyrinthectomy, we found that PNN number and staining intensity were strongly attenuated in the lateral vestibular nucleus on both sides, in parallel with remodelling of excitatory and inhibitory afferents. Moreover, PNNs were completely restored when vestibular deficits of the mice were abated. Interestingly, in mice with genetically reduced PNNs, vestibular compensation was accelerated. Overall, these results strongly suggest that temporal tuning of PNN expression may be crucial for vestibular compensation.

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  • COL4A6 is dispensable for autosomal recessive Alport syndrome 査読

    Tomohiro Murata, Kan Katayama, Toshitaka Oohashi, Timo Jahnukainen, Tomoko Yonezawa, Yoshikazu Sado, Eiji Ishikawa, Shinsuke Nomura, Karl Tryggvason, Masaaki Ito

    SCIENTIFIC REPORTS   6   2016年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Alport syndrome is caused by mutations in the genes encoding alpha 3, alpha 4, or alpha 5 (IV) chains. Unlike X-linked Alport mice, alpha 5 and alpha 6 (IV) chains are detected in the glomerular basement membrane of autosomal recessive Alport mice, however, the significance of this finding remains to be investigated. We therefore generated mice lacking both alpha 3 and alpha 6 (IV) chains and compared their renal function and survival with Col4a3 knockout mice of 129 x 1/Sv background. No significant difference was observed in the renal function or survival of the two groups, or when the mice were backcrossed once to C57BL/6 background. However, the survival of backcrossed double knockout mice was significantly longer than that of the mice of 129 x 1/Sv background, which suggests that other modifier genes were involved in this phenomenon. In further studies we identified two Alport patients who had a homozygous mutation in intron 46 of COL4A4. The alpha 5 and alpha 6 (IV) chains were focally detected in the glomerular basement membrane of these patients. These findings indicate that although a5 and a6 (IV) chains are induced in the glomerular basement membrane in autosomal recessive Alport syndrome, their induction does not seem to play a major compensatory role.

    DOI: 10.1038/srep29450

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  • Human collagen XV is a prominent histopathological component of sinusoidal capillarization in hepatocellular carcinogenesis. 査読

    Kouji Kimura, Masaru Nakayama, Ichiro Naito, Takaaki Komiyama, Kouichi Ichimura, Hiroaki Asano, Kazunori Tsukuda, Aiji Ohtsuka, Toshitaka Oohashi, Shinichiro Miyoshi, Yoshifumi Ninomiya

    International journal of clinical oncology   21 ( 2 )   302 - 309   2016年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Increased expression of collagen XV has been reported in hepatocellular carcinogenesis in mice. The aim of this study was to confirm the previous murine findings in human hepatocellular carcinoma (HCC) specimens, along with the histopathological distribution of collagen XV in tumoral tissues. METHODS: Sixty-three primary HCC specimens were examined. Immunostaining of collagen XV and quantitative reverse transcriptional PCR of COL15A1, which encodes collagen XV, were performed. RESULTS: Positive staining of collagen XV was observed in all tumoral regions, regardless of differentiation level or pathological type of HCC, along the sinusoid-like endothelium, whereas collagen XV was not expressed in any non-tumoral region. The intensity score of collagen XV immunostaining and the mRNA value of COL15A1 were significantly correlated. COL15A1 expression in tumors was 3.24-fold higher than in non-tumoral regions. Multivariate analysis showed that COL15A1 expression was significantly higher in the absence of hepatitis virus and moderately differentiated HCC. CONCLUSIONS: COL15A1 mRNA was up-regulated in HCC and collagen XV was expressed along the sinusoid-like endothelium of HCC but not in non-tumoral regions, which implies that collagen XV contributes to the capillarization of HCC.

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  • CCN4/WISP-1 positively regulates chondrogenesis by controlling TGF-β3 function. 査読 国際誌

    Yuya Yoshioka, Mitsuaki Ono, Azusa Maeda, Tina M Kilts, Emilio Satoshi Hara, Hany Khattab, Junji Ueda, Eriko Aoyama, Toshitaka Oohashi, Masaharu Takigawa, Marian F Young, Takuo Kuboki

    Bone   83   162 - 170   2016年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The CCN family of proteins plays important roles in development and homeostasis of bone and cartilage. To understand the role of CCN4 in chondrogenesis, human bone marrow stromal cells (hBMSCs) were transduced with CCN4 adenovirus (adCCN4) or siRNA to CCN4 (siCCN4) in the presence or absence of transforming growth factor-β3 (TGF-β3). Overexpression of CCN4 enhanced TGF-β3-induced SMAD2/3 phosphorylation and chondrogenesis of hBMSCs in an in vitro assay using a micromass culture model. On the other hand, knockdown of CCN4 inhibited the TGF-β3-induced SMAD2/3 phosphorylation and synthesis of cartilage matrix in micromass cultures of hBMSCs. Immunoprecipitation-western blot analysis revealed that CCN4 bound to TGF-β3 and regulated the ability of TGF-β3 to bind to hBMSCs. In vivo analysis confirmed there was a significant decrease in the gene expression levels of chondrocyte markers in cartilage samples from Ccn4-knock out (KO) mice, compared to those from wild type (WT) control. In order to investigate the regenerative properties of the articular cartilage in Ccn4-KO mice, articular cartilage defects were surgically performed in the knee joints of young mice, and the results showed that the cartilage was partially repaired in WT mice, but not in Ccn4-KO mice. In conclusion, these results show, for the first time, that CCN4 has a positive influence on chondrogenic differentiation by modulating the effects of TGF-β3.

    DOI: 10.1016/j.bone.2015.11.007

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  • The hyaluronan and proteoglycan link proteins: Organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity. 査読 国際誌

    Toshitaka Oohashi, Midori Edamatsu, Yoko Bekku, Daniela Carulli

    Experimental neurology   274 ( Pt B )   134 - 44   2015年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The hyaluronan and proteoglycanbinding link protein (Hapln) is a key molecule in the formation and control of hyaluronan-based condensed perineuronal matrix in the adult brain. This review summarizes the recent advances in understanding the role of Haplns in the formation and control of two distinct types of perineuronal matrices, one for "classical" PNN and the other for the specialized extracellular matrix (ECM) at the node of Ranvier in the central nervous system (CNS). We introduce the structural components of each ECM organization including the basic concept of supramolecular structure named "HLT model". We furthermore summarize the developmental and physiological role of perineuronal ECMs from the studies of Haplns and related molecules. Finally, we also discuss the potential mechanism modulating PNNs in the adult CNS. This layer of organized matrices may exert a direct effect via core protein or sugar moiety from the structure or by acting as a binding site for biologically active molecules, which are important for neuronal plasticity and saltatory conduction.

    DOI: 10.1016/j.expneurol.2015.09.010

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  • [Formation and roles of perineuronal extracellular matrices in the adult brain]. 査読

    Toshitaka Oohashi, Midori Edamatsu, Yoko Bekku

    Seikagaku. The Journal of Japanese Biochemical Society   87 ( 3 )   393 - 6   2015年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • RXR Partial Agonist Produced by Side Chain Repositioning of Alkoxy RXR Full Agonist Retains Antitype 2 Diabetes Activity without the Adverse Effects 査読

    Kohei Kawata, Ken-ichi Morishita, Mariko Nakayama, Shoya Yamada, Toshiki Kobayashi, Yuki Furusawa, Sakae Arimoto-Kobayashi, Toshitaka Oohashi, Makoto Makishima, Hirotaka Naitou, Erika Ishitsubo, Hiroaki Tokiwa, Akihiro Tai, Hiroki Kakuta

    JOURNAL OF MEDICINAL CHEMISTRY   58 ( 2 )   912 - 926   2015年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER CHEMICAL SOC  

    We previously reported RXR partial agonist CBt-PMN (1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid: <bold>5</bold>, EC50 = 143 nM, E-max = 75%), which showed a potent glucose-lowering effect without causing serious adverse effects. However, it remains important to elucidate the structural requirements for RXR efficacy and the glucose-lowering effect because RXR-permissive heterodimers such as PPAR/RXR or LXR/RXR are reported to be activated differently depending upon the chemical structure of RXR agonists. In this work, we show that an RXR partial agonist, NEt-4IB (6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: <bold>8b</bold>, EC50 = 169 nM, E-max = 55%), can be obtained simply by repositioning the side chains (interchanging the isobutoxy and isopropoxy groups) at the hydrophobic moiety of the RXR full agonist NEt-3IB (6-[ethyl-(3-isobutoxy-4-isopropylphenyl)amino]pyridine-3-carboxylic acid: <bold>7b</bold>, EC50 = 19 nM). NEt-4IB (<bold>8b</bold>) showed antitype 2 diabetes activity without the above side effects upon repeated oral administration to mice at 10 mg/kg/day, similarly to <bold>5</bold>.

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  • Eosinophil Cationic Protein Shows Survival Effect on H9c2 Cardiac Myoblast Cells with Enhanced Phosphorylation of ERK and Akt/GSK-3β under Oxidative Stress. 査読

    Hiroko Ishii, Shigeshi Kamikawa, Satoshi Hirohata, Akifumi Mizutani, Koji Abe, Masaharu Seno, Toshitaka Oohashi, Yoshifumi Ninomiya

    Acta medica Okayama   69 ( 3 )   145 - 53   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Eosinophil cationic protein (ECP) is well known as a cationic protein contained in the basic granules of activated eosinophils. Recent studies have reported that ECP exhibits novel activities on various types of cells, including rat neonatal cardiomyocytes. Here we evaluated the effects of ECP on rat cardiac myoblast H9c2 cells. Our results showed that ECP enhanced the survival of the cells, in part by promoting the ERK and Akt/GSK-3β signaling pathways. ECP attenuated the cytotoxic effects of H2O2 on H9c2 cells as well as the production of reactive oxygen species, the number of apoptotic cells and caspase 3/7 activity in the cells. In conclusion, ECP activated the ERK and Akt/GSK-3β pathways, resulting in anti-oxidative effects on H9c2 cells that attenuated apoptosis.

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  • Light and electron microscopic detection of inflammation-targeting liposomes encapsulating high-density colloidal gold in arthritic mice. 査読 国際誌

    Ami Maehara, Keiichiro Nishida, Masumi Furutani, Emi Matsumoto, Aiji Ohtsuka, Yoshifumi Ninomiya, Toshitaka Oohashi

    Inflammation research : official journal of the European Histamine Research Society ... [et al.]   63 ( 2 )   139 - 47   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: We have previously demonstrated the efficient and time-dependent transvascular localization of Sialyl Lewis X (SLX)-liposomes to inflammatory sites, but the final target of the SLX-liposomes remained uncertain. The aim of this study was to identify the target cells of the liposomes within the inflamed joints of collagen antibody-induced arthritis (CAIA) model mice. METHODS: SLX-liposomes and unlabeled liposomes encapsulating high-density colloidal gold were administered intravenously into the caudal vein of CAIA mice on day 5 after induction of arthritis when the inflammatory score was maximal (n = 6 per group). Six hours or 24 h after liposome administration, animals were euthanized and hind limbs and ankles were excised without perfusion. After fixation, synovial tissues were examined by light microscopy after silver enhancement of colloidal gold or by transmission electron microscopy. RESULTS: Silver-enhanced signals were detected within the cells around E-selectin-positive blood vessels in the synovium of the SLX-liposome group. These cells were positive for the macrophage/monocyte marker F4/80 or neutrophil marker Ly-6G. Transmission electron microscopy detected the colloidal gold signals together with liposome-like structures within the phagosomes of synovial macrophages. Transmission electron microscopy and energy dispersive X-ray spectrometry could determine gold elements in the lysosomes of synovial macrophages. CONCLUSIONS: The results of the current study demonstrate that SLX-liposomes primarily targeting E-selectin in activated endothelial cells could potentially deliver their contents into inflammatory cells around synovial blood vessels in arthritic joints.

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  • Design, synthesis, and preliminary ex vivo and in vivo evaluation of cationic magnetic resonance contrast agent for rabbit articular cartilage imaging 査読

    Takayoshi Irie, Kazuhiro Oda, Akihiko Shiino, Mitsuhiko Kubo, Shigehiro Morikawa, Noboru Urushiyama, Shuji Aonuma, Takahide Kimura, Toshiro Inubushi, Toshitaka Oohashi, Naoki Komatsu

    MedChemComm   4 ( 11 )   1508 - 1512   2013年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Since early-stage diagnosis of osteoarthritis (OA) is necessary to retard the progress of the disease, magnetic resonance (MR) and computed tomography (CT) imaging agents have been applied to evaluate the integrity of the extracellular matrix (ECM) in the articular cartilage (AC). Although several negatively charged contrast agents were employed, they provided indirect images of the AC based on the coulombic repulsion with anionic glycosaminoglycans (GAGs) in the ECM. To achieve direct imaging of the ECM, positively charged contrast agents have quite recently been designed for optical and CT imaging. In this paper, we report on a positively charged MR contrast agent, DOTA-Gd-G 2R8, which was applied preliminarily to ex vivo and in vivo imaging of rabbit AC. In the ex vivo imaging, the contrast agent was accumulated in the AC in high concentration due to the strong coulombic attraction between the negative charge of the GAGs and the positive charge of the octaarginine (R8). The thickness of the AC measured in the MR image was found to be comparable to that determined by the histological staining of the slice. The AC was also observed in vivo by MR imaging with the use of DOTA-Gd-G2R8. © 2013 The Royal Society of Chemistry.

    DOI: 10.1039/c3md00229b

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  • Ten-m2 is required for the generation of binocular visual circuits. 査読 国際誌

    Timothy R Young, Michael Bourke, Xiaohong Zhou, Toshitaka Oohashi, Atomu Sawatari, Reinhard Fässler, Catherine A Leamey

    The Journal of neuroscience : the official journal of the Society for Neuroscience   33 ( 30 )   12490 - 509   2013年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Functional binocular vision requires that inputs arising from the two retinae are integrated and precisely organized within central visual areas. Previous studies have demonstrated an important role for one member of the Ten-m/Odz/teneurin family, Ten-m3, in the mapping of ipsilateral retinal projections. Here, we have identified a distinct role for another closely related family member, Ten-m2, in the formation of the ipsilateral projection in the mouse visual system. Ten-m2 expression was observed in the retina, dorsal lateral geniculate nucleus (dLGN), superior colliculus (SC), and primary visual cortex (V1) of the developing mouse. Anterograde and retrograde tracing experiments in Ten-m2 knock-out (KO) mice revealed a specific decrease in ipsilateral retinal ganglion cells projecting to dLGN and SC. This reduction was most prominent in regions corresponding to ventral retina. No change in the topography of ipsilateral or contralateral projections was observed. While expression of a critical ipsilateral fate determinant, Zic2, appeared unaltered, a notable reduction in one of its downstream targets, EphB1, was observed in ventral retina, suggesting that Ten-m2 may interact with this molecular pathway. Immunohistochemistry for c-fos, a neural activity marker, revealed that the area of V1 driven by ipsilateral inputs was reduced in KOs, while the ratio of ipsilateral-to-contralateral responses contributing to binocular activation during visually evoked potential recordings was also diminished. Finally, a novel two-alternative swim task revealed specific deficits associated with dorsal visual field. These data demonstrate a requirement for Ten-m2 in the establishment of ipsilateral projections, and thus the generation of binocular circuits, critical for mammalian visual function.

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  • Three mechanisms assemble central nervous system nodes of Ranvier. 査読 国際誌

    Keiichiro Susuki, Kae-Jiun Chang, Daniel R Zollinger, Yanhong Liu, Yasuhiro Ogawa, Yael Eshed-Eisenbach, María T Dours-Zimmermann, Juan A Oses-Prieto, Alma L Burlingame, Constanze I Seidenbecher, Dieter R Zimmermann, Toshitaka Oohashi, Elior Peles, Matthew N Rasband

    Neuron   78 ( 3 )   469 - 82   2013年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Rapid action potential propagation in myelinated axons requires Na⁺ channel clustering at nodes of Ranvier. However, the mechanism of clustering at CNS nodes remains poorly understood. Here, we show that the assembly of nodes of Ranvier in the CNS involves three mechanisms: a glia-derived extracellular matrix (ECM) complex containing proteoglycans and adhesion molecules that cluster NF186, paranodal axoglial junctions that function as barriers to restrict the position of nodal proteins, and axonal cytoskeletal scaffolds (CSs) that stabilize nodal Na⁺ channels. We show that while mice with a single disrupted mechanism had mostly normal nodes, disruptions of the ECM and paranodal barrier, the ECM and CS, or the paranodal barrier and CS all lead to juvenile lethality, profound motor dysfunction, and significantly reduced Na⁺ channel clustering. Our results demonstrate that ECM, paranodal, and axonal cytoskeletal mechanisms ensure robust CNS nodal Na⁺ channel clustering.

    DOI: 10.1016/j.neuron.2013.03.005

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  • Bral2 is indispensable for the proper localization of brevican and the structural integrity of the perineuronal net in the brainstem and cerebellum. 査読 国際誌

    Yoko Bekku, Mai Saito, Markus Moser, Maki Fuchigami, Ami Maehara, Masaru Nakayama, Shozo Kusachi, Yoshifumi Ninomiya, Toshitaka Oohashi

    The Journal of comparative neurology   520 ( 8 )   1721 - 36   2012年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Perineuronal nets (PNNs) are pericellular coats of condensed matrix that enwrap the cell bodies and dendrites of many adult central nervous system (CNS) neurons. These extracellular matrices (ECMs) play a structural role as well as instructive roles in the control of CNS plasticity and the termination of critical periods. The cartilage link protein Crtl1/Hapln1 was reported to be a trigger for the formation of PNNs in the visual cortex. Bral2/Hapln4 is another link protein that is expressed in PNNs, mainly in the brainstem and cerebellum. To assess the role of Bral2 in PNN formation, we examined the expression of PNN components in targeted mouse mutants lacking Bral2. We show here that Bral2-deficient mice have attenuated PNNs, but the overall levels of chondroitin sulfate proteoglycans, lecticans, are unchanged with the exception of neurocan. Bral2 deficiency markedly affected the localization of brevican in all of the nuclei tested, and neurocan concomitant with Crtl1 in some of the nuclei, whereas no effect was seen on aggrecan even with the attenuation of Crtl1. Bral2 may have a role in the organization of the PNN, in association with brevican, that is independent of aggrecan binding. There was a heterogenous attenuation of PNN components, including glycosaminoglycans, indicating the elaborate molecular organization of the PNN components. Strikingly, a slight decrease in the number of synapses in deep cerebellar nuclei neurons was found. Taken together, these results imply that Bral2-brevican interaction may play a key role in synaptic stabilization and the structural integrity of the PNN.

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  • RXR Partial Agonist CBt-PMN Exerts Therapeutic Effects on Type 2 Diabetes without the Side Effects of RXR Full Agonists. 査読 国際誌

    Hiroki Kakuta, Nobumasa Yakushiji, Ryosuke Shinozaki, Fuminori Ohsawa, Shoya Yamada, Yui Ohta, Kohei Kawata, Mariko Nakayama, Manabu Hagaya, Chisa Fujiwara, Makoto Makishima, Shigeyuki Uno, Akihiro Tai, Ami Maehara, Masaru Nakayama, Toshitaka Oohashi, Hiroyuki Yasui, Yutaka Yoshikawa

    ACS medicinal chemistry letters   3 ( 5 )   427 - 32   2012年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER CHEMICAL SOC  

    Treating insulin resistance and type 2 diabetes in rodents, currently known retinoid X receptor (RXR) agonists induce significant adverse effects. Here we introduce a novel RXR partial agonist CBt-PMN (11b), which shows a potent glucose-lowering effect and improvements of insulin secretion and glucose tolerance without the serious adverse effects caused by RXR full agonists. We suggest that RXR partial agonists may be a new class of antitype 2 diabetes drug candidates.

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  • Mechanical stretch enhances COL2A1 expression on chromatin by inducing SOX9 nuclear translocalization in inner meniscus cells. 査読 国際誌

    Tomoko Kanazawa, Takayuki Furumatsu, Motomi Hachioji, Toshitaka Oohashi, Yoshifumi Ninomiya, Toshifumi Ozaki

    Journal of orthopaedic research : official publication of the Orthopaedic Research Society   30 ( 3 )   468 - 74   2012年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    The meniscus plays an important role in controlling the biomechanics of the knee. However, the mechanical stress-related response in meniscus cells remains unclear. We investigated mechanical stretch-regulated gene expression in human meniscus cells. Human inner and outer meniscus cells were prepared from the inner and outer halves of the lateral meniscus. The gene expressions of Sry-type HMG box (SOX) 9 and α1(II) collagen (COL2A1) were assessed by real-time PCR analyses after cyclic tensile strain (CTS) treatment (0.5 Hz, 5% stretch). The localization and phosphorylation of SOX9 were evaluated by immunohistochemical and Western blot (WB) analyses. Chromatin immunoprecipitation (IP) analysis was performed to assess the stretch-related protein-DNA complex formation between SOX9 and the COL2A1 enhancer on chromatin. Type II collagen deposition and SOX9 production were detected only in inner menisci. CTS treatments increased expression of the COL2A1 and SOX9 genes in inner meniscus cells, but not in outer meniscus cells. In addition, CTS treatments stimulated nuclear translocalization and phosphorylation of SOX9 in inner meniscus cells. Chromatin IP analyses revealed that CTS increased the association between SOX9 and its DNA-binding site, included in the COL2A1 enhancer, on chromatin. Our results indicate that inner and outer meniscus cells have different properties in mechanical stretch-induced COL2A1 expression. In inner meniscus cells, mechanical stretch may have an essential role in the epigenetic regulation of COL2A1 expression.

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  • [Cutting edge on research of cartilage metabolism. Recent progress in bio-molecular imaging of articular cartilage]. 査読

    Toshitaka Oohashi, Keiichiro Nishida

    Clinical calcium   21 ( 6 )   896 - 902   2011年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    In the process of cartilage degeneration seen in osteoarthritis, loss of proteoglycan from articular cartilage has been widely accepted as a critical early event, followed by collagen degradation designated as a point of no return. Recent advance in the development of targeted molecular probes and new imaging modalities enabled the detection of qualitative and functional change of articular cartilage. In this paper, we describe the recent progress of bio-molecular imaging of articular cartilage including our fluorescent-labeled glycosaminoglycan-binding octaarginine.

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  • Clonal overgrowth of esophageal smooth muscle cells in diffuse leiomyomatosis-Alport syndrome caused by partial deletion in COL4A5 and COL4A6 genes. 査読 国際誌

    Toshitaka Oohashi, Ichiro Naito, Yasuyoshi Ueki, Tomoki Yamatsuji, Rattiya Permpoon, Noriaki Tanaka, Yoshio Naomoto, Yoshifumi Ninomiya

    Matrix biology : journal of the International Society for Matrix Biology   30 ( 1 )   3 - 8   2011年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    This is a study of a patient who manifests all of the features of a diffuse leiomyomatosis-Alport syndrome (DL-ATS), and her two-year-old son who has already been diagnosed with Alport syndrome. Fourteen years ago, the patient underwent a partial esophageal resection followed by a replacement with jejunum. Recently, she underwent a surgical resection of the esophagus due to esophageal dysfunction. Genetic analyses of COL4A5 and COL4A6 on the X-chromosome were efficiently performed using the genomic DNA of her son. We have identified a novel deletion of 194-kb in length, encompassing COL4A5-COL4A6 promoters as well as nearly the entire large intron 1 of COL4A5 and intron 2 of COL4A6. To uncover the relationship of the esophagus-specific occurrence of the tumor and the expression of those genes, immunohistochemical analyses of type IV collagen α chains were conducted in the non-affected individuals. The esophageal smooth muscle-specific expression of α5(IV) and α6(IV) chains in the gastrointestinal tract was observed. Moreover, CAG repeat analysis of the androgen receptor gene and an immunohistochemical analysis in the leiomyoma revealed clonal overgrowth of the cells which received X-inactivation on the non-affected allele. These results may suggest that the dominant effect was caused by the partial deletion of the esophageal smooth muscle-specific genes, COL4A5 and COL4A6.

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  • Development of an active targeting liposome encapsulated with high-density colloidal gold for transmission electron microscopy. 査読

    Hideki Minematsu, Takayuki Otani, Toshitaka Oohashi, Masahiko Hirai, Kazunori Oie, Koichi Igarashi, Aiji Ohtsuka

    Journal of electron microscopy   60 ( 1 )   95 - 9   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Active targeting of the liposome is an attractive strategy for drug delivery and in vivo bio-imaging. We previously reported the specific accumulation of Sialyl Lewis X (SLX) liposome to inflamed tissue in arthritic model mice or tumor-bearing mice. SLX-liposome encapsulation with fluorescent substances allows for the visualization of these liposomes by the time-dependent transvascular accumulation of fluorescent signals in the histological sections. In the present study, we developed a new SLX-liposome encapsulated with colloidal gold for transmission electron microscopic observation. We herein describe the characterization of the colloidal gold-loaded SLX-liposomes and demonstrate its specific targeting to the endothelial cells of tumor blood vessels in tumor-bearing mice.

    DOI: 10.1093/jmicro/dfq071

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  • Bral1: its role in diffusion barrier formation and conduction velocity in the CNS. 査読 国際誌

    Yoko Bekku, Lýdia Vargová, Yoshinobu Goto, Ivan Vorísek, Lesia Dmytrenko, Masahiro Narasaki, Aiji Ohtsuka, Reinhard Fässler, Yoshifumi Ninomiya, Eva Syková, Toshitaka Oohashi

    The Journal of neuroscience : the official journal of the Society for Neuroscience   30 ( 8 )   3113 - 23   2010年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC NEUROSCIENCE  

    At the nodes of Ranvier, excitable axon membranes are exposed directly to the extracellular fluid. Cations are accumulated and depleted in the local extracellular nodal region during action potential propagation, but the impact of the extranodal micromilieu on signal propagation still remains unclear. Brain-specific hyaluronan-binding link protein, Bral1, colocalizes and forms complexes with negatively charged extracellular matrix (ECM) proteins, such as versican V2 and brevican, at the nodes of Ranvier in the myelinated white matter. The link protein family, including Bral1, appears to be the linchpin of these hyaluronan-bound ECM complexes. Here we report that the hyaluronan-associated ECM no longer shows a nodal pattern and that CNS nerve conduction is markedly decreased in Bral1-deficient mice even though there were no differences between wild-type and mutant mice in the clustering or transition of ion channels at the nodes or in the tissue morphology around the nodes of Ranvier. However, changes in the extracellular space diffusion parameters, measured by the real-time iontophoretic method and diffusion-weighted magnetic resonance imaging (MRI), suggest a reduction in the diffusion hindrances in the white matter of mutant mice. These findings provide a better understanding of the mechanisms underlying the accumulation of cations due to diffusion barriers around the nodes during saltatory conduction, which further implies the importance of the Bral1-based extramilieu for neuronal conductivity.

    DOI: 10.1523/JNEUROSCI.5598-09.2010

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  • Neurocan contributes to the molecular heterogeneity of the perinodal ECM. 査読

    Yoko Bekku, Toshitaka Oohashi

    Archives of histology and cytology   73 ( 2 )   95 - 102   2010年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INT SOC HISTOLOGY & CYTOLOGY  

    Neurocan is a central nervous tissue-specific chondroitin sulfate proteoglycan of the lectican family. Mainly expressed during modeling and remodeling stages of this tissue, it is thought to play an important role via binding to various extracellular matrix and cellular components. In adults, neurocan expression is associated with the perineuronal net structures. This study shows the neurocan immunolocalization at the node of Ranvier in mouse central nervous tissues. The N-terminal fragment of neurocan (Ncan130) was the predominant form detected in the optic nerve. The expression of neurocan in the white matter of brain tissue and nerve tracts revealed differential expression profiles compared with those of versican V2 and brevican, other perinodal extracellular matrix molecules. Double immunolabeling for neurocan and a nodal marker, Bral1, or a paranodal marker, caspr, demonstrated that neurocan was localized at the node of Ranvier. Neurocan expression was found at many--not all--nodal regions, and neurocan-positive nodes outnumbered brevican-positive nodes. The nodal localization of neurocan was diminished in Bral1-deficient mice. Taken together, these findings indicate that neurocan contributes to the molecular heterogeneity of the perinodal matrix, and its nodal expression is dependent on Bral1.

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  • Optical imaging of mouse articular cartilage using the glycosaminoglycans binding property of fluorescent-labeled octaarginine. 査読 国際誌

    K Inagawa, T Oohashi, K Nishida, J Minaguchi, T Tsubakishita, K O Yaykasli, A Ohtsuka, T Ozaki, T Moriguchi, Y Ninomiya

    Osteoarthritis and cartilage   17 ( 9 )   1209 - 18   2009年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: The aim of the current study was to examine the cartilage-specific binding property of polyarginine peptides (R4, 8, 12, and 16) and specifically to test octaarginine peptides for the optical imaging of articular cartilage in experimentally induced arthritis in mice. METHODS: Four rhodamine-labeled polyarginine peptides each with a different-length arginine chain (R4, 8, 12, or 16) were injected into the knee joints of C57BL/6J mice (n=20). The joints were excised 1h later and the fluorescent signal intensity in cartilage cryosections was compared for the four peptides. To examine the substrate of R8 in cartilage, femoral condyles obtained from another set of mice were treated with chondroitinase ABC (Ch'ase ABC), keratanase or heparitinase then immersed in R8-rhodamine. Fluorescent signals were examined by fluorescent microscopy. Next, R8-rhodamine was injected into the right knee joints of three control and three collagen antibody-induced arthritis (CAIA) mice, and fluorescent intensity in normal and degenerative cartilage was semi-quantitatively analysed on the histological sections using image software. Finally, femoral condyles from normal mice (n=2) and CAIA mice (n=2) were immersed in R8-rhodamine and calcein, then imaged using optical projection tomography (OPT). RESULTS: Fluorescent signals were specifically detected in the cartilage pericellular matrix from the surface to the tide mark but were completely absent in the calcified layer or bone marrow. The number of arginine residues significantly influenced peptide accumulation in articular cartilage, with R8 accumulating the most. The fluorescent signal in the femoral condylar cartilage diminished when it was treated with Ch'ase ABC. R8 accumulation was significantly decreased in the degenerative cartilage of CAIA mice, and this was demonstrated both histologically and in three-dimensional (3D)-reconstruction image by OPT. CONCLUSION: R8 may be a useful new experimental probe for optical imaging of normal and arthritic articular cartilage.

    DOI: 10.1016/j.joca.2009.03.010

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  • The 3’-untranslated region of ADAMTS1 regulates its mRNA stability. 査読

    Hatipoglu OF, Hirohata S, Yaykasli KO, Cilek MZ, Demircan K, Shinohata R, Yonezawa T, Oohashi T, Kusachi S, Ninomiya Y

    Acta Medica Okayama   63 ( 2 )   79 - 85   2009年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.18926/AMO/31831

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  • Brevican distinctively assembles extracellular components at the large diameter nodes of Ranvier in the CNS. 査読 国際誌

    Yoko Bekku, Uwe Rauch, Yoshifumi Ninomiya, Toshitaka Oohashi

    Journal of neurochemistry   108 ( 5 )   1266 - 76   2009年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Brevican is known to be an abundant extracellular matrix component in the adult brain and a structural constituent of perineuronal nets. We herein show that brevican, tenascin-R (TN-R) and phosphacan are present at the nodes of Ranvier on myelinated axons with a particularly large diameter in the central nervous system. A brevican deficiency resulted in a reorganization of the nodal matrices, which was characterized by the shift of TN-R, and concomitantly phosphacan, from an axonal diameter-dependent association with nodes to an axonal diameter independent association. Supported by the co-immunoprecipitation results, these observations indicate that the presence of TN-R and phosphacan at nodes is normally brevican-dependent, while in the absence of brevican these molecules can also be recruited by versican V2. The versican V2 and Bral1 distribution was not affected, thus indicating a brevican-independent role of these two molecules for establishing hyaluronan-binding matrices at the nodes. Our results revealed that brevican plays a crucial role in determining the specialization of the hyaluronan-binding nodal matrix assemblies in large diameter nodes.

    DOI: 10.1111/j.1471-4159.2009.05873.x

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  • ADAMTS9 activation by interleukin 1 beta via NFATc1 in OUMS-27 chondrosarcoma cells and in human chondrocytes. 査読 国際誌

    Kursat Oguz Yaykasli, Toshitaka Oohashi, Satoshi Hirohata, Omer Faruk Hatipoglu, Kiichi Inagawa, Kadir Demircan, Yoshifumi Ninomiya

    Molecular and cellular biochemistry   323 ( 1-2 )   69 - 79   2009年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    ADAMTS9 is a member of the disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) genes, with aggrecan-degrading activity. It has also been characterized to be reactive and highly activated ADAMTS by IL-1 beta in both chondrosarcoma cells and human chondrocytes (Demircan et al. Arthritis Rheum 52:1451-1460, 2005). In order to understand the regulation of ADAMTS9 gene expression a functional 3.0 kb human ADAMTS9 promoter has been cloned and characterized. A sequence analysis of the promoter revealed the presence of putative binding sites for Nuclear Factor of Activated T cells (NFAT), which is commonly found in the ADAMTS4 and ADAMTS5 promoters. NFATc1 was up-regulated in an activated form by IL-1 beta in human chondrocytes. The IL-1 beta inducible ADAMTS9 expression was inhibited by NFAT inhibitors, FK506 and 11Arg (11R)-VIVIT. Furthermore, direct binding of NFATc1 on distal and proximal promoters of ADAMTS9 was demonstrated by a chromatin immunoprecipitation assay. Promoter-reporter assays supported those results. These findings may provide a better understanding of the regulation of ADAMTS9 expression induced by inflammatory cytokines.

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  • THE ION-DIFFUSION BARRIER MODEL AT THE NODE OF RANVIER: FROM THE EXTRACELLULAR ION DIFFUSION ANALYSIS IN BRAL1-DEFICIENT MICE 査読

    Yoko Bekku, Lydia Vargova, Yoshinobu Goto, Yoshifumi Ninomiya, Eva Sykova, Toshitaka Oohashi

    JOURNAL OF PHYSIOLOGICAL SCIENCES   59   292 - 292   2009年

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    記述言語:英語   出版者・発行元:SPRINGER TOKYO  

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  • Transvascular accumulation of Sialyl Lewis X conjugated liposome in inflamed joints of collagen antibody-induced arthritic (CAIA) mice. 査読

    Jun Minaguchi, Toshitaka Oohashi, Kiichi Inagawa, Aiji Ohtsuka, Yoshifumi Ninomiya

    Archives of histology and cytology   71 ( 3 )   195 - 203   2008年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The aim of the current study was to investigate the specific accumulation of the Sialyl Lewis X (SLX) liposome in inflammation in the collagen-antibody induced arthritic (CAIA) model mice. The SLX-liposome encapsulating fluorescent substance (Cy5.5 or Cy3) was prepared for this study. The SLX-liposome was administered intravenously via the mouse caudal vein. After 1 to 24 h, the accumulation of SLX-liposome was observed using in vivo fluorescent imaging equipment (eXplore Optix), or the knee joints were removed for histological analysis. The in vivo fluorescent imaging showed that the signal was confined to the inflammatory site in the CAIA mice in an inflammatory dependent manner. The signal intensity was stronger at 24 h than at 1 h after injection. In the histological sections, the fluorescent signals were detected in the periarticular soft-tissue, especially in the hyperplastic synovium, including a pannus invasion with inflammatory cells in the CAIA. Intense signals were observed in vessel-like structures 1 h after injection; these were co-labeled with the vascular endothelial cell marker (CD31) and E-selectin, a ligand of the SLX-liposome expressed on activated endothelial cells. The diffused signals from the vessels increased time-dependently at 6 to 24 h after injection. This is the first report to examine the exact localization of the SLXliposome by encapsulated fluorescence in hyperplastic synovial tissue of CAIA mice. These results suggest the feasibility and potential use of SLX-liposome as a vehicle for the active targeting of drug delivery to inflammatory tissue.

    DOI: 10.1679/aohc.71.195

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  • Molecular cloning and developmental expression of a hyaluronan and proteoglycan link protein gene, crtl1/hapln1, in zebrafish. 査読

    Jeong Suk Kang, Yasuhiko Kawakami, Yoko Bekku, Yoshifumi Ninomiya, Juan Carlos Izpisúa Belmonte, Toshitaka Oohashi

    Zoological science   25 ( 9 )   912 - 8   2008年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The proteoglycan aggregate of the cartilage is composed of aggrecan, link protein (LP), and hyaluronan, providing resistance to compression in joints and cartilage structures. To further understand the function of LP during the process of chondrogenesis and bone formation in zebrafish, we cloned the zebrafish cDNA for hyaluronan and proteoglycan link protein 1 (crtl1/hapln1) and examined the expression of the gene during embryogenesis using in-situ hybridization. crtl1/hapln1 expression is first observed in the adaxial cells at the bud- stage. Throughout somitogenesis, crtl1/hapln1 is expressed in the sclerotomes, floor plate, and hypochord. In addition, crtl1/hapln1 is expressed in rhombomeres 3 and 5, pharyngeal arches, telecephalon, otic vesicles, and pectral fins. During chondrocranial/skull formation, crtl1/hapln1 expression is highest at around 4 dpf and is colocalized with aggrecan in the cartilaginous arches and with dermacan in the dermal bones.

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  • Ten_m3 regulates eye-specific patterning in the mammalian visual pathway and is required for binocular vision. 査読 国際誌

    Catherine A Leamey, Sam Merlin, Paul Lattouf, Atomu Sawatari, Xiaohong Zhou, Natasha Demel, Kelly A Glendining, Toshitaka Oohashi, Mriganka Sur, Reinhard Fässler

    PLoS biology   5 ( 9 )   e241 - 2092   2007年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Binocular vision requires an exquisite matching of projections from each eye to form a cohesive representation of the visual world. Eye-specific inputs are anatomically segregated, but in register in the visual thalamus, and overlap within the binocular region of primary visual cortex. Here, we show that the transmembrane protein Ten_m3 regulates the alignment of ipsilateral and contralateral projections. It is expressed in a gradient in the developing visual pathway, which is consistently highest in regions that represent dorsal visual field. Mice that lack Ten_m3 show profound abnormalities in mapping of ipsilateral, but not contralateral, projections, and exhibit pronounced deficits when performing visually mediated behavioural tasks. It is likely that the functional deficits arise from the interocular mismatch, because they are reversed by acute monocular inactivation. We conclude that Ten_m3 plays a key regulatory role in the development of aligned binocular maps, which are required for normal vision.

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  • ADAMTS-9 is synergistically induced by interleukin-1beta and tumor necrosis factor alpha in OUMS-27 chondrosarcoma cells and in human chondrocytes. 査読 国際誌

    Kadir Demircan, Satoshi Hirohata, Keiichiro Nishida, Omer F Hatipoglu, Toshitaka Oohashi, Tomoko Yonezawa, Suneel S Apte, Yoshifumi Ninomiya

    Arthritis and rheumatism   52 ( 5 )   1451 - 60   2005年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    OBJECTIVE: To compare induction of the aggrecanases (ADAMTS-1, ADAMTS-4, ADAMTS-5, ADAMTS-8, ADAMTS-9, and ADAMTS-15) by interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha) in chondrocyte-like OUMS-27 cells and human chondrocytes, and to determine the mechanism of induction of the most responsive aggrecanase gene. METHODS: OUMS-27 cells were stimulated for different periods of time and with various concentrations of IL-1beta and/or TNFalpha. Human chondrocytes obtained from osteoarthritic joints and human skin fibroblasts were also stimulated with IL-1beta and/or TNFalpha. Total RNA was extracted, reverse transcribed, and analyzed by quantitative real-time polymerase chain reaction and Northern blotting. ADAMTS-9 protein was examined by Western blotting, and the role of the MAPK signaling pathway for ADAMTS9 induction in IL-1beta-stimulated OUMS-27 cells was investigated. RESULTS: IL-1beta increased messenger RNA (mRNA) levels of ADAMTS4, ADAMTS5, and ADAMTS9 but not ADAMTS1 and ADAMTS8. The fold increase for ADAMTS9 mRNA was greater than that for mRNA of the other aggrecanase genes. The increase of ADAMTS9 mRNA by IL-1beta stimulation was greater in chondrocytes than in fibroblasts. The combination of IL-1beta and TNFalpha had a synergistic effect, resulting in a considerable elevation in the level of ADAMTS9 mRNA. ADAMTS-9 protein was also induced in IL-1beta-stimulated OUMS-27 cells. The MAPK inhibitors SB203580 and PD98059 decreased ADAMTS9 up-regulation in OUMS-27 cells. CONCLUSION: ADAMTS9 is an IL-1beta- and TNFalpha-inducible gene that appears to be more responsive to these proinflammatory cytokines than are other aggrecanase genes. Furthermore, these cytokines had a synergistic effect on ADAMTS9. Together with the known ability of ADAMTS-9 to proteolytically degrade aggrecan and its potential to cleave other cartilage molecules, the data suggest that ADAMTS-9 may have a pathologic role in arthritis.

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  • Suppression of chondrosarcoma cells by 15-deoxy-Delta 12,14-prostaglandin J2 is associated with altered expression of Bax/Bcl-xL and p21. 査読 国際誌

    Zheng-Nan Shen, Keiichiro Nishida, Hideyuki Doi, Toshitaka Oohashi, Satoshi Hirohata, Toshifumi Ozaki, Aki Yoshida, Yoshifumi Ninomiya, Hajime Inoue

    Biochemical and biophysical research communications   328 ( 2 )   375 - 82   2005年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    We previously reported that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), the most potent agonist for peroxisome proliferator-activated receptor gamma (PPAR gamma), induces apoptosis of human chondrosarcoma cell line OUMS-27. The current study aimed to explore the mechanism of 15d-PGJ(2)-induced apoptosis and inhibition of cell proliferation in OUMS-27 cells. The preliminary results of cDNA microarray analysis showed the down-regulation of anti-apoptotic Bcl-xL and up-regulation of pro-apoptotic Bax in the process of 15d-PGJ(2)-induced apoptosis. These changes were further confirmed at mRNA and protein levels by RT-PCR and Western blot analysis, respectively. Among cyclin-dependent kinase inhibitors, p21 was induced and up-regulated by 15d-PGJ(2), but p16 and p27 were not changed, suggesting that the involvement of p21 in inhibition of cell proliferation. Activation of caspase-3 by 15d-PGJ(2) was partly, but not completely, blocked by PPAR gamma antagonist (GW9662) suggesting the 15d-PGJ(2) exerted its effect by PPAR gamma-dependent and -independent pathways. Interestingly, immunohistochemical study on human chondrosarcoma samples revealed that Bcl-xL is frequently expressed by tumor cells. The results of the current study suggest that the potential ability of 15d-PGJ(2) in regulation of cell cycle and inhibition of Bcl-xL expression might be beneficial in the development of novel pharmacological agents for chondrosarcoma.

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  • [Bral1, Bral2: the novel brain specific-hyaluronan and protoglycan link protein genes]. 査読

    Toshitaka Oohashi, Yoko Bekku, Yoshifumi Ninomiya

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme   49 ( 15 Suppl )   2354 - 61   2004年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Dynamic induction of ADAMTS1 gene in the early phase of acute myocardial infarction. 査読 国際誌

    Keigo Nakamura, Satoshi Hirohata, Takashi Murakami, Toru Miyoshi, Kadir Demircan, Toshitaka Oohashi, Hiroko Ogawa, Kazuya Koten, Kenichi Toeda, Shozo Kusachi, Yoshifumi Ninomiya, Yasushi Shiratori

    Journal of biochemistry   136 ( 4 )   439 - 46   2004年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPANESE BIOCHEMICAL SOC  

    Extracellular matrix (ECM)-degrading enzymes such as matrix metalloproteases (MMPs) play an essential role in the repair of infarcted tissue, which affects ventricular remodeling after myocardial infarction. ADAMTS1 (A disintegrin and metalloprotease with thrombospondin motifs), a newly discovered metalloprotease, was originally cloned from a cancer cell line, but little is known about its contribution to disease. To test the hypothesis that ADAMTS1 appears in infarcted myocardial tissue, we examined ADAMTS1 mRNA expression in a rat myocardial infarction model by Northern blotting, real-time RT-PCR and in situ hybridization. Normal endothelium expressed little ADAMTS1 mRNA, while normal myocardium expressed no detectable ADAMTS1 mRNA. Up-regulation of ADAMTS1 was demonstrated by Northern blot analysis and real-time RT-PCR at 3 h after coronary artery ligation. In situ hybridization revealed strong ADAMTS1 mRNA signals in the endothelium and myocardium in the infarcted heart, mainly in the infarct zone, at 3 h after myocardial infarction. The rapid and transient up-regulation of the ADAMTS1 gene in the ischemic heart was distinct from the regulatory patterns of other MMPs. Our study demonstrated that the ADAMTS1 gene is a new early immediate gene expressed in the ischemic endothelium and myocardium.

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  • Lp3/Hapln3, a novel link protein that co-localizes with versican and is coordinately up-regulated by platelet-derived growth factor in arterial smooth muscle cells. 査読 国際誌

    Hiroko Ogawa, Toshitaka Oohashi, Masataka Sata, Yoko Bekku, Satoshi Hirohata, Keigo Nakamura, Tomoko Yonezawa, Shozo Kusachi, Yasushi Shiratori, Yoshifumi Ninomiya

    Matrix biology : journal of the International Society for Matrix Biology   23 ( 5 )   287 - 98   2004年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Link proteins (LPs) belong to the link-module superfamily, which can stabilize and enhance the binding of lecticans to hyaluronan. We report here the identification and characterization of a novel rat link protein gene (Lp3/Hapln3). The deduced protein sequence shares the typical modular elements of link proteins and has an estimated mass of 39 kDa. Examination of the rat genomic DNA sequence revealed that Lp3/Hapln3 and aggrecan genes were paired on chromosome 1q31. Another LP gene and the lectican gene were also paired at a different locus, as they are in the human and mouse genomes. Immunohistochemical analysis showed the prominent expression of Lp3/Hapln3 in the smooth muscle tissues of the vascular wall and gastrointestinal tract. Further comparative studies revealed that Lp3/Hapln3 was well co-localized with versican around the smooth muscle cells of blood vessels but not around endothelial cells. In vitro experiments using primary cultured rat arterial smooth muscle cells (ASMCs) demonstrated the coordinated up-regulation of Lp3/Hapln3 and versican by platelet-derived growth factor (PDGF). These data were supported by in vivo studies of a mechanical vascular injury model in mice. Altogether, our results suggest that Lp3/Hapln3 is involved, together with versican and hyaluronan, in the formation of the pericellular matrix of vascular smooth muscle cells.

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  • Characterization of dermacan, a novel zebrafish lectican gene, expressed in dermal bones. 査読 国際誌

    Jeong Suk Kang, Toshitaka Oohashi, Yasuhiko Kawakami, Yoko Bekku, Juan Carlos Izpisúa Belmonte, Yoshifumi Ninomiya

    Mechanisms of development   121 ( 3 )   301 - 12   2004年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    We report here the isolation and characterization of a cDNA encoding zebrafish dermacan, a novel member of hyaluronan (HA)-binding proteoglycans, which was termed after its characteristic expression in the zebrafish dermal bones. The deduced protein sequence shares the typical modular elements of lecticans. Sequence comparison covering the C-terminal globular domain demonstrated that dermacan shows high homology with zebrafish versican but is distinct from any other identified lecticans. Genomic DNA analysis demonstrated that dermacan and versican were encoded by distinct genes in the zebrafish genome. The expression of dermacan is initiated in the sclerotome and cephalic paraxial mesoderm at 16 h postfertilization. During the pharyngular period, dermacan transcripts were detected in the sclerotome, tail fin bud, pharyngular arch primordial region, and otic vesicle. In the development of craniofacial bones, dermacan expression was detected typically in the opercle and dentary. These regions belong to the craniofacial dermal bones. aggrecan expression, in contrast, was observed in the elements of craniofacial cartilage bones. In the dermacan-morpholino-injected embryos, dermal bones, e.g. opercle, dentary, and branchiostegal rays, as well as axial skeleton in the trunk, showed decreased ossification. We conclude that dermacan is a novel lectican gene, and that zebrafish lectican genes have genetically diverged. In addition, our data suggest the involvement of dermacan in zebrafish dermal bone development.

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  • Cartilage link protein interacts with neurocan, which shows hyaluronan binding characteristics different from CD44 and TSG-6. 査読 国際誌

    Uwe Rauch, Satoshi Hirakawa, Toshitaka Oohashi, Joachim Kappler, Gunnel Roos

    Matrix biology : journal of the International Society for Matrix Biology   22 ( 8 )   629 - 39   2004年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    The interaction of neurocan with hyaluronan was qualitatively characterized with alkaline phosphatase fusion proteins secreted by mammalian cells. The wild type neurocan hyaluronan binding domain fused to alkaline phosphatase bound to immobilized hyaluronan under physiological as well as moderately hypertonic conditions, whereas its ability to bind to immobilized chondroitin sulfate dropped rapidly with increasing salt concentration. Strong hyaluronan binding ability was still evident when in both link modules within the hyaluronan binding domain a basic amino acid was mutated, which is well conserved among link modules of hyaluronan binding proteins. A strong enhancement of the binding of neurocan to immobilized hyaluronan was observed after preincubation of the immobilized hyaluronan with cartilage link protein. Moreover, this preincubation mediated also the binding of a fusion protein representing only the immunoglobulin module of neurocan linked to alkaline phosphatase, which showed no binding to immobilized hyaluronan alone. The interaction of the neurocan immunoglobulin module with link protein could also be shown by overlay blot analysis. These observations suggest that the hyaluronan binding characteristics of paired link modules are different from those of single link modules, and that the reported temporal co-expression of cartilage link protein and of neurocan in developing brain implicates the possibility of a cooperative function of these molecules.

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  • Molecular cloning of Bral2, a novel brain-specific link protein, and immunohistochemical colocalization with brevican in perineuronal nets. 査読 国際誌

    Yoko Bekku, Wei-Dong Su, Satoshi Hirakawa, Reinhard Fässler, Aiji Ohtsuka, Jeong Suk Kang, Jennifer Sanders, Takuro Murakami, Yoshifumi Ninomiya, Toshitaka Oohashi

    Molecular and cellular neurosciences   24 ( 1 )   148 - 59   2003年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The hyaluronan binding chondroitin sulphate proteoglycans, called lecticans, are the abundant extracellular matrix molecules in the developing and/or adult brain. The link proteins (LPs) are also known to be coordinately present in brain. We report here the molecular cloning and expression analysis of a novel member of LPs: Bral2, predominantly expressed in brain. The Bral2 mRNA expression is first detected at P20 and continued through adulthood, suggesting its functional importance and association with adult-type lecticans. The substantial immunoreactivity of Bral2 is found in several nuclei throughout the midbrain and hindbrain in a perineuronal net pattern. In situ hybridization revealed that Bral2 is synthesized by these neurons themselves, especially by the GABAergic neurons in the cerebellar cortex. Interestingly, the colocalization and synergic importance of Bral2 and brevican in the perineuronal nets is indicated by the comparative immunohistochemical analysis using wild-type and brevican-deficient mouse brain. Our results suggest that Bral2 is involved in the formation of extracellular matrix contributing to perineuronal nets and facilitate the understanding of a functional role of these extracellular matrices.

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  • Molecular cloning of a novel transmembrane protein MOLT expressed by mature oligodendrocytes. 査読 国際誌

    Hiroyuki Nomoto, Tomoko Yonezawa, Kouichi Itoh, Katsuhiko Ono, Kiyotaka Yamamoto, Toshitaka Oohashi, Fumio Shiraga, Hiroshi Ohtsuki, Yoshifumi Ninomiya

    Journal of biochemistry   134 ( 2 )   231 - 8   2003年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A novel oligodendrocyte (OL)-specific cDNA was isolated from brain capillary endothelial cells and characterized. The cDNA encodes a protein of 1099 amino acids that contains a signal peptide and a transmembrane domain. The protein was expressed in mature OLs in vivo and in vitro cell cultures and was thus designated as mature OL transmembrane protein (MOLT). RT-PCR analysis showed that MOLT mRNA was expressed in brain, lung, pancreas, and testis. A polyclonal antibody raised against a part of the mouse MOLT reacted specifically with multipolar OLs possessing radially oriented processes that penetrated into the gray matter. More cells were detected in the white matter, and these had longitudinally oriented processes. In a rat OL lineage culture system, oligodendrocyte precursor cells did not initially produce MOLT mRNA and protein, but when they begun to differentiate into mature OLs, they started expressing MOLT. Consequently, MOLT may function as OLs become mature and may serve as a cell-surface marker for OL differentiation.

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  • The murine Ten-m/Odz genes show distinct but overlapping expression patterns during development and in adult brain. 査読 国際誌

    Xiao-Hong Zhou, Oliver Brandau, Kang Feng, Toshitaka Oohashi, Yoshifumi Ninomiya, Uwe Rauch, Reinhard Fässler

    Gene expression patterns : GEP   3 ( 4 )   397 - 405   2003年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The mouse TEN-M/ODZ proteins belong to a new family of type II transmembrane proteins with unknown function. The family consists of four members, which are expressed highly in brain and less in many other tissues. In the present study we have generated specific RNA probes and antibodies to characterize the expression of the 4 Ten-m/Odz genes in the developing and adult central nervous system (CNS) of mice. Ten-m/Odz3 and Ten-m/Odz4 mRNAs were first detectable at E7.5, Ten-m/Odz2 expression started at the 37 somite (E 10.5) stage, while Ten-m/Odz1 mRNA is not found before E15.5. In the adult mouse CNS mRNAs of the 4 Ten-m/Odzs were expressed in distinct patterns, which partially overlapped. Immunostaining and in situ hybridization localized proteins and mRNAs of Ten-m/Odzs in adjacent areas suggesting that TEN-M/ODZ proteins might be transported from the cell body along the axon or that they are shed from the cell surface and diffuse into distant regions.

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  • Vascular endothelial growth factor principally acts as the main angiogenic factor in the early stage of human osteoblastogenesis. 査読 国際誌

    Takayuki Furumatsu, Zheng Nan Shen, Akira Kawai, Keiichiro Nishida, Hironori Manabe, Toshitaka Oohashi, Hajime Inoue, Yoshifumi Ninomiya

    Journal of biochemistry   133 ( 5 )   633 - 9   2003年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Vascular endothelial growth factor (VEGF)-mediated angiogenesis is essential for bone formation. However, the effect of VEGF on osteoblastic cells during osteoblastogenesis is still controversial. The aim of this study was to clarify the relationship between osteoblastic cells derived from human mesenchymal stem cells (MSCs) and VEGF in the early stage of osteoblastic differentiation. Continuous dexamethasone treatment with a low concentration stimulated osteoblastogenesis of MSCs and the expression of VEGF121 mRNA. The VEGF secretion from osteoblastic cells also increased along with osteoblastogenesis. Neuropilin-1, which mainly binds VEGF165, was detected at all stages during early osteoblastogenesis, but VEGF receptor-1 and -2 were not detected on RT-PCR analyses. In this study, VEGF had no direct effect on the proliferation of osteoblastic cells. However, the secreted VEGF in the conditioned medium of osteoblastic cells exhibited high angiogenic power as to endothelial cell proliferation. Our findings indicated that VEGF121 principally acts as the main angiogenic factor in the early stage of human osteoblastogenesis. The present study also demonstrated the differential expression of VEGF121 during osteoblastogenesis. The increase of VEGF in the early stage might be a useful marker of induction of bone formation due to human MSCs.

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  • All four members of the Ten-m/Odz family of transmembrane proteins form dimers. 査読 国際誌

    Kang Feng, Xiao-Hong Zhou, Toshitaka Oohashi, Matthias Mörgelin, Ariel Lustig, Satoshi Hirakawa, Yoshifumi Ninomiya, Jürgen Engel, Uwe Rauch, Reinhard Fässler

    The Journal of biological chemistry   277 ( 29 )   26128 - 35   2002年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ten-m/Odz/teneurins are a new family of four distinct type II transmembrane molecules. Their extracellular domains are composed of an array of eight consecutive EGF modules followed by a large globular domain. Two of the eight modules contain only 5 instead of the typical 6 cysteine residues and have the capability to dimerize in a covalent, disulfide-linked fashion. The structural properties of the extracellular domains of all four mouse Ten-m proteins have been analyzed using secreted, recombinant molecules produced by mammalian HEK-293 cells. Electron microscopic analysis supported by analytical ultracentrifugation data revealed that the recombinant extracellular domains of all Ten-m proteins formed homodimers. SDS-PAGE analysis under nonreducing conditions as well as negative staining after partial denaturation of the molecules indicated that the globular COOH-terminal domains of Ten-m1 and -m4 contained subdomains with a pronounced stability against denaturing agents, especially when compared with the homologous domains of Ten-m2 and -m3. Cotransfection experiments of mammalian cells with two different extracellular domains revealed that Ten-m molecules have also the ability to form heterodimers, a property that, combined with alternative splicing events, allows the formation of a multitude of molecules with different characteristics from a limited set of genes.

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  • Human BRAL1 and BCAN genes that belong to the link-module superfamily are tandemly arranged on chromosome 1q21-23. 査読

    Hiroyuki Nomoto, Toshitaka Oohashi, Satoshi Hirakawa, Yasuyoshi Ueki, Hiroshi Ohtsuki, Yoshifumi Ninomiya

    Acta medica Okayama   56 ( 1 )   25 - 9   2002年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We herein determined by fluorescence in situ hybridization the chromosomal localization of 2 human genes, BRAL1 and BCAN, both of which belong to the link-module superfamily, i.e. to the same band of chromosome 1q21-23. Further analysis of the genomic organization of BRAL1 and BCAN revealed that the BRAL1 gene was located 20-kb upstream of the BCAN start site. We isolated a polymorphic dinucleotide (CA) repeat sequence from a genomic clone containing the BCAN gene. High heterozygosity (0.79) makes this polymorphism a useful marker in the study of genetic disorders. Knowledge of the structure of the genes and the marker provides essential information for further analysis of the gene locus at chromosome 1q21-23.

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  • Bral1, a brain-specific link protein, colocalizing with the versican V2 isoform at the nodes of Ranvier in developing and adult mouse central nervous systems. 査読 国際誌

    Toshitaka Oohashi, Satoshi Hirakawa, Yoko Bekku, Uwe Rauch, Dieter R Zimmermann, Wei-Dong Su, Aiji Ohtsuka, Takuro Murakami, Yoshifumi Ninomiya

    Molecular and cellular neurosciences   19 ( 1 )   43 - 57   2002年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Bral1, a brain-specific hyaluronan-binding protein, has been cloned recently. To gain insight into the role of Bral1, we generated a specific antibody against this protein. We have examined the detailed localization pattern of Bral1 protein and compared it with that of other members of the lectican proteoglycan family, such as brevican and versican, with which Bral1 is predicted to interact. The immunoreactivity of Bral1 antibody was predominantly observed in myelinated fiber tracts in the adult brain and could be detected at P20 in the white matter of the developing cerebellum, suggesting that expression starts when axonal myelination takes place. Furthermore, immunostaining demonstrated that Bral1 colocalized with the versican V2 isoform at the nodes of Ranvier. The present data suggest that Bral1 may play a pivotal role in the formation of the hyaluronan-associated matrix in the CNS that facilitates neuronal conduction by forming an ion diffusion barrier at the nodes.

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  • Neurocan is dispensable for brain development. 査読 国際誌

    X H Zhou, C Brakebusch, H Matthies, T Oohashi, E Hirsch, M Moser, M Krug, C I Seidenbecher, T M Boeckers, U Rauch, R Buettner, E D Gundelfinger, R Fässler

    Molecular and cellular biology   21 ( 17 )   5970 - 8   2001年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neurocan is a component of the extracellular matrix in brain. Due to its inhibition of neuronal adhesion and outgrowth in vitro and its expression pattern in vivo it was suggested to play an important role in axon guidance and neurite growth. To study the role of neurocan in brain development we generated neurocan-deficient mice by targeted disruption of the neurocan gene. These mice are viable and fertile and have no obvious deficits in reproduction and general performance. Brain anatomy, morphology, and ultrastructure are similar to those of wild-type mice. Perineuronal nets surrounding neurons appear largely normal. Mild deficits in synaptic plasticity may exist, as maintenance of late-phase hippocampal long-term potentiation is reduced. These data indicate that neurocan has either a redundant or a more subtle function in the development of the brain.

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  • The brain link protein-1 (BRAL1): cDNA cloning, genomic structure, and characterization as a novel link protein expressed in adult brain. 査読 国際誌

    S Hirakawa, T Oohashi, W D Su, H Yoshioka, T Murakami, J Arata, Y Ninomiya

    Biochemical and biophysical research communications   276 ( 3 )   982 - 9   2000年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We report here molecular cloning and expression analysis of the gene for a novel human brain link protein-1 (BRAL1) which is predominantly expressed in brain. The predicted open reading frame of human brain link protein-1 encoded a polypeptide of 340 amino acids containing three protein modules, the immunoglobulin-like fold and proteoglycan tandem repeat 1 and 2 domains, with an estimated mass of 38 kDa. The brain link protein-1 mRNA was exclusively present in brain. When analyzed during mouse development, it was detected solely in the adult brain. Concomitant expression pattern of mRNAs for brain link protein-1 and various lectican proteoglycans in brain suggests a possibility that brain link protein-1 functions to stabilize the binding between hyaluronan and brevican. The human BRAL1 gene contained 7 exons and spanned approximately 6 kb. The entire immunoglobulin-like fold was encoded by a single exon and the proteoglycan tandem repeat 1 and 2 domains were encoded by a single and two exons, respectively. The deduced amino acid sequence of human brain link protein-1 exhibited 45% identity with human cartilage link protein-1 (CRTL1), previously reported as link protein to stabilize aggregates of aggrecan and hyaluronan in cartilage. These results suggest that brain link protein-1 may have distinct function from cartilage link protein-1 and play specific roles, especially in the adult brain.

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  • Differential expression of mouse alpha5(IV) and alpha6(IV) collagen genes in epithelial basement membranes. 査読 国際誌

    K Saito, I Naito, T Seki, T Oohashi, E Kimura, R Momota, Y Kishiro, Y Sado, H Yoshioka, Y Ninomiya

    Journal of biochemistry   128 ( 3 )   427 - 34   2000年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We first completed the primary structure of the mouse alpha5(IV) and alpha6(IV) chains, from which synthetic peptides were produced and a chain-specific monoclonal antibodies were raised. Expression of collagen IV genes in various basement membranes underlying specific organ epithelia was analyzed by immunohistochemical staining using these monoclonal antibodies and other antibodies from human and bovine sequences. It was possible to predict the presence of the three collagen IV molecules: [alpha1(IV)](2) alpha2(IV), alpha3(IV)alpha4(IV)alpha5(IV), and [alpha5(IV)](2)alpha6(IV). In skin basement membrane two of the three forms, [alpha1(IV)](2)alpha2(IV) and [alpha5(IV)](2)alpha6(IV), were detected. The alpha3(IV)alpha4(IV)alpha5(IV) molecule was observed as the major form in glomerulus, alveolus, and choroid plexus, where basement membranes function as filtering units. The molecular form [alpha5(IV)](2)alpha6(IV) was present in basement membranes in tubular organs such as the epididymis, where the tubes need to expand in diameter. Thus, the distribution of the basement membranes with different molecular composition is consistent with tissue-specific function.

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  • Peri-implantation lethality in mice lacking the Sm motif-containing protein Lsm4. 査読 国際誌

    E Hirsch, T Oohashi, M Ahmad, S Stamm, R Fässler

    Molecular and cellular biology   20 ( 3 )   1055 - 62   2000年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Small nuclear ribonucleoproteins (snRNPs) are particles present only in eukaryotic cells. They are involved in a large variety of RNA maturation processes, most notably in pre-mRNA splicing. Several of the proteins typically found in snRNPs contain a sequence signature, the Sm domain, conserved from yeast to mammals. By using a promoter trap strategy to target actively transcribed loci in murine embryonic stem cells, a new murine gene encoding an Sm motif-containing protein was identified. Database searches revealed that it is the mouse orthologue of Lsm4p, a protein found in yeast and human cells and putatively associated with U6 snRNA. Introduction of the geo reporter gene cassette under the control of the murine Lsm4 (mLsm4) endogenous promoter showed that the gene was ubiquitously transcribed in embryonic and adult tissues. The insertion of the geo cassette disrupted the mLsm4 allele, and homozygosity for the mutation led to a recessive embryonic lethal phenotype. mLsm4-null zygotes survived to the blastocyst stages, implanted into the uterus, but died shortly thereafter. The early death of mLsm4p-null mice suggests that the role of mLsm4p in splicing is essential and cannot be compensated by other Lsm proteins.

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  • The extracellular matrix in the mouse brain: its reactions to endo-alpha-N-acetylgalactosaminidase and certain other enzymes. 査読

    T Murakami, A Ohtsuka, W D Su, T Taguchi, T Oohashi, T Murakami, K Abe, Y Ninomiya

    Archives of histology and cytology   62 ( 3 )   273 - 81   1999年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    As our previous studies have indicated, the cingulate cortex of the adult mouse brain contains many neurons with rich cell surface glycoproteins which are linked by collagenous ligands to perineuronal proteoglycans. The present study demonstrated that exclusive incubation with endo-alpha-N-acetylgalactosaminidase abolished the lectin Vicia villosa or Wisteria floribunda agglutinin (VVA or WFA) labeling of the nerve cell surface glycoproteins, while it neither interfered with the cationic iron colloid or aldehyde fuchsin stainings of the perineuronal proteoglycans nor abolished the Gömöri's ammoniacal silver impregnation of the collagenous ligands. Double incubations with endo-alpha-N-acetylgalactosaminidase and collagenase did not eliminate the lectin VVA or WFA labeling of the nerve cell surface glycoproteins, though they did eliminate the cationic iron colloid and aldehyde fuchsin stainings of the perineuronal proteoglycans as well as the Gömöri's ammoniacal silver impregnation of the collagenous ligands. Triple incubations with endo-alpha-N-acetylgalactosaminidase, collagenase, and endo-alpha-N-acetylgalactosaminidase abolished the lectin VVA or WFA labeling of the nerve cell surface glycoproteins, and also eliminated the cationic iron colloid and aldehyde fuchsin stainings of the perineuronal proteoglycans and the Gömöri's ammoniacal silver impregnation of the collagenous ligands. These findings indicate that: the nerve cell surface glycoproteins or their terminal N-acetylgalactosamines are digested by endo-alpha-N-acetylgalactosaminidase; these galactosamines associated with the collagenous ligands or perineuronal proteoglycans are not digested by endo-alpha-N-acetylgalactosaminidase; and the terminal N-acetylgalactosamines newly exposed by collagenase incubation are digested by this galactosaminidase. It was further demonstrated that hyaluronidase incubation neither digests the collagenous ligands nor revives the lectin VVA or WFA labeling of the nerve cell surface proteoglycans.

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  • Mouse ten-m/Odz is a new family of dimeric type II transmembrane proteins expressed in many tissues. 査読 国際誌

    T Oohashi, X H Zhou, K Feng, B Richter, M Mörgelin, M T Perez, W D Su, R Chiquet-Ehrismann, U Rauch, R Fässler

    The Journal of cell biology   145 ( 3 )   563 - 77   1999年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The Drosophila gene ten-m/odz is the only pair rule gene identified to date which is not a transcription factor. In an attempt to analyze the structure and the function of ten-m/odz in mouse, we isolated four murine ten-m cDNAs which code for proteins of 2,700-2, 800 amino acids. All four proteins (Ten-m1-4) lack signal peptides at the NH2 terminus, but contain a short hydrophobic domain characteristic of transmembrane proteins, 300-400 amino acids after the NH2 terminus. About 200 amino acids COOH-terminal to this hydrophobic region are eight consecutive EGF-like domains. Cell transfection, biochemical, and electronmicroscopic studies suggest that Ten-m1 is a dimeric type II transmembrane protein. Expression of fusion proteins composed of the NH2-terminal and hydrophobic domain of ten-m1 attached to the alkaline phosphatase reporter gene resulted in membrane-associated staining of the alkaline phosphatase. Electronmicroscopic and electrophoretic analysis of a secreted form of the extracellular domain of Ten-m1 showed that Ten-m1 is a disulfide-linked dimer and that the dimerization is mediated by EGF-like modules 2 and 5 which contain an odd number of cysteines. Northern blot and immunohistochemical analyses revealed widespread expression of mouse ten-m genes, with most prominent expression in brain. All four ten-m genes can be expressed in variously spliced mRNA isoforms. The extracellular domain of Ten-m1 fused to an alkaline phosphatase reporter bound to specific regions in many tissues which were partially overlapping with the Ten-m1 immunostaining. Far Western assays and electronmicroscopy demonstrated that Ten-m1 can bind to itself.

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  • Differential tissular expression and localization of type IV collagen alpha1(IV), alpha2(IV), alpha5(IV), and alpha6(IV) chains and their mRNA in normal breast and in benign and malignant breast tumors. 査読 国際誌

    S Nakano, K Iyama, M Ogawa, H Yoshioka, Y Sado, T Oohashi, Y Ninomiya

    Laboratory investigation; a journal of technical methods and pathology   79 ( 3 )   281 - 92   1999年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Type IV collagen, the major component of basement membrane (BM), is composed of six genetically distinct alpha chains. We investigated the cellular regulation and origin of these alpha(IV) chains in normal and neoplastic breast tissues by immunohistochemistry by using alpha(IV) chain-specific antibodies and by in situ hybridization. In normal breast, alpha1(IV) and alpha2(IV) chains were stained in all BM, whereas alpha5(IV) and alpha6(IV) chains were restrictively localized in a linear pattern in the BM of the mammary gland. Similar immunostaining profiles were observed in benign breast tumors and in the intraductal components of invasive ductal carcinoma. However, in invasive ductal carcinoma, alpha1(IV) and alpha2(1V) chains were discontinuously or negatively stained in the cancer cell nests, and the assembly of alpha5(IV) and alpha6(IV) chains into the BM was completely inhibited. Coexpression of alpha5(IV) and alpha6(IV) chains was related to the localization of alpha-smooth muscle actin (alpha-SMA)-positive myoepithelial cells. By in situ hybridization, in fibroadenoma and invasive ductal carcinoma, the signals for alpha1(IV) and alpha2(IV) mRNA were abundant in stromal cells. However, the signals for alpha5(IV) and alpha6(IV) mRNA were not seen in any of these cells. In contrast, in intraductal papilloma, coexpression of alpha1 (IV)/alpha2(IV) mRNA and alpha5(IV)/alpha6(IV) mRNA was identified in epithelial cells. The results indicate that the mammary gland forms a second network of BM composed of alpha5(IV)/alpha6(IV) chains, in addition to the classic network of alpha1(IV)/alpha2(IV) chains. The expression of type IV collagen alpha chains seems to be differentially regulated by the epithelial-myoepithelial interaction and to be associated with the invasive potential of breast cancer.

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  • Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. 査読 国際誌

    A J Coffey, R A Brooksbank, O Brandau, T Oohashi, G R Howell, J M Bye, A P Cahn, J Durham, P Heath, P Wray, R Pavitt, J Wilkinson, M Leversha, E Huckle, C J Shaw-Smith, A Dunham, S Rhodes, V Schuster, G Porta, L Yin, P Serafini, B Sylla, M Zollo, B Franco, A Bolino, M Seri, A Lanyi, J R Davis, D Webster, A Harris, G Lenoir, G de St Basile, A Jones, B H Behloradsky, H Achatz, J Murken, R Fassler, J Sumegi, G Romeo, M Vaudin, M T Ross, A Meindl, D R Bentley

    Nature genetics   20 ( 2 )   129 - 35   1998年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    X-linked lymphoproliferative syndrome (XLP or Duncan disease) is characterized by extreme sensitivity to Epstein-Barr virus (EBV), resulting in a complex phenotype manifested by severe or fatal infectious mononucleosis, acquired hypogammaglobulinemia and malignant lymphoma. We have identified a gene, SH2D1A, that is mutated in XLP patients and encodes a novel protein composed of a single SH2 domain. SH2D1A is expressed in many tissues involved in the immune system. The identification of SH2D1A will allow the determination of its mechanism of action as a possible regulator of the EBV-induced immune response.

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  • Differential expression of type IV collagen isoforms, alpha5(IV) and alpha6(IV) chains, in basement membranes surrounding smooth muscle cells. 査読 国際誌

    T Seki, I Naito, T Oohashi, Y Sado, Y Ninomiya

    Histochemistry and cell biology   110 ( 4 )   359 - 66   1998年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Smooth muscle is composed of cigar-shaped, non-striated cells, each of which is encapsulated by a basement membrane and forms the contractile portion of tubular organs such as the gastrointestinal tract, pulmonary tract, genitourinary tract, and vasculature, in which slow and sustained contractions are needed. We examined basement membranes produced by smooth muscle cells and, using alpha(IV) chain-specific monoclonal antibodies, analyzed type IV collagens in these organs. Detailed distribution analysis of the alpha chains in normal and Alport cases by use of specific antibodies indicated that there are at least three molecular forms of type IV collagen, [alpha1(IV)]2alpha2(IV),alpha3(IV)alpha4(IV)alpha5+ ++(IV), and alpha5(IV)/alpha6(IV). Smooth muscle cells in the urinary bladder and uterus were enclosed by basement membranes composed of alpha1, alpha2, alpha5, and alpha6 chains. The same alpha chains were present around smooth muscle cells in the muscular layer of the fundus of the stomach, whereas those in the antrum and further distal side of the gastrointestinal tract expressed mostly alphal and alpha2 chains. In addition, immunostaining analysis of the vasculature also showed that most of the smooth muscle cells were positive for alpha1 and alpha2 chains; however, alpha5 and alpha6 chains were also expressed by smooth muscle cells in the aorta and some arteries where blood pressure changes significantly. These results suggest that the smooth muscle cells enclosed by alpha5/alpha6-containing basement membranes might have some particular function related to mechanical stress or tensile strength during the characteristic contractile activity of tubular organs.

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  • Differential expression of type IV collagen isoforms, alpha 5(IV) and alpha 6(IV) chains, in basement membranes surrounding smooth muscle cells 査読

    T Seki, Naito, I, T Oohashi, Y Sado, Y Ninomiya

    HISTOCHEMISTRY AND CELL BIOLOGY   110 ( 4 )   359 - 366   1998年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER VERLAG  

    Smooth muscle is composed of cigar-shaped, non-striated cells, each of which is encapsulated by a basement membrane and forms the contractile portion of tubular organs such as the gastrointestinal tract, pulmonary tract, genitourinary tract, and vasculature, in which slow and sustained contractions are needed. We examined basement membranes produced by smooth muscle cells and, using alpha(IV) chain-specific monoclonal antibodies, analyzed type IV collagens in these organs. Detailed distribution analysis of the alpha chains in normal and Alport cases by use of specific antibodies indicated that there are at least three molecular forms of type IV collagen, [alpha 1(IV)](2)alpha 2(IV), alpha 3(IV)alpha 4(IV)alpha 5(IV), and alpha 5(IV)/alpha 6(IV). Smooth muscle cells in the urinary bladder and uterus were enclosed by basement membranes composed of alpha 1, alpha 2, alpha 5, and alpha 6 chains. The same alpha chains were present around smooth muscle cells in the muscular layer of the fundus of the stomach, whereas those in the antrum and further distal side of the gastrointestinal tract expressed mostly alpha 1 and alpha 2 chains. In addition, immunostaining analysis of the vasculature also showed that most of the smooth muscle cells were positive for alpha 1 and alpha 2 chains; however, alpha 5 and alpha 6 chains were also expressed by smooth muscle cells in the aorta and some arteries where blood pressure changes significantly. These results suggest that the smooth muscle cells enclosed by alpha 5/alpha 6-containing basement membranes might have some particular function related to mechanical stress or tensile strength during the characteristic contractile activity of tubular organs.

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  • Organization and Expression of Basement Membrane Collagen IV Genes and Their Roles in Human Disorders.(共著) 査読 国際誌

    Journal of Biochemistry   123 ( 5 )   767 - 76   1998年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Two genes, COL4A3 and COL4A4 coding for the human alpha3(IV) and alpha4(IV) collagen chains are arranged head-to-head on chromosome 2q36. 査読 国際誌

    R Momota, M Sugimoto, T Oohashi, K Kigasawa, H Yoshioka, Y Ninomiya

    FEBS letters   424 ( 1-2 )   11 - 6   1998年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We first isolated and characterized genomic DNA fragments that cover the 5' flanking sequences of COL4A3 and COL4A4 encoding the human basement membrane alpha3(IV) and alpha4(IV) collagen chains, respectively. Nucleotide sequence analysis indicated that the two genes are arranged head-to-head. To determine transcription start site for COL4A4 gene, we performed RACE and RNase protection assays, indicating that there are two alternative transcripts presumably derived from two different promoters. Interestingly, one transcription start site (from exon 1') of COL4A4 is only 5 bp away from the reported transcription start site of COL4A3, whereas the other transcript (from exon 1) starts 373 nucleotides downstream from the first one, generating the two kinds of transcripts that differ in the 5' UTR regions. Expression of these two transcripts appears tissue-specific; exon 1 transcript was expressed predominantly in epithelial cells, while exon 1' transcript showed rather ubiquitous and low expression. The nucleotide sequence of the promoter region is composed of dense CpG dinucleotides, GC boxes, CTC boxes and a CCAAT box but no TATA box. These results provide information to delineate the promoter activity for the tissue-specific expression of the six type IV collagen genes and basement membrane assembly in different tissues and organs.

    DOI: 10.1016/S0014-5793(98)00128-8

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  • Expression of type XVII collagen alpha 1 chain mRNA in the mouse heart. 査読

    J Kondo, S Kusachi, Y Ninomiya, H Yoshioka, T Oohashi, M Doi, T Murakami, H Moritani, H Kumashiro, T Tsuji

    Japanese heart journal   39 ( 2 )   211 - 20   1998年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The type XVII collagen alpha 1 chain has been identified as a component of the type I hemidesmosome, and is thus thought to play a role in extracellular matrix (ECM) maintenance and signal transduction between the cell and the ECM. We examined the expression of type XVII collagen alpha 1 chain mRNA in the mouse heart by Northern blot analysis and determined the sequential changes of its expression in different developmental stages of the heart using the reverse transcriptase-polymerase chain reaction (RT-PCR) method. Northern blotting: Total RNA was extracted from 10 adult mouse hearts by the guanidine/cesium method. Hybridization was performed with mouse cDNA for alpha 1 (XVII) collagen. RT-PCR: Total RNA was extracted from 7 embryos, 4 neonates and 8 adult mice. Reverse transcription was performed using oligo-dT primer and MMLV. Amplification was carried out in alpha 1 (XVII) collagen and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). GAPDH served as an internal control. Northern blotting revealed a 5.6 kb signal that was identical to that of the alpha 1 (XVII) of skin and transformed keratinocyte reported previously. The sequences of the PCR products were also identical to those reported. The normalized expression ratios of alpha 1 (XVII) were 0.91 +/- 0.20 in the embryonic heart, 0.36 +/- 0.20 in the neonatal heart and 0.96 +/- 0.21 in the adult heart. In conclusion, we identified the expression of type XVII collagen alpha 1 chain mRNA in the mouse heart, suggesting that the type I hemidesmosome is located in the heart. The results of the RT-PCR at different developmental stages of the heart suggest that type XVII collagen contributes not only to cardiogenesis in the embryonic stage but also to maintenance of architecture and function in the adult heart.

    DOI: 10.1536/ihj.39.211

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  • Topoisomerase I and II consensus sequences in a 17-kb deletion junction of the COL4A5 and COL4A6 genes and immunohistochemical analysis of esophageal leiomyomatosis associated with Alport syndrome. 査読 国際誌

    Y Ueki, I Naito, T Oohashi, M Sugimoto, T Seki, H Yoshioka, Y Sado, H Sato, T Sawai, F Sasaki, M Matsuoka, S Fukuda, Y Ninomiya

    American journal of human genetics   62 ( 2 )   253 - 61   1998年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Diffuse esophageal leiomyomatosis (DL), a benign smooth-muscle-cell tumor, is characterized by abnormal cell proliferation. DL is sometimes associated with X-linked Alport syndrome (AS), an inherited nephropathy caused by COL4A5 gene mutations. COL4A5 is tightly linked, in a head-to-head fashion, to the functionally related and coordinately regulated COL4A6 gene. No X-linked AS cases are due to COL4A6 mutations, but all DL/AS cases are always associated with deletions spanning the 5' regions of the COL4A5/COL4A6 cluster. Unlike the COL4A5 breakpoints, those of COL4A6 are clustered within intron 2 of the gene. We identified a DL/AS deletion and the first characterization of the breakpoint sequences. We show that a deletion eliminates the first coding exon of COL4A5 and the first two coding exons of COL4A6. The breakpoints share the same sequence, which, in turn, is closely homologous to the consensus sequences of topoisomerases I and II. Additional DNA evidence suggested that the male patient is a somatic mosaic for the mutation. Immunohistochemical analysis using alpha-chain-specific monoclonal antibodies supported this conclusion, since it revealed the absence of the alpha5(IV) and alpha6(IV) collagen chains in most but not all of the basement membranes of the smooth-muscle-cell tumor. We also documented a similar segmental staining pattern in the glomerular basement membranes of the patient's kidney. This study is particularly relevant to the understanding of DL pathogenesis and its etiology.

    DOI: 10.1086/301703

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  • There is temporal and spatial expression of alpha1 (IV), alpha2 (IV), alpha5 (IV), alpha6 (IV) collagen chains and beta1 integrins during the development of the basal lamina in an "in vitro" skin model. 査読 国際誌

    R Fleischmajer, K Kühn, Y Sato, E D MacDonald 2nd, J S Perlish, T C Pan, M L Chu, Y Kishiro, T Oohashi, S M Bernier, Y Yamada, Y Ninomiya

    The Journal of investigative dermatology   109 ( 4 )   527 - 33   1997年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Temporal and spatial expression of alpha1 (IV), alpha2 (IV), alpha3 (IV), alpha4 (IV), alpha5 (IV), and alpha6 (IV) collagen chains was studied during the formation of the basal lamina in an "in vitro" skin model. A sequential study was performed at 7-d and 14-d cultures (lamina densa absent) and at 28-, 36-, and 56-d cultures (lamina densa present). Expression of beta1, beta4, alpha1, alpha2, alpha3, alpha5, alpha6 integrin subunits and co-localization with collagen IV was studied by regular and laser confocal indirect immunofluorescence microscopy. mRNA expression of alpha2 (IV) and alpha6 (IV) chains was estimated by northern blots. The earliest expression of alpha1 (IV) and alpha2 (IV) collagen chains was noted in 7-d cultures restricted to basal keratinocytes. At 14-d cultures, alpha1 (IV) and alpha2 (IV) chains were noted in basal keratinocytes and as a broad band (10 microm) in the adjacent dermis. At this stage 80% of the alpha2 (IV) mRNA was expressed in the dermis and 20% in the epidermis. At 28-, 36-, and 56-d cultures the alpha1 (IV) and alpha2 (IV) chains were present in a linear distribution at the epidermo-dermal junction and in the upper dermis. The alpha6 (IV) collagen chains were expressed much later at 36-d cultures and the alpha5 (IV) at 56 d, both mostly in a linear distribution but also in the adjacent dermis. Alpha6 (IV) mRNA was demonstrated in the dermis of 36-d cultures. There was co-localization of collagen IV and beta1 integrin subunits in 14-d cultures at the matrix site of keratinocytes. Functional perturbation studies with AIIB2 monoclonal antibody (anti-beta1 subunits) and competitive inhibition with a collagen cyanogen bromide digestion derived fragment (CB3[IV]) that contains the collagen IV ligand for alpha1beta1, alpha2beta1 integrins, altered the pattern of collagen IV deposition.

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  • Differential expression of alpha 1(IV), alpha 2(IV), alpha 5(IV) and alpha 6(IV) collagen chains in the basement membrane of basal cell carcinoma. 査読 国際誌

    K Tanaka, K Iyama, M Kitaoka, Y Ninomiya, T Oohashi, Y Sado, T Ono

    The Histochemical journal   29 ( 7 )   563 - 70   1997年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Type IV collagen, the major component of basement membrane, consists primarily of alpha 1(IV) and alpha 2(IV) chains. Recently, other types of collagen IV chains, i.e. alpha 3(IV), alpha 4(IV), alpha 5(IV) and alpha 6(IV) chains, have been identified by protein chemistry and molecular cloning. We have examined the diversity of the assembly of alpha (IV) chains of the basement membrane surrounding tumour nests of basal cell carcinomas, in tissues from 11 patients, by immunohistochemical analysis using specific monoclonal antibodies to six alpha (IV) chain. The immunostaining profile of each chain differed with respect to the histological subtypes of basal cell carcinoma. In the morphea-like subtype, which was more invasive, alpha 1(IV) and alpha 2(IV) chains were discontinuously stained, and alpha 5(IV) and alpha 6(IV) chains were entirely absent. However, in the superficial subtype, which was non-aggressive, alpha 1(IV), alpha 2(IV), alpha 5(IV) and alpha 6(IV) chains were well stained compared with the other subtypes of basal cell carcinoma. In addition, in the solid subtype, which showed slow growth and ulceration, alpha 1(IV) and alpha 2(IV) chains were continuously stained, and alpha 5(IV) and alpha 6(IV) chains were discontinuous or absent. The assembly of alpha 5(IV) and alpha 6(IV) chains into the basement membrane was inhibited in the solid and morphea subtypes of BCC. This differential expression of type IV collagen chains seems to be associated with the invasive potential of basal cell carcinoma.

    DOI: 10.1023/A:1026428010104

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  • The primary structure of the Cl(-)-translocating ATPase, b subunit of Acetabularia acetabulum, which belongs to the F-type ATPase family. 査読 国際誌

    C Moritani, T Ohhashi, H Kadowaki, M Tagaya, T Fukui, F Lottspeich, D Oesterhelt, M Ikeda

    Archives of biochemistry and biophysics   339 ( 1 )   115 - 24   1997年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The genes possibly encoding the b subunit (50 kDa) of the Cl(-)-translocating ATPase of Acetabularia acetabulum were cloned from total RNA and from poly(A)+ RNA and sequenced. The deduced amino acid sequence of the open reading frame consisted of 478 amino acids and showed high similarity to the beta subunit of chloroplast F1-ATPase. Gene fragments encoding the putative beta subunit of chloroplast F1- (273 bp) and mitochondrial F1-ATPases (332 bp) were also cloned from A. acetabulum and sequenced, respectively. The deduced amino acid sequence of the chloroplast F1-ATPase showed 92.5% identity to be primary structure of the b subunit of the Cl(-)-translocating ATPase, while the nucleotide sequences were 79.9% identical. The deduced amino acid sequence of the latter was 77.3% identical to that of the b subunit of the Cl(-)-translocating ATPase and the nucleotide sequences were 67.5% identical. By Northern analysis, these three beta-like genes were demonstrated to be transcribed with different sizes of RNA species. A putative chloroplast F1-beta fragment also hybridized with chloroplast DNA isolated from the organism.

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  • Absence of alpha 6(IV) collagen in kidney and skin of X-linked Alport syndrome patients. 査読 国際誌

    S Hino, T Takemura, Y Sado, M Kagawa, T Oohashi, Y Ninomiya, K Yoshioka

    Pediatric nephrology (Berlin, Germany)   10 ( 6 )   742 - 4   1996年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To identify the abnormalities of the type IV collagen alpha 6 chain, alpha 6(IV), in Alport syndrome, we examined renal and skin tissue using rat monoclonal antibodies against non-consensus amino acid sequences of alpha 6(IV). Immunofluorescence of normal human kidney and skin tissue revealed linear alpha 6(IV) staining in the basement membrane (BM) of Bowman's capsule, in some tubules, and also in the epidermal BM. Renal specimens from five male patients of four families with X-linked Alport syndrome showed no reactivity for alpha 6(IV) in Bowman's capsules and tubules. In these patients, alpha 1(IV) and alpha 2(IV) were normal, whereas alpha 3(IV), alpha 4(IV), and alpha 5(IV) were absent from the BMs of the kidney. In skin tissue of male patients, neither alpha 5(IV) nor alpha 6(IV) were detected. The epidermal BM of female heterozygotes with X-linked Alport syndrome showed a mosaic staining for alpha 5(IV) and alpha 6(IV). These findings indicate that, in addition to a disturbed alpha 3(IV)-alpha 4(IV)-alpha 5(IV) network, patients with X-linked Alport syndrome have abnormalities in alpha 6(IV) of the renal and epidermal BMs at the protein level.

    DOI: 10.1007/s004670050206

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  • Nephritogenicity and alpha-chain composition of NC1 fractions of type IV collagen from bovine renal basement membrane. 査読 国際誌

    S Rauf, M Kagawa, Y Kishiro, S Inoue, I Naito, T Oohashi, M Sugimoto, Y Ninomiya, Y Sado

    Virchows Archiv : an international journal of pathology   428 ( 4-5 )   281 - 8   1996年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Nephritogenicity (anti-GBM-nephritis-inducing activity) and alpha-chain composition of globular-do-main (NCI) fractions of type IV collagen from bovine renal, pulmonary, and placental basement membranes (BMs) was examined by injecting these fractions with adjuvant into WKY/NCrj rats and by Western blotting using epitope-defined monoclonal antibodies to the six different alpha chains of type IV collagen. A purified nephritogenic fraction from renal BM contained alpha 1-alpha 6(IV)NCI, whereas a non-nephritogenic fraction contained only alpha 1-alpha 2(IV)NCI. Renal and pulmonary NCI had strong nephritogenic activity: placental NCI had weak activity. The renal and pulmonary fractions contained alpha 1-alpha 6(IV)NCI, and the placental fraction had a large amount of alpha 1-alpha 2(IV)NCI and a very small amount of alpha 3-alpha 6(IV)NCI. Immunohistochemical study of bovine renal BM with the monoclonal antibodies revealed that bovine glomerular BM contained alpha 1-alpha 5(IV) chains, but not the alpha 6(IV) chain. The absence of alpha 6(IV) chain in glomerular BM in bovine and in humans indicates that alpha 6(IV) chain is not a target antigen of anti-GBM nephritis. Nephritogenicity is apparently a property of alpha 3-alpha 5(IV)NCI.

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  • Isolation and structure of the COL4A6 gene encoding the human alpha 6(IV) collagen chain and comparison with other type IV collagen genes. 査読 国際誌

    T Oohashi, Y Ueki, M Sugimoto, Y Ninomiya

    The Journal of biological chemistry   270 ( 45 )   26863 - 7   1995年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The genes COL4A5 and COL4A6, coding for the basement membrane collagen chains, alpha 5(IV) and alpha 6(IV), respectively, are located head-to-head in close proximity on human chromosome Xq22, and COL4A6 is transcribed from two alternative promoters in a tissue-specific fashion (Sugimoto M., Oohashi T., and Ninomiya Y. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 11679-11683). Immunofluorescence studies using alpha chain-specific antibodies demonstrated that the two genes are expressed in a tissue-specific manner (Ninomiya, Y., Kagawa, M., Iyama, K., Naito, L., Kishiro, Y., Seyer, J. M., Sugimoto, M., Oohashi, T., and Sado, Y. (1995) J. Cell Biol. 130, 1219-1229). We report here for the first time the isolation and the structural organization of the human COL4A6 gene. The entire gene presumably exceeds 200 kilobase pairs and contains 46 exons. Exons 1' and 1 encode the two different 5'-UTRs and the two amino-terminal parts of of the signal peptide. The carboxyl part of the signal peptide and the 7 S domain are coded for by the following 6 different exons, 2-7, whereas the exons 7-42 encode the central COL 1 domain, which contains the Gly-X-Y repeats. The last three exons, 43-45, encode the carboxyl-terminal NC1 domain. Sizes of more than a half of the exons of the gene are the same as those of Col4a2 but quite different from those of COL4A5. Within the COL4A6 gene we found three CA repeat markers that can be used for allele detection. The detailed structure of the COL4A6 gene and the high heterozygosity microsatellite markers located within the gene will be useful for linkage analysis and familial diagnosis of diseases caused by mutations of this gene.

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  • ESTABLISHMENT BY THE RAT LYMPH-NODE METHOD OF EPITOPE-DEFINED MONOCLONAL-ANTIBODIES RECOGNIZING THE 6 DIFFERENT ALPHA-CHAINS OF HUMAN TYPE-IV COLLAGEN 査読

    Y SADO, M KAGAWA, Y KISHIRO, K SUGIHARA, NAITO, I, JM SEYER, M SUGIMOTO, T OOHASHI, Y NINOMIYA

    HISTOCHEMISTRY AND CELL BIOLOGY   104 ( 4 )   267 - 275   1995年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER VERLAG  

    A group of rat monoclonal antibodies recognizing the six different alpha chains of human type IV collagen have been established by our novel method. The method is designated the rat lymph node method in which enlarged medial iliac lymph nodes of a rat injected with an antigen emulsion via hind footpads are used as a source of B cells for cell fusion to produce hybridomas. The immunogens used were synthetic peptides having non-consensus amino acid sequences near the carboxyl termini of type IV collagen alpha chains. Hybridomas were screened both by ELISA with synthetic peptides and by indirect immunofluorescence with cryostat sections of human kidneys. Because the epitopes of all antibodies were determined by multipin-peptide scanning, they were confirmed to be isoform-specific. They are useful for identification of alpha chains of type IV collagen at the protein level in normal and abnormal conditions. The combined use of synthetic peptides as immunogens, the rat lymph node method as making monoclonal antibodies, and the multipin-peptide scanning as epitope mapping is found to be a strong tool for identification of peptides and proteins whose amino acid sequences are known or have been deduced.

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  • Establishment by the rat lymph node method of epitope-defined monoclonal antibodies recognizing the six different alpha chains of human type IV collagen. 査読 国際誌

    Y Sado, M Kagawa, Y Kishiro, K Sugihara, I Naito, J M Seyer, M Sugimoto, T Oohashi, Y Ninomiya

    Histochemistry and cell biology   104 ( 4 )   267 - 75   1995年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A group of rat monoclonal antibodies recognizing the six different alpha chains of human type IV collagen have been established by our novel method. The method is designated the rat lymph node method in which enlarged medial iliac lymph nodes of a rat injected with an antigen emulsion via hind footpads are used as a source of B cells for cell fusion to produce hybridomas. The immunogens used were synthetic peptides having non-consensus amino acid sequences near the carboxyl termini of type IV collagen alpha chains. Hybridomas were screened both by ELISA with synthetic peptides and by indirect immunofluorescence with cryostat sections of human kidneys. Because the epitopes of all antibodies were determined by multipin-peptide scanning, they were confirmed to be isoform-specific. They are useful for identification of alpha chains of type IV collagen at the protein level in normal and abnormal conditions. The combined use of synthetic peptides as immunogens, the rat lymph node method as making monoclonal antibodies, and the multipin-peptide scanning as epitope mapping is found to be a strong tool for identification of peptides and proteins whose amino acid sequences are known or have been deduced.

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  • Differential expression of two basement membrane collagen genes, COL4A6 and COL4A5, demonstrated by immunofluorescence staining using peptide-specific monoclonal antibodies. 査読 国際誌

    Y Ninomiya, M Kagawa, K Iyama, I Naito, Y Kishiro, J M Seyer, M Sugimoto, T Oohashi, Y Sado

    The Journal of cell biology   130 ( 5 )   1219 - 29   1995年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Genes for the human alpha 5(IV) and alpha 6(IV) collagen chains have a unique arrangement in that they are colocalized on chromosome Xq22 in a head-to-head fashion and appear to share a common bidirectional promoter. In addition we reported a novel observation that the COL4A6 gene is transcribed from two alternative promoters in a tissue-specific manner (Sugimoto, M., T. Oohashi, and Y. Ninomiya. 1994. Proc. Natl. Acad. Sci. USA. 91:11679-11683). To know whether the translation products of both genes are colocalized in various tissues, we raised alpha 5(IV) and alpha 6(IV) chain-specific rat monoclonal antibodies against synthetic peptides reflecting sequences near the carboxy terminus of each noncollagenous (NC)1 domain. By Western blotting alpha 6(IV) chain-specific antibody recognized 27-kD monomers and associated dimers of the human type IV collagen NC1 domain, which is the first demonstration of the presence in tissues of the alpha 6(IV) polypeptide as predicted from its cDNA sequence. Immunofluorescence studies using anti-alpha 6(IV) antibody demonstrated that in human adult kidney the alpha 6(IV) chain was never detected in the glomerular basement membrane, whereas the basement membranes of the Bowman's capsules and distal tubules were positive. The staining pattern of the glomerular basement membrane was quite different from that obtained with the anti-alpha 5(IV) peptide antibody. The alpha 5(IV) and alpha 6(IV) chains were colocalized in the basement membrane in the skin, smooth muscle cells, and adipocytes; however, little if any reaction was seen in basement membranes of cardiac muscles and hepatic sinusoidal endothelial cells. Thus, both genes are expressed in a tissue-specific manner, perhaps due to the unique function of the bidirectional promoter for both genes, which is presumably different from that for COL4A1 and COL4A2.

    DOI: 10.1083/jcb.130.5.1219

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  • The genes COL4A5 and COL4A6, coding for basement membrane collagen chains alpha 5(IV) and alpha 6(IV), are located head-to-head in close proximity on human chromosome Xq22 and COL4A6 is transcribed from two alternative promoters. 査読 国際誌

    M Sugimoto, T Oohashi, Y Ninomiya

    Proceedings of the National Academy of Sciences of the United States of America   91 ( 24 )   11679 - 83   1994年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The genes for the alpha 5(IV) and alpha 6(IV) chains of human basement membrane collagen type IV have been found together on chromosome X at segment q22 and have been reported to be arranged in a head-to-head fashion. Here we report the 5' flanking sequences of COL4A5 and COL4A6 and that COL4A6 is transcribed from two alternative promoters in a tissue-specific fashion. Analysis of the sequence immediately upstream of the transcription start sites revealed some features of housekeeping genes--i.e., the lack of a TATA motif and the presence of CCAAT and CTC boxes. Further analysis revealed that COL4A6 contains two alternative promoters that control the generation of two different transcripts. One transcription start site (from exon 1') is 442 bp away from the transcription start site of COL4A5, while an alternative transcription start site (from exon 1) is located 1050 bp from the first one and drives the expression of a second transcript that encodes an alpha 6(IV) chain with a different signal peptide. Reverse transcription-PCR experiments revealed that the transcript from exon 1' is abundant in placenta, whereas the transcript from exon 1 is more frequently found in kidney and lung. These results provide additional clues to answering the general question of what mechanisms are used to generate unique basement membrane structures in different tissues.

    DOI: 10.1073/pnas.91.24.11679

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  • Purification and characterization of a membrane-bound ATPase from Acetabularia cliftonii that corresponds to a Cl(-)-translocating ATPase in Acetabularia acetabulum. 査読 国際誌

    C Moritani, T Ohhashi, S Satoh, D Oesterhelt, M Ikeda

    Bioscience, biotechnology, and biochemistry   58 ( 11 )   2087 - 9   1994年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A Mg(2+)-ATPase was solubilized from membranes of Acetabularia cliftonii using nonanoyl-N-methylgluconamide and purified by ion-exchange and gel permeation chromatography. One active ATPase fraction after Mono Q chromatography had a specific activity of 10 units/mg of protein. Judged from subunit composition [54 (a), 50 (b) with a fainter band around 40 kDa], catalytic properties, and N-terminal amino acid sequence of the b subunit, the isolated enzyme was comparable to the Cl(-)-ATPase of Acetabularia acetabulum. Immunological characterization of both subunits showed significant similarity to the F type of ATPase. Cl(-)-transport activity was observed by reconstitution studies into liposomes.

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  • Identification of a new collagen IV chain, alpha 6(IV), by cDNA isolation and assignment of the gene to chromosome Xq22, which is the same locus for COL4A5. 査読 国際誌

    T Oohashi, M Sugimoto, M G Mattei, Y Ninomiya

    The Journal of biological chemistry   269 ( 10 )   7520 - 6   1994年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To date, five distinct alpha chains have been identified in basement membrane collagen IV. We have cloned a gene encoding a new alpha chain belonging to basement membrane collagen IV by cDNA isolation under low stringency conditions. Isolation of overlapping clones and the technique of 5' rapid amplification of cDNA ends enabled us to derive the primary structure of the entire polypeptide. The deduced collagen polypeptide contained 1678 amino acid residues, including a 21-residue signal peptide, a 24-residue amino-terminal NC domain, a central 1405-residue collagenous (COL1) domain, and a 228-residue carboxyl-terminal NC1 domain. We have designated this newly found alpha chain as the alpha 6(IV) chain. The gene was mapped to chromosome Xq22 by in situ hybridization of metaphase lymphocytes. This is the same region of chromosome X where the gene coding for the alpha 5(IV) collagen chain (COL4A5) resides. Mutations in COL4A5 have been characterized in more than 50 patients with Alport syndrome. However, some of the X-linked cases of Alport syndrome are not apparently caused by COL4A5 mutations. The gene we describe in this paper therefore seems to be a candidate for mutations in this group of Alport syndrome patients.

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  • Chloroplast ATPase in Acetabularia acetabulum: purification and characterization of chloroplast F1-ATPase. 査読 国際誌

    S Satoh, C Moritani, T Ohhashi, K Konishi, M Ikeda

    Bioscience, biotechnology, and biochemistry   58 ( 3 )   521 - 5   1994年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    ATPases were isolated from chloroplasts of the unicellular marine alga Acetabularia acetabulum. Two preparations of ATPase, a chloroplast-enriched fraction and an alpha beta gamma-complex were compared. The alpha beta gamma-complex was released into an EDTA solution and purified by anion-exchange chromatography, hydrophobic chromatography, and gel permeation chromatography. The subunit composition of this enzyme appeared to be 52-53 (alpha), 51 (beta), and 40 (gamma) kDa from SDS-PAGE. ATPase activity was enriched about 260-fold to a specific activity of approximate 4.1 U.mg protein-1. The catalytic properties of the alpha beta gamma-complex were as follows: pH optimum at 7.5; substrate specificity, ATP > ITP, GTP > UTP = CTP (Km for ATP 0.2 mM); divalent cation requirement, Mg2+ = Mn2+ = Co2+ > Zn2+ > Ni2+ > Ca2+; ATPase activity was inhibited by monovalent anions (NO3-, SCN-), while monovalent cations had neither inhibitory nor stimulatory effect. Orthovanadate had no inhibitory effect on the enzyme activity of alpha beta gamma-complex. Azide was the most effective inhibitor of the alpha beta gamma-complex. N-Terminal amino acid sequences of the alpha and beta subunits were not obtained and appeared to be blocked. The gamma subunit gave a sequence of AGLKEMKD-XIGSVXNTKKI, which showed 60% similarity to the gamma subunits of spinach and Chlamydomonas reinhardtii CF1-ATPase and EF1-ATPase.

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  • Isolation and characterization of human cDNAs and genomic DNAs encoding alpha-4(IV) and alpha-6(IV) chains reveal the presence of a distinct subclass of collagen IV genes. 査読 国際誌

    M Sugimoto, T Oohashi, M G Mattei, A Fukutomi, N Kashihara, N Matsuo, H Yoshioka, Y Ninomiya

    Contributions to nephrology   107   29 - 35   1994年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • cDNA isolation and partial gene structure of the human alpha 4(IV) collagen chain. 査読 国際誌

    M Sugimoto, T Oohashi, H Yoshioka, N Matsuo, Y Ninomiya

    FEBS letters   330 ( 2 )   122 - 8   1993年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A novel collagen IV chain, alpha 4(IV), has recently been identified in basement membranes. We describe part of the primary structure of the human alpha 4(IV) polypeptide for the first time, which has been determined by cloning and sequencing of cDNAs encoding 241 amino acid residues of the COL domain and 231 residues of the NC1 domain. We also characterized a genomic DNA fragment containing 4 exons coding for the entire NC1 domain. Among five known alpha chains of collagen IV, the alpha 4(IV) chain is distinct from the other four chains. However, it is more similar to the alpha 2(IV) chain than to the alpha 1(IV), alpha 3(IV) and alpha 5(IV) chains in terms of amino acid sequence homology, domain structure of polypeptides and exon/intron structure of the genes, suggesting the presence of two phylogenetically distinct subclasses of collagen IV alpha chains; one composed of alpha 2 and alpha 4 chains and the other of alpha 1, alpha 3 and alpha 5 chains.

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  • Improvement of reconstitution of the Cl--translocating ATPase isolated from Acetabularia acetabulum into liposomes and several anion pump characteristics 査読

    Toshitaka Ohhashi, Takashi Katsu, Mikiko Ikeda

    BBA - Biomembranes   1106 ( 1 )   165 - 170   1992年4月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The improved reconstitution of the Mono Q-III fraction, a Cl--translocating ATPase, isolated from Acetabularia acetabulum (Ikeda et al. (1990) Biochemistry 29, 2057-2065) into liposomes rendered transport properties of this enzyme clear. The liposomes were prepared by the reversed-phase method using egg lecithin and cholesterol in a molar ration of 2:1 and the purified ATPase was incorporated into the liposomes by a dialysis for 3 h. About 80% of the ATPase was incorporated into the liposomes. The weight ratio of the enzyme to lipid was 1:400-600. A sigmoid curve was obtained when the Cl--transport activity of the enzyme was plotted against Cl- concentration. Hill's plot afforded a half-subsrate concentration [S]0.5 of 45 mM and a Hill's coefficient n of 2.33. Effects of Br- and F- on the Cl--transport were also examined in the reconstituted system, both halide ions decrease the 36Cl- efflux significantly. These kinetic data are in good agreement with the electrophysiological data presented by Tittor et al. (1983) J. Membr. Biol. 75, 129-139). © 1992.

    DOI: 10.1016/0005-2736(92)90235-E

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  • Improvement of reconstitution of the Cl(-)-translocating ATPase isolated from Acetabularia acetabulum into liposomes and several anion pump characteristics. 査読 国際誌

    T Ohhashi, T Katsu, M Ikeda

    Biochimica et biophysica acta   1106 ( 1 )   165 - 70   1992年4月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The improved reconstitution of the Mono Q-III fraction, a Cl(-)-translocating ATPase, isolated from Acetabularia acetabulum (Ikeda et al. (1990) Biochemistry 29, 2057-2065) into liposomes rendered transport properties of this enzyme clear. The liposomes were prepared by the reversed-phase method using egg lecithin and cholesterol in a molar ratio of 2:1 and the purified ATPase was incorporated into the liposomes by a dialysis for 3 h. About 80% of the ATPase was incorporated into the liposomes. The weight ratio of the enzyme to lipid was 1:400-600. A sigmoid curve was obtained when the Cl(-)-transport activity of the enzyme was plotted against Cl- concentration. Hill's plot afforded a half-substrate concentration [S]0.5 of 45 mM and a Hill's coefficient n of 2.33. Effects of Br- and F- on the Cl(-)-transport were also examined in the reconstituted system, both halide ions decreased the 36Cl- efflux significantly. These kinetic data are in good agreement with the electrophysiological data presented by Tittor et al. ((1983) J. Membr. Biol. 75, 129-139).

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  • Preparative high-yield electroelution of proteins after separation by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and its application to analysis of amino acid sequences and to raise antibodies. 査読 国際誌

    T Ohhashi, C Moritani, H Andoh, S Satoh, S Ohmori, F Lottspeich, M Ikeda

    Journal of chromatography   585 ( 1 )   153 - 9   1991年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A method for the preparative high-yield electroelution of proteins from sodium dodecyl sulphate (SDS) polyacrylamide gel strips was established. The method consisted of SDS-polyacrylamide gel electrophoresis, detection of proteins with sodium acetate and electrophoretic elution at 200 V for 3 h by utilizing a horizontal flat-bed gel electrophoresis apparatus. Standard proteins with molecular masses of 14-66 kilodalton (cytochrome c, aldolase, ovalbumin and bovine serum albumin) were recovered with an average yield of 73.6 +/- 2.3%. A membrane-bound protein, rat skeletal muscle Ca(2+)-ATPase (100 kilodalton) was also well recovered (over 60%). This method was applicable to the purification of proteins required for N-terminal amino acid sequencing and to raise antibodies.

    DOI: 10.1016/0021-9673(91)85069-R

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  • Characterization of fibroblast-derived prolidase. The presence of two forms of prolidase. 査読 国際誌

    T Oono, H Yasutomi, T Ohhashi, H Kodama, J Arata

    Journal of dermatological science   1 ( 5 )   319 - 23   1990年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Crude enzyme solutions of prolidase were extracted from cultured human skin fibroblasts derived from control and prolidase-deficient sisters. Two forms of prolidases (prolidase-I and II) were partially purified by high performance liquid chromatography equipped with an ion exchange column. On gel filtration, the relative molecular weights of prolidase-I and II were estimated to be MW = 105,000 and 151,000, respectively. The substrate specificity of partially purified prolidase-I and II in control fibroblasts was estimated against Gly-Pro, Ala-Pro, Met-Pro. Each form of prolidase differed in its substrate specificity. In prolidase-deficient sisters, the elder with typical clinical manifestations and the younger with only slight clinical manifestations, the activity of prolidase-I was absent. However, the activity of prolidase-II was sufficiently present in both sisters. The substrate specificity of prolidase-II in the patients was similar to that of control. No difference in substrate specificity was found between these two patients.

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  • Characterization of prolidase I and II from erythrocytes of a control, a patient with prolidase deficiency and her mother. 査読 国際誌

    T Ohhashi, T Ohno, J Arata, K Sugahara, H Kodama

    Clinica chimica acta; international journal of clinical chemistry   187 ( 1 )   1 - 9   1990年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Prolidase I (EC 3.4.13.9) was purified to homogeneity from the erythrocytes of a normal human (control) and the patient's mother, and prolidase II from erythrocytes of a control and the patient's mother, and prolidase from the patient's erythrocytes was also highly purified. The various properties of the patient's prolidase were compared to those of prolidase from a control and the patient's mother. Prolidase I from a control and the patient's mother had a molecular weight of about 112,000, and was composed of two subunits with an identical molecular weight of 56,000. The Km values for Gly-Pro of the control's and the patient's mother's prolidase I were 2.90 +/- 0.22 and 2.88 +/- 0.27 mM, but the Vmax values for Gly-Pro of the mother's enzyme was reduced about 30% compared to that of control enzymes (mother: 6.02 units/mg protein, control: 22.21 units/mg protein). Isoionic points of these enzymes by chromatofocusing were pH 4.6 approximately 4.7. Prolidase II from the control and the patient's mother, and the patient's prolidase had a molecular weight of about 185,000, and was composed of two subunits with an identical molecular weight of 95,000. The Km and Vmax values for various substrates of prolidase II from a control and the patient's mother, and the patient's prolidase were almost the same.

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  • Characteristics and partial purification of prolidase and prolinase from leukocytes of a normal human and a patient with prolidase deficiency. 査読 国際誌

    H Kodama, T Ohhashi, C Ohba, T Ohno, J Arata, I Kubonishi, I Miyoshi

    Clinica chimica acta; international journal of clinical chemistry   180 ( 1 )   65 - 72   1989年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • CHARACTERISTICS OF PARTIALLY PURIFIED PROLIDASE FROM ERYTHROCYTES OF NORMAL INDIVIDUALS, OF 2 PATIENTS WITH PROLIDASE DEFICIENCY, AND OF THE PATIENTS MOTHER 査読

    T OHHASHI, T OHNO, J ARATA, H KODAMA

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   5 ( 3 )   183 - 192   1988年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JOURNAL CLINICAL BIOCHEMISTRY & NUTRITION  

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  • Biochemical investigations on prolidase and prolinase in erythrocytes from patients with prolidase deficiency. 査読 国際誌

    H Kodama, H Mikasa, T Ohhashi, T Ohno, J Arata

    Clinica chimica acta; international journal of clinical chemistry   173 ( 3 )   317 - 23   1988年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Biochemical studies on prolidase in sera from control, patients with prolidase deficiency and their mother. 査読 国際誌

    T Ohhashi, T Ohno, J Arata, H Kodama

    Journal of inherited metabolic disease   11 ( 2 )   166 - 73   1988年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Prolidase activity in serum from normal subjects and the mother of two patients was readily detected without adding Mn2+ to the assay, and the activity was increased by addition of Mn2+ to the assay or preincubation with Mn2+. However, the activity in serum from patients with prolidase deficiency against gly-pro, leu-pro and val-pro could not be detected irrespective of Mn2+ conditions and activity against met-pro, ala-pro and phe-pro also showed a marked reduction compared to controls. Both normal and the patients' mother's prolidase activity against gly-pro was reduced about 20% at 60 degrees C compared to the activity at 37 degrees C, but the addition of Mn2+ at 55 degrees C increased the activity about 1.8-fold, whereas prolidase activity of patients could not be increased by the addition of Mn2+. The addition of Co2+ increased prolidase activity in serum from control and the patients' mother but did not increase the heat stability. These results indicate that prolidase in serum from patients with prolidase deficiency is altered rather than markedly reduced in amount.

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  • コラーゲン遺伝子の構造機能および発現調節(共著)

    新生化学実験講座 第10巻 血管内皮と平滑筋 

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MISC

  • 変形性関節症関連microRNAの検索並びに解析

    大月 孝志, オメル・ファルク・ハティポール, 品岡 玲, メフメット・ゼイネル・チレッキ, 西村 拓人, 浅野 恵一, 稲垣 純子, 大橋 俊孝, 西田 圭一郎, 岡田 保典, 廣畑 聡

    日本結合組織学会学術大会プログラム・抄録集   50回   111 - 111   2018年6月

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    記述言語:日本語   出版者・発行元:日本結合組織学会  

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  • The hyaluronan and proteoglycan link proteins: organizers of the brain ecm and key molecules for neuronal function and plasticity

    T. Oohashi, T. Sakaba

    JOURNAL OF NEUROCHEMISTRY   142   53 - 53   2017年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:WILEY  

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  • がん微小環境の実体 がん微小環境におけるバーシカン分解酵素ADAMTSの局在と血管新生におけるバーシカンの意義

    浅野 恵一, 廣畑 聡, 大月 孝志, オメル・ファルク・ハティポール, 稲垣 純子, 大橋 俊孝

    日本結合組織学会学術大会プログラム・抄録集   49回   56 - 56   2017年6月

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    記述言語:日本語   出版者・発行元:日本結合組織学会  

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  • 変形性関節症へのヒアルロン酸投与、いつ投与すべきか? 動物モデルからの知見

    大月 孝志, 品岡 玲, 熊岸 加苗, 河野 真優美, 篠原 真歩, 浅野 恵一, 稲垣 純子, 大橋 俊孝, 西田 圭一郎, 廣畑 聡

    日本結合組織学会学術大会プログラム・抄録集   48回   60 - 60   2016年6月

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    記述言語:日本語   出版者・発行元:日本結合組織学会  

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  • 伸展刺激の強度による細胞外マトリックスタンパクおよびマトリックス分解酵素発現への影響

    大月 孝志, 金道 幸子, 長谷川 みさ, 稲垣 純子, 浅野 恵一, 障子 友理, 熊岸 加苗, 西田 圭一郎, 大橋 俊孝, 廣畑 聡

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [2P0078] - [2P0078]   2015年12月

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    記述言語:日本語   出版者・発行元:(公社)日本生化学会  

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  • メカニカルストレスが軟骨様細胞の細胞外マトリックス及びマトリックス分解酵素のmRNA発現へ示す効果の検討

    大月 孝志, 金道 幸子, 長谷川 みさ, 平田 彩, 川地 輝幸, 浅野 恵一, 稲垣 純子, 障子 友理, 熊岸 加苗, 西田 圭一郎, 大橋 俊孝, 廣畑 聡

    日本結合組織学会学術大会プログラム・抄録集   47回   134 - 134   2015年5月

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    記述言語:日本語   出版者・発行元:日本結合組織学会  

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  • 関節軟骨造影剤を用いた関節軟骨プロテオグリカンの評価

    大橋 俊孝, 加来田 博貴, 芳谷 学, 山田 翔也, 大月 孝志, 廣畑 聡, 二宮 善文, 西田 圭一郎

    日本結合組織学会学術大会プログラム・抄録集   47回   97 - 97   2015年5月

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    記述言語:日本語   出版者・発行元:日本結合組織学会  

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  • ADAMTSによるバーシカン分解と腫瘍内血管新生の関連

    浅野 恵一, 稲垣 純子, 障子 友理, Hofmann Matthias, 大月 孝志, 廣畑 聡, 大橋 俊孝

    日本結合組織学会学術大会プログラム・抄録集   47回   114 - 114   2015年5月

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    記述言語:日本語   出版者・発行元:日本結合組織学会  

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  • 新規X線造影剤による変形性膝関節症ラット関節軟骨の高解像度マイクロCT造影

    大橋 俊孝, 加来田 博貴, 芳谷 学, 大月 孝志, 大野 充昭, 山田 翔也, 前原 亜美, 廣畑 聡, 西田 圭一郎, 窪木 拓男, 二宮 善文

    日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集   46回・61回   106 - 106   2014年6月

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    記述言語:日本語   出版者・発行元:日本結合組織学会・マトリックス研究会  

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  • Structurally simple cartilage probes constructed with epsilon-lysine oligomers targeting chondroitin sulfates

    Hiroki Kakuta, Manabu Hagaya, Shoya Yamada, Fuminori Ohsawa, Ami Maehara, Aki Yoshida, Mitsuaki Ono, Ryuichi Nakahara, Keiichiro Nishida, Toshitaka Oohashi

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   246   2013年9月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER CHEMICAL SOC  

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  • まれなEGFR変異を有する肺腺癌の1例

    木村 紘爾, 山根 正修, 豊岡 伸一, 古川 公之, 大橋 俊孝, 山本 寛斉, 宗 淳一, 大藤 剛宏, 三好 新一郎

    日本呼吸器外科学会雑誌   27 ( 3 )   P04 - 06   2013年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • レチノイドX受容体パーシャルアゴニストNEt-4IBの創出と薬効・副作用評価

    加来田 博貴, 川田 浩平, 中山 真理子, 山田 翔也, 小林 俊貴, 古沢 優貴, 大橋 俊孝, 田井 章博, 矢間 太

    ビタミン   87 ( 4 )   254 - 254   2013年4月

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    記述言語:日本語   出版者・発行元:(公社)日本ビタミン学会  

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  • Discovery of a novel benzotriazole-type retinoid X receptor partial-agonist decreasing plasma glucose level in type-2 diabetes mellitus with decreased side effects

    Hiroki Kakuta, Nobumasa Yakushiji, Fuminori Ohsawa, Shoya Yamada, Mariko Nakayama, Kohei Kawata, Yui Ohta, Chisa Fujiwara, Toshitaka Oohashi, Makoto Makishima, Akihiro Tai, Hiroyuki Yasui, Yutaka Yoshikawa

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2012-946

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  • 関節軟骨に特異的に結合するX線造影化イメージングプローブの創出研究

    芳谷 学, 大澤 史宜, 加来田 博貴, 大橋 俊孝

    日本薬学会年会要旨集   132年会 ( 2 )   271 - 271   2012年3月

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    記述言語:日本語   出版者・発行元:(公社)日本薬学会  

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  • アルポート症候群

    大橋俊孝, 喜多村真治

    別冊 日本臨床 先天代謝異常症候群(下)   20   704 - 707   2012年

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  • ADAMTS1は腫瘍壊死因子刺激下の内皮細胞におけるアポトーシスに関連する

    オメル・ファルク・ハティポール, 小比賀 真就, 廣畑 聡, 小川 弘子, メフメット・ゼェイネル・チレッキ, 稲垣 純子, 大月 孝志, 石井 裕子, 幡中 邦彦, 草地 省蔵, 米澤 朋子, 大橋 俊孝, 二宮 善文

    日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集   43回・58回   104 - 104   2011年5月

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    記述言語:日本語   出版者・発行元:日本結合組織学会・マトリックス研究会  

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  • ADAMTS1は血管新生を阻害しアポトーシスを抑制する

    廣畑 聡, 小比賀 真就, オメル・ファルク・ハティポール, 小川 弘子, メフメット・ゼェイネル・チレッキ, 稲垣 純子, 大月 孝志, 石井 裕子, 幡中 邦彦, 草地 省蔵, 米澤 朋子, 大橋 俊孝, 二宮 善文

    日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集   43回・58回   103 - 103   2011年5月

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    記述言語:日本語   出版者・発行元:日本結合組織学会・マトリックス研究会  

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  • 関節軟骨のバイオイメージング

    大橋俊孝, 西田圭一郎

    Clin Calcium   21 ( 6 )   100 - 106   2011年

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  • 軟骨組織のバイオイメージング

    大橋俊孝

    臨床整形外科   45 ( 5 )   454 - 457   2010年

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  • Brevican organizes hyaluronan-binding extracellular assemblies distinctively at the large diameter nodes of Ranvier in the CNS

    Yoko Bekku, Yoshifumi Ninomiya, Toshitaka Oohashi

    NEUROSCIENCE RESEARCH   65   S73 - S73   2009年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER IRELAND LTD  

    DOI: 10.1016/j.neures.2009.09.254

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  • 軟骨のバイオイメージング

    大橋俊孝

    関節外科   2009年

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  • Bral1, brain-specific link protein, is essential for stabilizing extracellular matrix at the node of Ranvier in the CNS

    Yoko Bekku, Yoshifumi Ninomiya, Toshitaka Oohashi

    NEUROSCIENCE RESEARCH   58   S40 - S40   2007年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER IRELAND LTD  

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  • Alport症候群に合併した食道びまん性平滑筋腫症の1例

    西江学, 猶本良夫, 白川靖博, 山辻知樹, 浅海信也, 田中紀章, 大原信哉, 内藤一郎, 大橋俊孝, 二宮善文

    消化器外科   2005年

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  • 5) Identification and Characterization of a novel rat link protein gene : Lp3/Hapln3(第84回日本循環器学会中国地方会)

    小川 弘子, 廣畑 聡, 三好 亨, 村上 充, 白鳥 康史, 大橋 俊孝, 二宮 善文, 草地 省蔵, 佐田 政隆

    Circulation journal : official journal of the Japanese Circulation Society   68 ( 0 )   2004年10月

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    記述言語:日本語   出版者・発行元:社団法人日本循環器学会  

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  • 新規の脳特異的ヒアルロン酸-プロテオグリカン結合蛋白質: Bral1, Bral2

    大橋俊孝, 別宮洋子, 二宮善文

    蛋白質核酸酵素   49,15,2354-2361   2004年

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  • バーシカンV2・脳リンクプロテイン会合体の中枢神経ランビエ絞輪での発現とその機能

    大橋俊孝, 別宮洋子, 平川聡史, 李勝天, 松井秀樹, 二宮善文

    Connective tissue   34 ( 1 )   2002年4月

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    出版者・発行元:日本結合組織学会  

    ヒアルロン酸(HA)結合型の細胞外マトリックス及び細胞膜蛋白質は、HA結合ドメインとして機能するリンクモジュールを持つ。そのうちHA結合型コンドロイチン硫酸プロテオグリカン(CSPG)はレクティカンプロテオグリカンと呼ばれる。レクティカンファミリーは、Aggrecan,Versican,Neurocan,Brevicanの4遺伝子からなり、通常HA/Lectican/Link Proteinの会合体として機能すると考えられる。我々は最近中枢神経特異的リンクプロテイン遺伝子Bral1をクローニングし、Bral1は中枢神経特異的プロテオグリカンversican V2とランビエ絞輪にcolocalizeすることを報告した。ランビエ絞輪は神経の活動電位の発生と跳躍伝導に重要であることが知られている。我々はBral1が絞輪の細胞外部において、ヒアルロン酸にversicanコアプロテインを固定し、その結果versicanコアプロテインに結合している多数のグリコサミノグリカン鎖をランビエ絞輪に蓄積させ陰性に荷電させているのではないかと予想している。即ち、電位依存性NaイオンチャンネルによりNaイオンが細胞内外に出入りし活動電位を生ずるための細胞外環境を整えている役割をしていると考えている。我々は絞輪における「細胞外Naイオンプール」という仮説をたて、Bral1がその中心的な分子であるのでは...

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  • 成熟した脳・脊髄のプロテオグリカン

    村上宅郎, 大塚愛二, 大橋俊孝, 二宮善文

    細胞   33,8,44-47   2001年

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  • Alport症候群(共著)

    百田龍輔, 大橋俊孝

    日本臨床 別冊 先天代謝異常症候群(下巻)   522 - 525   1998年

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  • Alternative transcripts are also found in the human COL4A4 gene expression.

    R Momota, T Oohashi, M Sugimito, Naito, I, Y Sado, Y Ninomiya

    MATRIX BIOLOGY   15 ( 3 )   171 - 172   1996年9月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:GUSTAV FISCHER VERLAG  

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  • PARTIAL GENE STRUCTURE OF THE HUMAN ALPHA-4(IV) COLLAGEN CHAIN

    M SUGIMOTO, T OOHASHI, H YOSHIOKA, N MATSUO, Y NINOMIYA

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE   34 ( 4 )   1203 - 1203   1993年3月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT-RAVEN PUBL  

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講演・口頭発表等

  • Analysis of the perineuronal net formation in the mouse medial nucleus of the trapezoid body (MNTB)

    International Symposium on Glyco-Neuroscience  2014年 

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  • リジンオリゴマーからなる関節軟骨特異的X線プローブの創出

    第27回日本軟骨代謝学会  2014年 

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  • 成熟脳のペリニューロナルECMの形成と機能について

    第21回 プロテオグリカンフォーラム  2014年 

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  • Role of nodal protroglycan-enriched ECM on formation and maintenance of CNS node of Ranvier

    8th International Conference on Proteoglycans  2013年 

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  • 幹細胞癌におけるXV型コラーゲン発現とその臨床応用

    第45回日本結合組織学会学術大会  2013年 

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  • 中枢神経ランビエ絞輪の形成・維持への細胞外マトリックス分子の関与

    第45回日本結合組織学会学術大会  2013年 

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  • 炎症標的化金コロイド内包リポソームのリウマチ関節炎症部位への集積の光学・電子顕微鏡観察

    第26回日本軟骨代謝学会  2013年 

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  • 神経細胞局所のヒアルロン酸結合性細胞外マトリックスの機能-ミッシングリンク-

    第3回 新潟プロテオグリカン研究会  2013年 

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  • マウス聴覚系内側台形体核(MNTB)におけるペリニューロナルネット形成

    第36回日本分子生物学会年会  2013年 

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  • Analysis of the perineuronal net formation in the mouse medial nucleus of the trapezoid body (MNTB)

    9th Pan Pasific Connective Tissue Society Symposium  2013年 

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  • バイオイメージングを用いた関節軟骨の評価

    第40回日本臨床バイオメカニクス学会  2013年 

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  • Changes of the extracellular matrix and extracellular space diffusion parameters in the thalamus of aged Bral2 deficient mice

    SfN 2013  2013年 

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  • Structurally simple cartilage probes constructed with epsilon-lysine oligomers targeting chondroitin sulfates

    8th International Conference on Proteoglycans  2013年 

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  • Bral2はbrevicanのペリニューロナルネットの構造形成に重要である

    第43回日本結合組織学会  2011年 

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  • 関節軟骨のバイオイメージング

    第33回生体膜と薬物シンポジウム  2011年 

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  • THE ION-DIFFUSION BARRIER MODEL AT THE NODE OF RANVIER: FROM THE EXTRACELLULAR ION DIFFUSION ANALYSIS IN BRAL1-DEFICIENT MICE

    7th International Conference on Proteoglycans  2011年 

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  • Bral2はbrevicanのペリニューロナルネットの構造形成に重要である

    第84回日本生化学会大会  2011年 

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  • Neurocan-GFP, a novel probe for hyaluronan in atherosclerotic plaques

    大43回日本動脈硬化学会総会・学術集会  2011年 

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  • 半月板細胞におけるII型コラーゲンの発現制御-メカニカルストレスによるエピジェネティックな転写制御

    第43回日本結合組織学会  2011年 

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  • 炎症標的化金コロイド内包リポソームのリウマチ関節炎症部位への集積

    第43回日本結合組織学会  2011年 

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  • The nodal ECM barrier model in the CNS: From an extracellular ion diffusion anaslsis in Bral1-deficient mice

    Ninth Biennial Satellite Meeting of the International Society for Neurochemistry on Myeline Biology: Myeline Development, Function and Related Diseases  2009年 

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  • OUMS-27軟骨肉腫細胞または軟骨細胞におけるNFATc1を解したIL-1bによるADAMTS9遺伝子の活性化

    第22回日本軟骨代謝学会  2009年 

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  • 生体構成成分を可視化する

    生体機能制御学講座研究構想シンポジウム  2009年 

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  • THE ION-DIFFUSION BARRIER MODEL AT THE NODE OF RANVIER: FROM THE EXTRACELLULAR ION DIFFUSION ANALYSIS IN BRAL1-DEFICIENT MICE

    IUPS 2009(国際生理学会議)  2009年 

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  • 軟骨組織のバイオイメージング

    第27回日本骨代謝学会学術集会  2009年 

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  • 軟骨基質集積ナノプローブを用いた軟骨組織のバイオイメージング

    第5回北海道結合組織勉強会  2009年 

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  • Optical imaging of mouse articular cartilage using the glycosaminoglycans binding property of fluorescent-labeled octaarginine

    第8回環太平洋結合組織学会  2009年 

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  • Brevican determines specialization of the hyaluronan-binding nodal matrix assemblies at the large diameter nodes of Ranvier in the CNS

    第8回環太平洋結合組織学会  2009年 

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  • 関節軟骨変性疾患の分子標的治療システムの開発

    ナノバイオ標的医療等の新たな医療の創造とその基盤技術研究事業成果報告会  2009年 

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  • 軟骨基質集積ペプチドを用いた軟骨組織のバイオイメージング

    第18回日本バイオイメージング学会  2009年 

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  • The active targeting liposome encapusulated high-density colloidal gold

    11th Liposome Research days conference  2008年 

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  • 新しい軟骨基質結合ペプチドを用いた関節軟骨in vivo蛍光イメージング法の開発

    第40回日本結合組織学会学術集会・第55回日本マトリックス研究会大会合同学術集会  2008年 

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  • 新しい軟骨基質結合ペプチドを用いた関節軟骨in vivo蛍光イメージング法の開発

    第21回日本軟骨代謝学会  2008年 

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  • The inhibition of the ADAMTS9 induced by Interleukin 1b using 11R-VIVIT peptide in OUMS27 Chondrosarcoma cells and in Human Chondrocytes.

    American Society of Matrix Biology  2008年 

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  • Bral1欠損マウスでは脳梁での細胞外イオン拡散が促進される

    北米神経科学会議 2008  2008年 

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  • A 3D Imaging of Mouse Knee Joint Articular Surface by Optical Projection Tomography

    WMIC(World Molecular Imaging Congress) 2008  2008年 

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  • The inhibition of the ADAMTS9 induced by Interleukin 1b using 11R-VIVIT peptide in OUMS27 Chondrosarcoma cells and in Human Chondrocytes.

    第11回 国際リポソーム会議  2008年 

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  • 高密度金コロイド内包標的指向性リポソームの開発

    第40回日本結合組織学会学術集会・第55回日本マトリックス研究会大会合同学術集会  2008年 

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  • シアリルルイスX糖鎖結合リポソームの炎症組織特異的集積性

    第4回北海道結合組織勉強会  2008年 

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  • 軟骨特異的集積ペプチド(CSBP)を用いたin vivo 蛍光イメージングおよびDDS の試み

    第4回北海道結合組織勉強会  2008年 

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  • シアリルルイスX糖鎖結合リポソームのリウマチ関節炎症部位への集積についての組織学的検討

    第40回日本結合組織学会学術集会・第55回日本マトリックス研究会大会合同学術集会  2008年 

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  • 関節炎モデルマウスにおけるシアリルルイスX糖鎖結合リポソームの特異的集積に関する検討

    BMB2008(第31回日本分子生物学会年会・第81回日本生化学会大会合同大会)  2008年 

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  • The inhibition of the ADAMTS9 induced by Interleukin 1b using 11R-VIVIT peptide in OUMS27 Chondrosarcoma cells and in Human Chondrocytes.

    アメリカマトリックス生物学会 年会  2008年 

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  • Deletion of the brain-specific link protein Bral-1 facilitates extracellular diffusion in the mouse corpus callosum.

    SfN 2008  2008年 

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  • ペプチドや核酸などの遺伝子性薬剤を放出するステントの開発

    平成18年度 特別電源所在権科学技術振興事業研究成果発表会  2007年 

     詳細を見る

  • Cellular mechanism for cytokine induction in hyaluronan-stimulated human mononuclear cells.

    Hyaluronan 2007  2007年 

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  • Developmental and transgenic expression of crtl1/hapln1 in zebrafish

    第20回日本軟骨代謝学会  2007年 

     詳細を見る

  • 光投射型断層撮影イメージング技術(OPT)によるマウス関節標本の3D画像解析

    BMB2007  2007年 

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  • The effect of the length of arginine chain on the internalization into the Rat AoSMC.

    アメリカ糖質生物学会(Glycobiology 2007)  2007年 

     詳細を見る

  • Nodal extracellular molecule Bral1 plays a key role in assembling stable extracellular matrices in the CNS

    SfN(Society for Neuroscience)2007  2007年 

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  • Bral1, brain-specific link protein, is essential for stabilizing extracellular matrix at the node of Ranvier in the CNS

    日本神経科学学会Neuro2007  2007年 

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  • Differential expression of ADAMTS1 gene in cancer cell lines.

    第39回日本結合組織学会  2007年 

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  • 光投射型断層撮影イメージング技術(OPT)によるマウス関節標本の3D画像解析

    日本結合組織学会・マトリックス研究会合同大会  2007年 

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  • PTD法を利用した遺伝子性薬剤放出型ステントの開発

    平成17年度 特別電源所在権科学技術振興事業研究成果発表会  2006年 

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  • 脳リンクプロテイン-CSPG複合体の機能制御に関する研究

    特定領域研究第4回公開シンポジウム  2006年 

     詳細を見る

  • Alport-leiomyomatosis症候群1例のIV型コラーゲン遺伝子変異解析および免疫組織化学的解析

    第53回日本マトリックス研究会  2006年 

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  • ADAMTSプロテアーゼのうちADAMTS-4が心筋梗塞早期に誘導され、梗塞辺縁部でバーシカンを分解する

    日本分子生物学会 2006 フォーラム  2006年 

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  • Developmental and transgenic expression of crtl1/hapln1 in zebrafish

    American Society of Matrix Biology  2006年 

     詳細を見る

  • 脳リンクプロテインによる脳実質ヒアルロン酸‐CSPG複合体の機能制御に関する研究 (Brain link proteins: The role in the formation and function of the chondroitin sulfate proteoglycan complexes in the brain.)

    文部科学省科学研究費特定領域研究「糖鎖によるタンパク質と分子複合体の調節機能」第4回夏期シンポジウム  2006年 

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  • Adenoviral gene therapy using NC1 domain of collagen IV suppresses vessel formation and tumor growth

    欧州結合組織連合学術集会(FECTS)  2006年 

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  • Aggrecanase member of ADAMTS proteases are differently regulated in ventricular remodeling

    20th IUBMB International Congress of Biochemistry and Molecular Biology  2006年 

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  • Bral1, brain-specific link protein, is essential for stabilizing extracellular matrix at the node of Ranvier in the CNS.

    20th IUBMB International Congress of Biochemistry and Molecular Biology  2006年 

     詳細を見る

  • Hyaluronan induced cytokine expression in peripheral blood mononuclear cells

    Glycomatrix, Extracellular Glycomatrix in Health and Disease  2006年 

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  • Tumor-specific expression of the noncollagenous domain-1 of collagen IV suppresses endothelial tube formation and tumor growth in mice.

    第38回日本結合組織学会学術大会  2006年 

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  • PTD法を利用した遺伝子性薬剤放出ステントの開発

    岡山県産業振興財団 医療・福祉・健康ミクロものづくり共同研究事業成果発表会  2006年 

     詳細を見る

  • Alport-leiomyomatosis症候群1例のIV型コラーゲン遺伝子解析および免疫組織化学的解析

    第52回日本マトリックス研究会  2005年 

     詳細を見る

  • 脳リンクプロテイン-CSPG複合体の機能制御に関する研究

    特定領域(グライコ)研究第3回夏期シンポジウム  2005年 

     詳細を見る

  • GM-CSF刺激によりヒト末梢血単核球におけるバーシカンの発現は増加する

    日本結合組織学会  2005年 

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  • Analysis of neurocan/link protein interactions and distribution of hyaluronan with alkaline phosphatase and GFP fusion proteins.

    The 19th FECTS meeting  2004年 

     詳細を見る

  • Idenstification and Characterization of a novel rat link protein: Lp3/Hapln3

    第84回日本循環器学会中国地方会  2004年 

     詳細を見る

  • ヒト大腸がん細胞におけるIV型コラーゲンα鎖の動態とその遺伝子発現の解析

    第48回マトリックス研究会  2004年 

     詳細を見る

  • Characterization of dermacan, a novel zebrafish lectican gene, expressed in dermal bones.

    第48回マトリックス研究会  2004年 

     詳細を見る

  • Lp3/Hapln3, A novel Rat Link Protein is Upregulated in Pressure Overload Heart.

    第68回日本循環器学会  2004年 

     詳細を見る

  • Dynamic induction od ADAMTS1 gene in the early phase of acute myocardial infarction.

    2nd national meeting of the American Society for matrix Biology  2004年 

     詳細を見る

  • Lp3/Hapln3, a novel llink protein which colocalize with versican and is coordinately upregulated by PDGF.

    2nd national meeting of the American Society for matrix Biology  2004年 

     詳細を見る

  • 軟骨細胞におけるIL-1βとTNF-αによるアグリカナーゼ遺伝子発現誘導の多様性

    第77回日本生化学会  2004年 

     詳細を見る

  • 血管障害モデルにおけるヒアルロン酸結合リンクプロテインLp3/Hapln3の発現解析

    第77回日本生化学会  2004年 

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  • 中枢神経系軸索ランビエ絞輪における脳特異的リンクプロテイン1, Bral1/Hapln2の機能解析

    Neuro2004  2004年 

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  • 新規マトリックスプロテインLp3/Hapln3:クローニングおよびその発現解析

    第84回日本動脈硬化学会  2004年 

     詳細を見る

  • Expression of Versican and its Degrading Enzymes in Acute Myocardial Infarction

    5th Pan-Pacific Connective Tissue Societies Symposium  2003年 

     詳細を見る

  • Brain link proteins: New insights for hyaluronan-binding proteoglycan in the brain

    5th Pan-Pacific Connective Tissue Societies Symposium  2003年 

     詳細を見る

  • Dermacan: a novel zebrafish lectican gene expressed in dermal bones and required for dermal bone formation

    第26回日本分子生物学会年会  2003年 

     詳細を見る

  • Identification of the new rat Vascular link protein, Vasl1

    日本生化学会  2003年 

     詳細を見る

  • Brain link proteins: new insights for hyaluronan-binding proteoglycans in the brain

    Hyaluronan 2003  2003年 

     詳細を見る

  • Zebrafish dermacan, A new member of the hyaluronan-binding proteoglycan family, lectican

    3rd International conferenca on proteoglycans: Pathobiology of proteoglycans  2003年 

     詳細を見る

  • 脳リンクプロテインによる脳実質コンドロイチン硫酸プロテオグリカン複合体機能制御に関する研究

    科学研究費特定領域研究、糖鎖によるタンパク質と分子複合体の機能調節、 第一回夏期シンポジウム  2003年 

     詳細を見る

  • Perineuronal nets: 分子生物学的手法による新展開

    日本顕微鏡学会、第59回学術講演会  2003年 

     詳細を見る

  • 新規脳リンクプロテインBral1の中枢神経ランビエ絞輪における発現と機能

    プロテオグリカンフォーラム、神経組織プロテオグリカン研究会合同会  2002年 

     詳細を見る

  • 新規脳リンクプロテインBral2のクローニングと発現

    第75回日本生化学会  2002年 

     詳細を見る

  • Expression and possible function of versican/Bral1 complex at the nodes of Ranvier in the CNS.

    第45回日本神経化学会  2002年 

     詳細を見る

  • バーシカンV2・脳リンクプロテイン会合体の中枢神経ランビエ絞輪での発現とその機能

    第34回日本結合組織学会・第49回マトリックス研究会合同会議  2002年 

     詳細を見る

  • 新規脳リンクプロテインBral1の中枢神経ランビエ絞輪における発現と機能

    第8回プロテオグリカンフォーラム、第2回神経組織プロテオグリカン研究会合同会  2002年 

     詳細を見る

  • 脳神経系におけるリンクモジュール遺伝子の発現

    日本マトリックス研究会  2001年 

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  • 脳リンクプロテイン(Bral1)はランビエ絞輪で「細胞外Naイオンプール」の中心的役割をはたしているか?

    日本生化学会  2001年 

     詳細を見る

  • 脳特異的リンクプロテイン(Bral1)の発現パターンの解析

    日本神経科学会 Neuro2001  2001年 

     詳細を見る

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Works(作品等)

  • BioJapan2013

    2013年

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  • JST 六大学合同新技術説明会

    2013年

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  • 米国ライセンシング協会展示発表

    2013年

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  • Licencing Executives Society 2013

    2013年

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受賞

  • Best Oral Presentation Award

    2018年11月   PPCTSS (Pan-Pasific Connective Tissue Society Symposium)  

     詳細を見る

  • 日本結合組織学会優秀演題賞

    2011年  

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    受賞国:日本国

    researchmap

  • 日本バイオイメージング学会 ベストイメージング賞

    2009年  

     詳細を見る

    受賞国:日本国

    researchmap

  • 結城賞(岡山医学会)

    1995年  

     詳細を見る

    受賞国:日本国

    researchmap

 

担当授業科目

  • 人体構成学I(演習・実習) (2021年度) 特別  - その他

  • 人体構成学I(講義・演習) (2021年度) 特別  - その他

  • 人体構成学II(演習・実習) (2021年度) 特別  - その他

  • 人体構成学II(講義・演習) (2021年度) 特別  - その他

  • 分子医化学 (2021年度) 特別  - その他

  • 分子医化学実習 (2021年度) 特別  - その他

  • 分子医化学I(演習・実習) (2021年度) 特別  - その他

  • 分子医化学I(講義・演習) (2021年度) 特別  - その他

  • 分子医化学II(演習・実習) (2021年度) 特別  - その他

  • 分子医化学II(講義・演習) (2021年度) 特別  - その他

  • 分子医科学演習 (2021年度) 特別  - その他

  • 医学セミナー(テュートリアル) (2021年度) 第1学期  - 火2~3

  • 医学セミナー(チュートリアル) (2021年度) 第1学期  - 火2~3

  • 医学研究インターンシップ (2021年度) 特別  - その他

  • 医歯科学概論 (2021年度) 集中  - その他

  • 医科学実習Ⅰ (2021年度) 特別  - その他

  • 医科学実習Ⅱ (2021年度) 特別  - その他

  • 基礎病態演習 (2021年度) 特別  - その他

  • 歯科学実習Ⅰ (2021年度) 特別  - その他

  • 歯科学実習Ⅱ (2021年度) 特別  - その他

  • 生化学 (2021年度) 集中  - その他

  • 生化学・分子医化学実習 (2021年度) 特別  - その他

  • 分子医化学 (2020年度) 特別  - その他

  • 分子医化学I(演習・実習) (2020年度) 特別  - その他

  • 分子医化学I(講義・演習) (2020年度) 特別  - その他

  • 分子医化学II(演習・実習) (2020年度) 特別  - その他

  • 分子医化学II(講義・演習) (2020年度) 特別  - その他

  • 分子医科学演習 (2020年度) 通年  - その他

  • 分子医科学総論 (2020年度) 通年  - その他

  • 医学セミナー(テュートリアル) (2020年度) 第1学期  - 火2,火3

  • 医学セミナー(チュートリアル) (2020年度) 第1学期  - 火2,火3

  • 医学教育実習 (2020年度) 特別  - その他

  • 医学研究インターンシップ (2020年度) 特別  - その他

  • 医科学実習 (2020年度) 特別  - その他

  • 医科学実習Ⅰ (2020年度) 通年  - その他

  • 医科学実習Ⅱ (2020年度) 通年  - その他

  • 医科学演習 (2020年度) 通年  - その他

  • 基礎病態演習 (2020年度) 特別  - その他

  • 生化学 (2020年度) 集中  - その他

  • 生化学・分子医化学実習 (2020年度) 特別  - その他

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