Updated on 2025/10/04

写真a

 
YONEZAWA Tomoko
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Assistant Professor
Position
Assistant Professor
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Research Areas

  • Life Science / Molecular biology

Professional Memberships

 

Papers

  • Optimizing β-TCP with E-rhBMP-2-infused fibrin for vertical bone regeneration in a mouse calvarium model Reviewed

    Kun Zhao, Mitsuaki Ono, Xindi Mu, Ziyi Wang, Shichao Xie, Tomoko Yonezawa, Masahiro Okada, Takuya Matsumoto, Takuo Kuboki, Toshitaka Oohashi

    Regenerative Biomaterials   12   2025.1

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    Publishing type:Research paper (scientific journal)   Publisher:Oxford University Press (OUP)  

    Abstract

    Effective reconstruction of large bone defects, particularly in thickness, remains one of the major challenges in orthopedic and dental fields. We previously produced an Escherichia coli-based industrial-scale GMP-grade recombinant human bone morphogenetic protein-2 (E-rhBMP-2) and showed that the combination of E-rhBMP-2 with beta-tricalcium phosphate (β-TCP/E-rhBMP-2) can effectively promote bone reconstruction. However, the limited mechanical strength and poor morphology retention of β-TCP granules are key points that need optimization to obtain more effective grafts and further expand its clinical applications. Therefore, we combined β-TCP/E-rhBMP-2 with fibrin gel to enhance its mechanical properties and usability for vertical bone regeneration. We investigated the mechanical properties and vertical bone regeneration effects of the materials applied, with or without fibrin containing E-rhBMP-2, in a calvarial defect model in mice. Compression tests were conducted to assess the initial stability of the materials. Scanning electron microscopy and Fourier transform infrared spectroscopy were conducted to characterize the presence of fibrin on the scaffold. After 4 and 12 weeks of implantation, micro-computed tomography and histological and immunofluorescent analyses were performed to assess the morphology and volume of the newly formed bone. The fibrin-containing groups had significantly higher initial mechanical strength and higher ability to maintain their morphology in vivo compared to the counterparts without fibrin. However, fibrin gel alone suppressed the bone formation ability of β-TCP/E-rhBMP-2 whereas the presence of high doses of E-rhBMP-2 in fibrin gel resulted in material resorption and enhanced new bone formation. In conclusion, fibrin gel significantly improved the mechanical strength and surgical manageability of the β-TCP/E-rhBMP-2 scaffold, and the addition of E-rhBMP-2 to the fibrin gel further enhanced the vertical bone regeneration and initial structural integrity of the scaffold.

    DOI: 10.1093/rb/rbae144

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    Other Link: https://academic.oup.com/rb/article-pdf/doi/10.1093/rb/rbae144/61841803/rbae144.pdf

  • Local E-rhBMP-2/β-TCP Application Rescues Osteocyte Dendritic Integrity and Reduces Microstructural Damage in Alveolar Bone Post-Extraction in MRONJ-like Mouse Model Reviewed

    Anh Tuan Dang, Mitsuaki Ono, Ziyi Wang, Ikue Tosa, Emilio Satoshi Hara, Akihiro Mikai, Wakana Kitagawa, Tomoko Yonezawa, Takuo Kuboki, Toshitaka Oohashi

    International Journal of Molecular Sciences   25 ( 12 )   6648 - 6648   2024.6

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    Publishing type:Research paper (scientific journal)   Publisher:MDPI AG  

    The pathology of medication-related osteonecrosis of the jaw (MRONJ), often associated with antiresorptive therapy, is still not fully understood. Osteocyte networks are known to play a critical role in maintaining bone homeostasis and repair, but the exact condition of these networks in MRONJ is unknown. On the other hand, the local application of E-coli-derived Recombinant Human Bone Morphogenetic Protein 2/β-Tricalcium phosphate (E-rhBMP-2/β-TCP) has been shown to promote bone regeneration and mitigate osteonecrosis in MRONJ-like mouse models, indicating its potential therapeutic application for the treatment of MRONJ. However, the detailed effect of BMP-2 treatment on restoring bone integrity, including its osteocyte network, in an MRONJ condition remains unclear. Therefore, in the present study, by applying a scanning electron microscope (SEM) analysis and a 3D osteocyte network reconstruction workflow on the alveolar bone surrounding the tooth extraction socket of an MRONJ-like mouse model, we examined the effectiveness of BMP-2/β-TCP therapy on the alleviation of MRONJ-related bone necrosis with a particular focus on the osteocyte network and alveolar bone microstructure (microcrack accumulation). The 3D osteocyte dendritic analysis showed a significant decrease in osteocyte dendritic parameters along with a delay in bone remodeling in the MRONJ group compared to the healthy counterpart. The SEM analysis also revealed a notable increase in the number of microcracks in the alveolar bone surface in the MRONJ group compared to the healthy group. In contrast, all of those parameters were restored in the E-rhBMP-2/β-TCP-treated group to levels that were almost similar to those in the healthy group. In summary, our study reveals that MRONJ induces osteocyte network degradation and microcrack accumulation, while application of E-rhBMP-2/β-TCP can restore a compromised osteocyte network and abrogate microcrack accumulation in MRONJ.

    DOI: 10.3390/ijms25126648

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  • Inverse genetics tracing the differentiation pathway of human chondrocytes Reviewed

    H.T. Do, M. Ono, Z. Wang, W. Kitagawa, A.T. Dang, T. Yonezawa, T. Kuboki, T. Oohashi, S. Kubota

    Osteoarthritis and Cartilage   2024.6

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.joca.2024.06.009

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  • Exploring the Regulators of Keratinization: Role of BMP-2 in Oral Mucosa Reviewed

    Xindi Mu, Mitsuaki Ono, Ha Thi Thu Nguyen, Ziyi Wang, Kun Zhao, Taishi Komori, Tomoko Yonezawa, Takuo Kuboki, Toshitaka Oohashi

    Cells   13 ( 10 )   807 - 807   2024.5

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    The oral mucosa functions as a physico-chemical and immune barrier to external stimuli, and an adequate width of the keratinized mucosa around the teeth or implants is crucial to maintaining them in a healthy and stable condition. In this study, for the first time, bulk RNA-seq analysis was performed to explore the gene expression of laser microdissected epithelium and lamina propria from mice, aiming to investigate the differences between keratinized and non-keratinized oral mucosa. Based on the differentially expressed genes (DEGs) and Gene Ontology (GO) Enrichment Analysis, bone morphogenetic protein 2 (BMP-2) was identified to be a potential regulator of oral mucosal keratinization. Monoculture and epithelial–mesenchymal cell co-culture models in the air–liquid interface (ALI) indicated that BMP-2 has direct and positive effects on epithelial keratinization and proliferation. We further performed bulk RNA-seq of the ALI monoculture stimulated with BMP-2 in an attempt to identify the downstream factors promoting epithelial keratinization and proliferation. Analysis of the DEGs identified, among others, IGF2, ID1, LTBP1, LOX, SERPINE1, IL24, and MMP1 as key factors. In summary, these results revealed the involvement of a well-known growth factor responsible for bone development, BMP-2, in the mechanism of oral mucosal keratinization and proliferation, and pointed out the possible downstream genes involved in this mechanism.

    DOI: 10.3390/cells13100807

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  • LCZ696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats. Reviewed International journal

    Toru Miyoshi, Kazufumi Nakamura, Naofumi Amioka, Omer F Hatipoglu, Tomoko Yonezawa, Yukihiro Saito, Masashi Yoshida, Satoshi Akagi, Hiroshi Ito

    Scientific reports   12 ( 1 )   4930 - 4930   2022.3

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    Doxorubicin (DOX)-based chemotherapy induces cardiotoxicity, which is considered the main bottleneck for its clinical application. In this study, we investigated the potential benefit of LCZ696, an angiotensin receptor-neprilysin inhibitor against DOX-induced cardiotoxicity in rats and H9c2 cells and determined whether the mechanism underlying any such effects involves its antioxidant activity. Male Sprague-Dawley rats were randomly separated into four groups, each consisting of 15 rats (DOX (1.5 mg/kg/day intraperitoneally for 10 days followed by non-treatment for 8 days); DOX + valsartan (31 mg/kg/day by gavage from day 1 to day 18); DOX + LCZ696 (68 mg/kg/day by gavage from day 1 to day 18); and control (saline intraperitoneally for 10 days). DOX-induced elevation of cardiac troponin T levels on day 18 was significantly reduced by LCZ696, but not valsartan. The DOX-induced increase in myocardial reactive oxygen species (ROS) levels determined using dihydroethidium was significantly ameliorated by LCZ696, but not valsartan, and was accompanied by the suppression of DOX-induced increase in p47phox. LCZ696 recovered the DOX-induced decrease in phosphorylation of adenosine monophosphate-activated protein kinase and increased the ratio of Bax and Bcl-2. In H9c2 cardiomyocytes, LCZ696 reduced DOX-induced mitochondrial ROS generation and improved cell viability more than valsartan. Our findings indicated that LCZ696 ameliorated DOX-induced cardiotoxicity in rat hearts in vivo and in vitro, possibly by mediating a decrease in oxidative stress.

    DOI: 10.1038/s41598-022-09094-z

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  • Pemafibrate Prevents Rupture of Angiotensin II-Induced Abdominal Aortic Aneurysms. Reviewed International journal

    Naofumi Amioka, Toru Miyoshi, Tomoko Yonezawa, Megumi Kondo, Satoshi Akagi, Masashi Yoshida, Yukihiro Saito, Kazufumi Nakamura, Hiroshi Ito

    Frontiers in cardiovascular medicine   9   904215 - 904215   2022

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    Background: Abdominal aortic aneurysm (AAA) is a life-threatening disease that lacks effective preventive therapies. This study aimed to evaluate the effect of pemafibrate, a selective peroxisome proliferator-activated receptor alpha (PPARα) agonist, on AAA formation and rupture. Methods: Experimental AAA was induced by subcutaneous angiotensin II (AngII) infusion in ApoE - / - mice for 4 weeks. Pemafibrate (0.1 mg/kg/day) was administered orally. Dihydroethidium staining was used to evaluate the reactive oxygen species (ROS). Results: The size of the AngII-induced AAA did not differ between pemafibrate- and vehicle-treated groups. However, a decreased mortality rate due to AAA rupture was observed in pemafibrate-treated mice. Pemafibrate ameliorated AngII-induced ROS and reduced the mRNA expression of interleukin-6 and tumor necrosis factor-α in the aortic wall. Gelatin zymography analysis demonstrated significant inhibition of matrix metalloproteinase-2 activity by pemafibrate. AngII-induced ROS production in human vascular smooth muscle cells was inhibited by pre-treatment with pemafibrate and was accompanied by an increase in catalase activity. Small interfering RNA-mediated knockdown of catalase or PPARα significantly attenuated the anti-oxidative effect of pemafibrate. Conclusion: Pemafibrate prevented AAA rupture in a murine model, concomitant with reduced ROS, inflammation, and extracellular matrix degradation in the aortic wall. The protective effect against AAA rupture was partly mediated by the anti-oxidative effect of catalase induced by pemafibrate in the smooth muscle cells.

    DOI: 10.3389/fcvm.2022.904215

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  • Protective Role of Limitrin in Experimental Autoimmune Optic Neuritis Reviewed International coauthorship International journal

    Bo Young Chun, Jong-Heon Kim, Youn-Kwan Jung, Yoon Seok Choi, Gunwoo Kim, Tomoko Yonezawa, Kyoungho Suk

    Investigative Opthalmology & Visual Science   62 ( 9 )   8 - 8   2021.7

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    Publishing type:Research paper (scientific journal)   Publisher:Association for Research in Vision and Ophthalmology (ARVO)  

    DOI: 10.1167/iovs.62.9.8

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  • Lack of collagen α6(IV) chain in mice does not cause severe-to-profound hearing loss or cochlear malformation, a distinct phenotype from nonsyndromic hearing loss with COL4A6 missense mutation. Reviewed International journal

    Shaoying Tang, Tomoko Yonezawa, Yukihide Maeda, Mitsuaki Ono, Takahiro Maeba, Toru Miyoshi, Ryusuke Momota, Yasuko Tomono, Toshitaka Oohashi

    PloS one   16 ( 4 )   e0249909 - e0249909   2021.4

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Public Library of Science (PLoS)  

    Congenital hearing loss affects 1 in every 1000 births, with genetic mutations contributing to more than 50% of all cases. X-linked nonsyndromic hereditary hearing loss is associated with six loci (DFNX1-6) and five genes. Recently, the missense mutation (c.1771G&gt;A, p.Gly591Ser) in <italic>COL4A6</italic>, encoding the basement membrane (BM) collagen α6(IV) chain, was shown to be associated with X-linked congenital nonsyndromic hearing loss with cochlear malformation. However, the mechanism by which the <italic>COL4A6</italic> mutation impacts hereditary hearing loss has not yet been elucidated. Herein, we investigated <italic>Col4a6</italic> knockout (KO) effects on hearing function and cochlear formation in mice. Immunohistochemistry showed that the collagen α6(IV) chain was distributed throughout the mouse cochlea within subepithelial BMs underlying the interdental cells, inner sulcus cells, basilar membrane, outer sulcus cells, root cells, Reissner’s membrane, and perivascular BMs in the spiral limbus, spiral ligament, and stria vascularis. However, the click-evoked auditory brainstem response analysis did not show significant changes in the hearing threshold of <italic>Col4a6</italic> KO mice compared with wild-type (WT) mice with the same genetic background. In addition, the cochlear structures of <italic>Col4a6</italic> KO mice did not exhibit morphological alterations, according to the results of high-resolution micro-computed tomography and histology. Hence, loss of <italic>Col4a6</italic> gene expression in mice showed normal click ABR thresholds and normal cochlear formation, which differs from humans with the <italic>COL4A6</italic> missense mutation c.1771G&gt;A, p.Gly591Ser. Therefore, the deleterious effects in the auditory system caused by the missense mutation in <italic>COL4A6</italic> are likely due to the dominant-negative effects of the α6(IV) chain and/or α5α6α5(IV) heterotrimer with an aberrant structure that would not occur in cases with loss of gene expression.

    DOI: 10.1371/journal.pone.0249909

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  • Deficiency of CD44 prevents thoracic aortic dissection in a murine model. Reviewed International journal

    Omer F Hatipoglu, Toru Miyoshi, Tomoko Yonezawa, Megumi Kondo, Naofumi Amioka, Masashi Yoshida, Satoshi Akagi, Kazufumi Nakamura, Satoshi Hirohata, Hiroshi Ito

    Scientific reports   10 ( 1 )   6869 - 6869   2020.4

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    Thoracic aortic dissection (TAD) is a life-threatening vascular disease. We showed that CD44, a widely distributed cell surface adhesion molecule, has an important role in inflammation. In this study, we examined the role of CD44 in the development of TAD. TAD was induced by the continuous infusion of β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, and angiotensin II (AngII) for 7 days in wild type (WT) mice and CD44 deficient (CD44-/-) mice. The incidence of TAD in CD44-/- mice was significantly reduced compared with WT mice (44% and 6%, p < 0.01). Next, to evaluate the initial changes, aortic tissues at 24 hours after BAPN/AngII infusion were examined. Neutrophil accumulation into thoracic aortic adventitia in CD44-/- mice was significantly decreased compared with that in WT mice (5.7 ± 0.3% and 1.6 ± 0.4%, p < 0.01). In addition, BAPN/AngII induced interleukin-6, interleukin-1β, matrix metalloproteinase-2 and matrix metalloproteinase-9 in WT mice, all of which were significantly reduced in CD44-/- mice (all p < 0.01). In vitro transmigration of neutrophils from CD44-/- mice through an endothelial monolayer was significantly decreased by 18% compared with WT mice (p < 0.01). Our findings indicate that CD44 has a critical role in TAD development in association with neutrophil infiltration into adventitia.

    DOI: 10.1038/s41598-020-63824-9

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  • 細胞外基質が細胞遊走に及ぼす影響の評価を目的とした細胞遊走アッセイ

    塩出 雄亮, 森實 祐基, 平野 雅幸, 土居 真一郎, 戸島 慎二, 荒木 亮一, 高橋 耕介, 松前 洋, 神崎 勇希, 細木 三佳, 米澤 朋子, 白神 史雄

    日本眼科学会雑誌   122 ( 臨増 )   226 - 226   2018.3

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  • 剥離した内境界膜に含まれる終末糖化産物の定量評価

    的場 亮, 森實 祐基, 木村 修平, 米澤 朋子, 須野 学, 岡野内 俊雄, 高畠 隆, 三原 研一, 佐々木 ミチ, 飯島 克昌, 白神 史雄

    日本眼科学会雑誌   120 ( 臨増 )   185 - 185   2016.3

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  • ミュラー細胞の増殖、遊走における4型コラーゲンの役割

    塩出 雄亮, 森實 祐基, 的場 亮, 平野 雅幸, 土居 真一郎, 荒木 亮一, 米澤 朋子, 白神 史雄

    日本眼科学会雑誌   119 ( 臨増 )   168 - 168   2015.3

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  • ARPE-19の細胞増殖におけるAMP依存性キナーゼの役割

    塚本 真啓, 木村 修平, 米澤 朋子, 小阪 淳, 森實 祐基

    日本眼科学会雑誌   117 ( 臨増 )   352 - 352   2013.3

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  • Distribution of alpha(IV) collagen chains in the ocular anterior segments of adult mice Reviewed

    Kenji Saito, Tomoko Yonezawa, Jun Minaguchi, Masae Kurosaki, Shiho Suetsugu, Ai Nakajima, Hiroyuki Nomoto, Yuki Morizane, Yoshikazu Sado, Manabu Sugimoto, Shozo Kusachi, Yoshifumi Ninomiya

    CONNECTIVE TISSUE RESEARCH   52 ( 2 )   147 - 156   2011.4

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    DOI: 10.3109/03008207.2010.492062

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  • Tumor-specific expression of the RGD-alpha3(IV)NC1 domain suppresses endothelial tube formation and tumor growth in mice. Reviewed

    Miyoshi T, Hirohata S, Ogawa H, Doi M, Obika M, Yonezawa T, Sado Y, Kusachi S, Kyo S, Kondo S, Shiratori Y, Hudson BG, Ninomiya Y

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology   20 ( 11 )   1904 - 1906   2006.9

  • ヒト皮膚および付属器の基底膜IV型コラーゲンα鎖構成

    長谷川 治子, 内藤 一郎, 中野 和代, 米澤 朋子, 西田 圭一郎, 田口 勇仁, 佐渡 義一, 二宮 善文, 大塚 愛二

    解剖学雑誌   80 ( 1 )   20 - 20   2005.3

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  • ヒト皮膚とその付属器の基底膜を構成するIV型コラーゲン分子のα鎖構成

    長谷川 治子, 内藤 一郎, 中野 和代, 米澤 朋子, 西田 圭一郎, 田口 勇仁, 佐渡 義一, 二宮 善文, 大塚 愛二

    解剖学雑誌   80 ( Suppl. )   151 - 151   2005.3

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  • Limitrin, a Novel Immunoglobulin Superfamily Protein Localized to Glia Limitans Formed by Astrocyte Endfeet Reviewed

    Tomoko Yonezawa, Aiji Ohtsuka, Teruhito Yoshitaka, Shuichi Hirano, Hiroyuki Nomoto, Kiyotaka Yamamoto, Yoshifumi Ninomiya

    GLIA   44 ( 3 )   190 - 204   2003.12

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1002/glia.10279

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MISC

  • Bioinformatics Insights into Pathophysiology and Therapeutic Targets in Alport Syndrome

    Xindi Mu, Tomoko Yonezawa, Tran Thi Thanh Binh, Bui Hai Dang, Mitsuaki Ono, Toshitaka Oohashi, Ziyi Wang

    2025.6

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  • 皮膚創傷治癒におけるXVIII型コラーゲンの機能解析 Reviewed

    Zhang Xiaowen, 米澤朋子, 前場崇宏, 上野智規, 大野充昭, 佐々木隆子, 百田龍輔, 水野一乘, 服部俊治, 大橋俊孝

    第47回日本分子生物学会年会、抄録集   2024.11

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  • R-Shinyを用いたインタラクティブなscRNA-seqデータ解析

    大野充昭, Wang Ziyi, 米澤朋子, 大橋俊孝, 窪木拓男

    NGS EXPO 2024   2024.9

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  • 下垂体後葉Neurovascular unitにおけるIV型コラーゲンの解析

    第49回日本神経内分泌学会学術集会抄録集   2023.10

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  • 長鎖型XVIII型コラーゲンは新規膜結合型コラーゲンである可能性が高い

    上野 智規, 米澤 朋子, 百田 龍輔, 佐々木 隆子, 大橋 俊孝, 水野 一乘

    日本結合組織学会学術大会プログラム・抄録集   55回   147 - 147   2023.6

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  • β3インテグリン遺伝子導入ヒト表皮角化細胞を用いた難治性潰瘍に対する新規再生医療の開発

    久保 美代子, 山本 健一, 木下 理恵, 米澤 朋子, 大橋 俊孝, 阪口 政清

    日本結合組織学会学術大会プログラム・抄録集   55回   134 - 134   2023.6

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  • XVIII型コラーゲン欠損マウスにおける皮膚創傷治癒の解析

    米澤朋子, 前川明日華, 前場崇宏, 百田龍輔, 渋谷千晶, 岩田宗一郎, 大野充昭, 大橋俊孝

    第54回日本結合組織学会抄録集   2022.6

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  • XVIII型コラーゲン欠損マウスの肝臓で起こると思われる代謝機能の変化

    第54回日本結合組織学会抄録集   2022.6

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  • アルポート症候群モデルマウスにおける眼病変と遺伝子発現変化

    第52回日本結合組織学会抄録集   2020.9

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  • コラーゲン研究の新展開:基礎から創薬まで マウス皮膚創傷モデルにおけるXVIII型コラーゲンの解析

    米澤 朋子, 前場 崇宏, Tang Shaoying, 大野 充昭, 百田 龍輔, 稲川 喜一, 大橋 俊孝

    日本生化学会大会プログラム・講演要旨集   93回   [1S08e - 06]   2020.9

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  • Col4a3ノックアウトマウスにおける網膜の表現型解析

    米澤 朋子, 松前 洋, 神崎 勇希, Chuyuan Lou, 前場 崇宏, 森實 祐基, 美名口 順, Miner Jeffrey, 大橋 俊孝

    日本結合組織学会学術大会プログラム・抄録集   50回   106 - 106   2018.6

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  • Orally Administered Eicosapentaenoic Acid Attenuates Vascular Oxidative Stress and the Development of Angiotensin-II Induced Aortic Aneurysm Formation

    Toru Mivoshi, Kazufumi Nakamura, Tomoko Yonezawa, Daiji Miura, Masashi Yoshida, Hiroshi Morita, Satoshi Akagi, Kunihisa Kohno, Yukihiro Saito, Yoshifumi Ninomiya, Kengo Kusano, Hiroshi Ito

    CIRCULATION   126 ( 21 )   2012.11

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  • Contrasting Effects of Imidapril and Losartan on Matrix Metalloproteinase in Human Abdominal Aortic Aneurysm

    Toru Miyoshi, Tomoko Yonezawa, Kazufumi Nakamura, Masashi Yoshida, Hiroshi Morita, Masashi Yoshida, Masayuki Doi, Atsushi Aoki, Kengo Kusano, Yoshifumi Ninomiya, Hiroshi Ito

    CIRCULATION   126 ( 21 )   2012.11

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  • ADAMTS1のin vitroでのリンパ管新生阻害効果

    稲垣 純子, 高橋 克之, 小川 弘子, Hatipoglu Omer F, Cilek Mehmet Zeynel, 小比賀 真就, 米澤 朋子, 大橋 俊孝, 廣畑 聡, 二宮 善文

    日本生化学会大会プログラム・講演要旨集   84回   2P - 0343   2011.9

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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   43rd   104 - 104   2011.5

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    J-GLOBAL

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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   43rd   103 - 103   2011.5

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    J-GLOBAL

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  • UTILIZATION OF ADAMTSI AS A NEW TOOL FOR DETECTING HYPOXIA

    Mehmet Zeynel Cilek, Satoshi Hirohata, Omer Faruk Hatipoglu, Kadir Demircan, Junko Inagaki, Tomoko Yonezawa, Toshikata Oohashi, Yoshifumi Ninomiya

    IUBMB LIFE   61 ( 3 )   357 - 358   2009.3

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    Web of Science

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  • がん細胞株におけるADAMTS1の発現レベルの検討

    メフメット・ゼネユル・チレッキ, 廣畑 聡, カディール・デミルジャン, オメル・ファルク・ハティポール, 小川 弘子, 米澤 朋子, 草地 省蔵, 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   39回・54回   144 - 144   2007.5

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  • 中枢神経における新規構造「フラクトン」を構築するIV型コラーゲン(Type IV collagen of the novel structure "fractone" in mouse central nervous system)

    米澤 朋子, 遊木 陽子, 赤木 雪恵, 内藤 一郎, 平野 修一, 大塚 愛二, 佐渡 義一, 二宮 義文

    神経化学   43 ( 2-3 )   381 - 381   2004.8

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  • Cloning and Immunohistochemical Studies of Limitrin in the Mouse Brain and Retina

    H Nomoto, T Yonezawa, A Ohtsuka, F Shiraga, H Ohtsuki, Y Ninomiya

    ARVO Annual Meeting Abstract   2002.12

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  • アストロサイトに発現する新規遺伝子HBE283の解析

    米澤 朋子, 大塚 愛二, 山本 清高, 平野 修一, 二宮 善文

    生化学   73 ( 8 )   739 - 739   2001.8

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Presentations

  • Functional analysis of collagen XVIII in skin wound healing

    Xiaowen Zhang, Tomoko Yonezawa, Takahiro Maeba, Tomonori Ueno, Mitsuaki Ono, Takako Sasaki, Ryusuke Momota, Kazunori Mizuno, Shunji Hattori, Toshitaka Oohashi

    2024.11.29 

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    Event date: 2024.11.26 - 2024.11.29

    Language:English   Presentation type:Poster presentation  

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  • 下垂体後葉Neurovascular unitにおけるIV型コラーゲンの解析

    第49回日本神経内分泌学会学術集会  2023.10.28 

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    Event date: 2023.10.27 - 2023.10.28

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  • Skin wound healing in Collagen knockout mice

    2022.6.26 

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    Event date: 2022.6.25 - 2022.6.26

    Language:Japanese  

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  • Possible matabolic changes in the liver of Collagen XVIII knock out mice

    Ryusuke Momota, Tomoko Yonezawa, Hiroyuki Yanai, Toshihiko Oohashi

    2022.6.26 

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    Event date: 2022.6.25 - 2022.6.26

    Language:Japanese   Presentation type:Oral presentation (general)  

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  • コラーゲン研究の新展開:基礎から創薬まで マウス皮膚創傷モデルにおけるXVIII型コラーゲンの解析

    米澤 朋子, 前場 崇宏, Tang Shaoying, 大野 充昭, 百田 龍輔, 稲川 喜一, 大橋 俊孝

    日本生化学会大会プログラム・講演要旨集  2020.9  (公社)日本生化学会

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    Event date: 2020.9

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  • Collagen XVIII deposition in the basement membrane zone beneath the newly forming epidermis during wound healing in mice

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

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    Event date: 2019.5.31 - 2019.6.1

    Presentation type:Poster presentation  

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  • Lack of expression of alpha6(IV) collagen does not result in cochlear malformation and hearing loss in mice

    1 Shaoying Tang, 1 Tomoko Yonezawa, 2 Yukihide Maeda, 1 Mitsuaki Ono, 1 Takahiro Maeba, 1 Toshitaka Oohashi

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    Event date: 2019.5.31 - 2019.6.1

    Presentation type:Poster presentation  

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  • Ultrastructural analysis of retina in Col4a3 knockout mouse

    T. Yonezawa, H. Matsumae, Y. Kanzaki, L. Chuyuan, T. Maeba, Y. Morizane, T. Oohashi

    2018.6.29 

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    Event date: 2018.6.30

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  • Ocular abnormalities and the change of gene expression in Alport syndrome model mice

    Tang Shaoying, Tomoko Yonezawa, Ryusuke Momota, Hiroshi Matsumae, Yuki Kanzaki, Yuki Morizane, Toshitaka Oohashi

    2020.9.19 

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  • マウス皮膚創傷モデルにおけるXVIII型コラーゲンの解析

    米澤朋子, 前場崇宏, Tang Shaoying, 大野充昭, 百田龍輔, 稲川喜一, 大橋俊孝

    生化学学会2020  2020.9.14 

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Research Projects

  • 1細胞解析による基底膜の形成機序を軸とした再上皮化メカニズムの解明

    Grant number:23K09100  2023.04 - 2026.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    米澤 朋子, 大野 充昭, 百田 龍輔

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    Grant amount:\4680000 ( Direct expense: \3600000 、 Indirect expense:\1080000 )

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  • 難治性潰瘍での変性コラーゲンの局在証明、再上皮化遅延の病態解明とその治療法開発

    Grant number:23K09079  2023.04 - 2026.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    久保 美代子, 山本 健一, 米澤 朋子, 大橋 俊孝

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    Grant amount:\4680000 ( Direct expense: \3600000 、 Indirect expense:\1080000 )

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  • 大動脈解離におけるメカノバイオロジー機構の解明

    Grant number:21K08052  2021.04 - 2024.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    三好 亨, 中村 一文, 米澤 朋子, 片野坂 友紀

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    Grant amount:\4160000 ( Direct expense: \3200000 、 Indirect expense:\960000 )

    胸部大動脈解離は大動脈中膜が突然破断する疾患であるが、その病態はほとんど解明されていないため、発症予測や進行阻止は困難である。我々は、これまでの研究で大動脈瘤・解離の進展にインテグリンや接着因子が関与することを報告してきた。一方で、血管壁にかかるずり応力や伸展刺激などのメカニカルストレスが大動脈解離に重要であることが示唆されている。
    メカノセンサーは、血管のメカニカルストレスに応答し、血管の恒常性に寄与していることが分かっている。現在知られているメカのセンサーの中で、大動脈平滑筋での発現が確認されているメカノセンサーTRPV2 (transient receptor potential vanilloid 2)が重要な役割を担うのではないかと考え本実験を開始した。つまり、本研究の目的は、ヒト胸部大動脈解離組織およびマウス胸部大動脈解離モデルの両方からTRPV2の分子動態について検討し、大動脈解離におけるメカノバイオロジー機構を解明することである。
    本研究では、マウス大動脈解離は、C57BL/6マウスにlysyl oxidase 阻 害 薬 (150mg/kg/day) とアンジオテンシン II (1000ng/kg/min)を同時に、2週間浸透圧ポンプで皮下投与し作成することとした。結果であるが、コントロールマウスでの大動脈解離の発生率は約80%と高率であった。しかし、血管平滑筋におけるTRPV2の発現が欠損したマウスでは、コントロールマウスに比べて大動脈解離の発現頻度が低いことが分かった。また、大動脈破裂を起こす頻度も、血管平滑筋におけるTRPV2の発現が欠損したマウスでは、コントロールマウスに比べて低かった。さらに組織学的な検討においても、解離部位における血腫の形成も認められた。

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  • Functional deteriorations of liver/pancreas caused by age-related changes of type XVIII collagen

    Grant number:20K11556  2020.04 - 2023.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    百田 龍輔, 米澤 朋子, 大塚 愛二, 大橋 俊孝, 内藤 一郎

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    Grant amount:\4290000 ( Direct expense: \3300000 、 Indirect expense:\990000 )

    脂肪肝の症状がはっきりとみられるXVIII型コラーゲン欠損老齢マウスだけでなく、若い欠損マウスで”予兆”のような現象を改善することで脂肪肝、NAFLDへの進行を予防できるのではないかと考え、加齢マウスだけでなく2ヶ月齢の若いマウスを用いて改めて、網羅的に遺伝子発現と組織学的な検討を行った。若い欠損マウスは細胞内脂肪滴の蓄積では組織学的に大きな差は認められなかったが、血管周囲の構造について野生型と比較して若干違いが見られたのでその再現性について確認を行っている。
    さらに、野生型、欠損の若いマウスについても、双方の肝臓からRNAを抽出し、RNA-seqにより全転写産物の解析を進めている。前年度の加齢マウスで行ったネットワーク解析、コンピューターによる代謝シミュレーションを行い、代謝経路・産物について経時的にどう変化するかについて検討する予定である。
    また、新たにリピドミクスの系を立ち上げたので、マウスの血液中や肝臓に蓄積する脂質組成について比較検討を行っている。すなわち、上記のコンピューターシミュレーションの結果を生体で実際に起きているかどうか確認を進めている。
    一方、上記のシミュレーション結果をもとに、ネットワーク解析などから中心的な役割を果たす複数の代謝経路、遺伝子産物、代謝産物を同定した。これらの候補遺伝子産物で薬理学的な調節が可能な候補を抽出した。また、その機能を調節できるような化合物検索をバーチャルに行う高性能GPU搭載コンピューターの解析環境を立ち上げた。現在これらの結果をもとに論文作成に取り掛かっている。

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  • Investigation of the role of longevity genes in the retina using genome editing technology

    Grant number:18K09410  2018.04 - 2021.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Morizane Yuki

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    Grant amount:\4420000 ( Direct expense: \3400000 、 Indirect expense:\1020000 )

    Age-related macular degeneration (AMD) is an intractable ocular disease that leads to blindness, and the number of patients with AMD is expected to increase rapidly. In this study, we targeted sirtuins (SIRTs) and KCNJ13, one of the potassium channels in RPE, among the genes thought to be related to the function of RPE, and aimed to clarify the effects of these genes on the function of RPE using genome editing technology. As for KCNJ13 gene, we found that the KCNJ13 gene in iPS-RPE is regulated by genome editing, but not by genome editing. Since the RPE is essentially a monolayer epithelial cell that forms tight junctions and functions as a blood-eye barrier, the deletion of the KCNJ13 gene may affect other RPE and retinal functions. Therefore, the deletion of the KCNJ13 gene may affect other RPE and retinal functions, and may be involved in the pathogenesis of AMD.

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  • Impact of integrin on the development of aortic dissection

    Grant number:18K08758  2018.04 - 2021.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    MIYOSHI Toru

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    Grant amount:\4290000 ( Direct expense: \3300000 、 Indirect expense:\990000 )

    For animal experiments, aortic dissection model was made by subcutaneous infusion of lysyl oxidase inhibitor and angiotensin II. The incidence of aortic dissection in integrin α1 Knockout (Itga1KO) mice was significantly reduced compared with control mice. These results suggests that Itga1 play an important role in the development of aortic dissection. Next, the differences in mRNA expressions between Itga1 KO mice and control mice of aortic dissection model were evaluated by real-time quantitative PCR. The mRNA expressions of inflammatory genes and matrix matrix metalloproteinase in Itga1 KO mice were significantly lower than those in control mice. Taken together, Itga1 may be crucial for the development of aortic dissection.

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  • The Role of Inverted Internal Limiting Membrane Flap in Macular Hole Closure

    Grant number:15K20262  2015.04 - 2018.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (B)

    SHIODE Yusuke

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    Grant amount:\3900000 ( Direct expense: \3000000 、 Indirect expense:\900000 )

    We investigated the mechanism of macular hole (MH) closure following the inverted internal limiting membrane (ILM) technique. We performed the inverted ILM flap surgical technique as an experimental MH model in monkeys, and investigated the process of MH closure immunohistochemically. We then investigated the effects of type IV collagen, fibronectin, and laminin, which are constituent proteins of the ILM, on the proliferation and migration of cultivated Muller cells(MIO-M1). We also investigated the expression of neurotrophic factors in human ILM and MIO-M1 cells. From these results, during MH closure, the ILM functioned as a scaffold for the proliferation and migration of Muller cells, and may promote Muller cell activation. Neurotrophic factors produced by activated Muller cells and present on the surface of the ILM may contribute to MH closure.

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  • The role of integrin in the development of abdominal aortic aneurysm

    Grant number:15K09157  2015.04 - 2018.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    MIYOSHI Toru

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    Grant amount:\4680000 ( Direct expense: \3600000 、 Indirect expense:\1080000 )

    Abdominal aortic aneurysm is a silent disease, but lethal once ruptured. The prevention of AAA expansion and rupture is clinically difficult. This study investigated whether alpha1 integrin, an adhesion molecule, is involved in the development of AAA in murine model. Genetic deficiency of alpha1 integrin suppressed the rupture of AAA in angiotensin II infusion model. These findings suggest that alpha1 integrin may be a promising target to treat AAA.

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  • Metabolism and function of xanthophyll in the retina

    Grant number:15K10867  2015.04 - 2018.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Morizane Yuki, SHIODE Yusuke, Matoba Ryo

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    Grant amount:\4940000 ( Direct expense: \3800000 、 Indirect expense:\1140000 )

    In this study, with the aim of clarifying the mechanism by which xanthophyll is incorporated into the retina and the role played by retinal function, we investigated the uptake into the cell, its pathway, and the effect on cell migration by using retinal pigment epithelial cells and retinal glial cells which constitute the retina. It was revealed that lutein is taken up into cells in concentration and time dependence. Inhibition of the known lutein transport pathway did not cause a significant change in lutein uptake. Also, lutein had no significant effect on cell migration. It is important to investigate the metabolism of intracellular lutein and the role of lutein further in the near future.

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  • Analysis of trans-plasma membrane molecular machinery between collagen types XV/XVIII and mitochondria

    Grant number:26350892  2014.04 - 2017.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Momota Ryusuke, OOHASHI Toshitaka, YONEZAWA Tomoko, KOMIYAMA Takaaki, NARASAKI Masahiro

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    Grant amount:\4810000 ( Direct expense: \3700000 、 Indirect expense:\1110000 )

    To identify the molecules which would compose "the tran-plasma membrane molecular machinery" of collagen types XV/XVIII and mitochondria, we have screened thousands of genes expressed in muscular tissues and identified possible candidate G-protein coupled receptors. In addition, our histological analyses on collagen types XV/XVIII mutant animals revealed abnormal structures of cytoskeletons, which would potentially compromise the mitochondrial and cellular functions. Moreover, we had successfully optimized the immunohistochemical conditions for the anti-collagen XV/XVIII monoclonal antibodies, which enabled us to use variously processed tissue samples to diagnose human diseases caused by defective collagen XV/XVIII.

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  • The evaluation of CD44 in pathogenesis of abdominal aortic aneurysm and the development of new therapy

    Grant number:24591053  2012.04 - 2015.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    MIYOSHI Toru, NAKAMURA Kazufumi, YONEZAWA Tomoko, YOSHIDA Masashi

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    Grant amount:\4940000 ( Direct expense: \3800000 、 Indirect expense:\1140000 )

    Immunohistochemical analysis of human abdominal aortic aneurysm revealed that the increased expression of CD44 and the degradation of hyaluronic acid were possibly involved in pathogenesis of abdominal aortic aneurysm. Experimental abdominal aortic aneurysm using CaCl2-induced model, the incidence of abdominal aortic aneurysm was significantly less in CD44 knockout mice compared to wild type mice. Liposome targeting CD44 was developed and the utility of its liposome is being studied.

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  • Inhibition of RPE senescence by AMPK activation

    Grant number:24592630  2012.04 - 2015.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    YUKI Morizane, KOSAKA Jun, YONEZAWA Tomoko

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    Grant amount:\5330000 ( Direct expense: \4100000 、 Indirect expense:\1230000 )

    Retinal pigment epithelial cells (RPE) has a variety of physiological functions to maintain homeostasis of the retina. In the age-related macular degeneration, homeostasis of the retina collapses by decreased function of the RPE associated with aging, and leads to visual disturbance. In this study, for the ARPE-19 and human iPS-derived RPE, we induced senescence of RPE by chronic oxidative stress, and revealed a change in the functions of the RPE associated with aging. In addition, using models of inflammation to induce epithelial-mesenchymal transition in the RPE, we revealed that the activation of AMPK inhibits epithelial-mesenchymal transformation in the RPE.

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  • Role of basement membranes in small-vessel disease of brain

    Grant number:23390348  2011.04 - 2014.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    NINOMIYA YOSHIFUMI, YONEZAWA Tomoko, OOHASHI Toshitaka, HIROHATA Satoshi, OHTSUKA Aiji, HATANAKA Kunihiko, SAITO Kenji, MOMOTA Ryusuke, OGAWA Hiroko, INAGAKI Jyunko

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    Grant amount:\19240000 ( Direct expense: \14800000 、 Indirect expense:\4440000 )

    Abnormalities of the basement membranes in brain small vessels are considered to cause the break-down of blood-brain barrier (BBB) and intracerebral hemorrhage. We established the mouse encephalopathy model by the administration of TNF-alpha intravenously, in which BBB permeability increase transiently. To know the change of type IV collagen, as major component of the basement membranes, in the encephalopathy model, we performed Western blot and immunohistochemistry. The results suggested that the degradation of type IV collagen was associated with the break-down of BBB.

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  • The function of glia limitans in spinal cord injury

    Grant number:21791398  2009 - 2010

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (B)

    YONEZAWA Tomoko

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    Grant amount:\4420000 ( Direct expense: \3400000 、 Indirect expense:\1020000 )

    Astroglia form a glia limitans around the injured tissue after spinal cord injury. We used a mouse spinal cord injury model and found that the glia limitans was associated with the suppression of infiltration of inflammatory cells and the perivascular space provides a conduit for inflammatory cells to the expansion from the injury core. In addition, we found that type IV collagen induced expression of thrombospondin-1 in astrocytes. Our results suggest that glia limitans play an important role in the repair process following injured central nervous tissue.

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  • マイクロバブルを用いた骨・関節感染症の治療

    Grant number:18659447  2006 - 2007

    日本学術振興会  科学研究費助成事業  萌芽研究

    阿部 信寛, 吉鷹 輝仁, 西田 圭一郎, 米澤 朋子

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    Grant amount:\3300000 ( Direct expense: \3300000 )

    整形外科において骨や手術時に挿入した人工物におこる感染症はしばしば難治性である。この難治性にはバイオフィルムが関与すると言われており、バイオフィルムは抗生剤の効果を減少させ、残存すると感染を再燃させる。マイクロバブルは下水管の洗浄や半導体におけるシリコンウエハーの洗浄に利用されている。マイクロバブルの粒径はバイオフィルムの狭間よりも小さく、バイオフィルムの除去に有用とされる。
    昨年度明らかとなったバイオフィルム形成能が高い黄色ブドウ球菌を用いて、バイオフィルムの作成と洗浄の実験を行った。整形外科感染症のモデルとしてポリフィラメントの繊維成分を当初は用いていたが、慢性骨髄炎など生体骨内の環境を再現するためには不十分であったため、連通孔を有する人工骨にバイオフィルムを作成するモデルの検討を行った。連通孔を介して深部にまでバイオフィルムを作成するために陰圧下で培地を浸潤させること、培地にグルコースを混ぜることにより安定したバイオフィルムが作成可能であった。このバイオフィルムを作用させた人工骨を動物に移植することで容易に慢性骨髄炎モデルとすることができた。
    また,昨年度から開発を進めてきたマイクロバブル発生装置については、条件の最適化や効率的な発生方法の検討を行ったが、マイクロバブルの持続時間が短かったため洗浄、滅菌が困難であった。そこで人工骨に作成したバイオフィルムのモデルに対してマイクロバブルの洗浄が有用かを検討するために、滅菌状態は維持できないがマイクロバブルを長時間安定して供給できる器械をレンタルし、洗浄実験を行い一定の効果を得た。
    今後はオゾンを含有させたマイクロバブルでのin vitroでの洗浄実験と、in vivoでの洗浄実験を行い、臨床応用への研究を継続していく予定である。

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  • Function of newly identified basal lamina structure fractone and regulation of neural stem cell differentiation at subventricular zone

    Grant number:16390048  2004 - 2005

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    NINOMIYA Yoshifumi, YONEZAWA Tomoko, OOHASHI Toshitaka, HIROHATA Satoshi, OHTSUKA Aiji, NAITO Ichiro

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    Grant amount:\14400000 ( Direct expense: \14400000 )

    We analyzed molecular components of the new basement membrane-like structure of capillaries in the brain, fractone. We also tried identification and separation of adult neural stem cells existing subventricular zone, and investigated mechanisms of stem cell differentiation.
    [1]Molecular and cellular analysis of the new basement membrane like structure fractone.
    We detected the basement mambrane molecules such as laminin and type IV collagen in the mouse fractone by immunohistochemistry. Especially, several laminin chains and type IV collagen chains were present in the fractone, but fibronectin was not expressed there. Moreover, the fractone was distributed around almost all of subventricular zone in the brain and spinal code but it was not present in some areas of the third and forth ventricle. Developmental studies showed that the fractone started its expression around subventricular zone at postnatal day seven, and then expression pattern was limited to lateral part of ventricle at postnatal day 14. Furthermore, we recognized the fractone structure more precisely using immunoelectron-microscopic analysis.
    [2]Identification and separation of neural stem cells from subventricular zone
    We tried to separate neural stem cells from adult mouse subventricular zones and allowed them to further differentiate into neurons and astrocytes in various conditions. To set-up differentiation conditions, we prepared substrates rich in matrix macromolecules.
    [3]Control of stem cell differentiation by extracellular matrix
    We successfully culture neurospheres prepared from subventricular zone of the lateral ventricles and set-up conditions to further differentiate into neurons and astrocytes.

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  • 血液脳関門破綻の新しい分子機構の解明

    Grant number:16790821  2004 - 2005

    日本学術振興会  科学研究費助成事業  若手研究(B)

    米澤 朋子

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    Grant amount:\3400000 ( Direct expense: \3400000 )

    中枢神経系疾患では血液脳関門(BBB)の破綻を伴うがその分子機構はよく分かっていない.本研究は,中枢神経系疾患動物モデルを作製し,グリア境界膜の破綻とBBB破綻との関連性,さらにその破綻によって発現変化をきたす分子について解析し,グリア境界膜のBBBに対する重要性およびその形成と維持の分子メカニズムを明らかにすることを目的とした.本研究の成果によってグリア境界膜の働きが血液脳関門に重要であると示唆され,外傷モデルにおける血液脳関門不全が生じるメカニズムの一つを見出した.
    1,中枢神経系疾患モデルの作製
    外傷モデルとして「マウス脳凍結損傷モデル」及び「マウス脊髄損傷モデル」を確立した.
    2,脊髄損傷モデルにおけるグリア境界膜の組織学的な解析
    損傷組織の経時的な変化を組織染色,免疫組織染色によって解析した.limitrinは損傷後に速やかに消失し,壊死組織周辺の組織修復に伴いグリア境界膜への局在が回復した.さらに他のグリア境界膜構成分子についても観察した.これらの結果から,損傷によってグリア境界膜は破綻し,その後,修復されると示唆された.またグリア境界膜の構成単位である基底膜構築も変化し,血液脳関門不全の兆候を伴うことが明らかとなった.
    3,limitrin遺伝子破壊マウスの作製と表現型解析
    上記研究の結果からグリア境界膜の機能に重要と示唆された分子の一つである,limitrinの遺伝子破壊マウスを作製し,表現型解析を行った.

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  • Toe role of novel aggrecanase in rheumatoid arthritis and its diagnostic potential

    Grant number:15390459  2003 - 2004

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    HIROHATA Satoshi, NINOMIYA Yoshifumi, OOHASHI Toshitaka, YONEZAWA Tomoko, NISHIDA Keiichiro

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    Grant amount:\15000000 ( Direct expense: \15000000 )

    1 Expression analysis of novel aggrecanase
    RNA was extracted from IL-1 b stimulated chondrosarcoma cells and chondrocytes and the aggrecanase expressions were analyzed by quantitative RT-PCR. When compared with fibroblasts, chondrosarcoma cells and chondrocytes showed higher induction of novel aggrecanase, thus indicating this novel aggrecanase is IL-1 induced specifically in cartilage cells. When chondrosarcoma cells were stimulated with IL-1b and TNFa, novel aggrecanase induced synergistically.
    2 Antibody against novel aggrecanase
    We raised a polyclonal antibody against novel aggrecanase, and checked its specificity by Western blotting. A novel aggrecanase was induced by IL-1b stimulation by Western blot analysis.
    3 KO mouse
    We got hetero mice
    4 Signal mechanism for novel aggrecanase induction
    MAP kinase inhibitor(PD98059,SB203580) were added to IL- 1b stimulated chondrosarcoma cells and the signaling pathway was determined.

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  • 血管新生を制御するマルチプレキシンコラーゲンを用いた肝癌の診断と治療

    Grant number:15659170  2003 - 2004

    日本学術振興会  科学研究費助成事業  萌芽研究

    二宮 善文, 米澤 朋子, 廣畑 聡

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    Grant amount:\2800000 ( Direct expense: \2800000 )

    血管新生を抑制するマルチプレキシンコラーゲンの性質を調べる意味で、以下の実験を行い、結果を得ることが出来た。マルチプレキシンコラーゲンの一つであるXVIII型コラーゲンは、そのカルボキシル末端の約250アミノ酸残基のNCドメインの中にはエンドスタチンとよばれ、腫瘍の周囲の血管新生を抑制することが1997年に初めて報告されてから、有望な抗がん作用を示す薬剤になりうる可能性を秘めていると思われて来た。しかしながら、いくつかの研究グループはその部分のペプチドに再現性を認めず、その作用機序を含め未解決の部分は多い。そこで、今回私どもは、XVIII型コラーゲンを多く産生する肝臓細胞株を探し出し、それをヌードマウスに打つことによって作られる腫瘍塊を作成した。そこで、XVIII型コラーゲンに特異的モノクローン抗体を担癌マウスに接種することにより、癌塊が増悪腫大するかどうかを観察することとした。その結果、この特異的モノクローン抗体はがん細胞をアポトーシスに導くことなく、肝癌の容積の増大を認めた。しかしながら、この特異抗体だけでは腫瘍細胞の増殖を促進することはなさそうであった。これらの結果は、エンドスタチンの抗腫瘍効果を支持する重要な所見であり、それだけでなく今回使用したものクローン抗体は、特異的にXVIII型コラーゲンに反応し、エンドスタチンの抗腫瘍効果を抑制することにまで至ったものであり、重要な知見であると思われる。

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  • Function of subendothelial basement membranes in Blood-Brain Barrier

    Grant number:14370434  2002 - 2003

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    NINOMIYA Yoshifumi, HIROHATA Satoshi, OOHASHI Toshitaka, YONEZAWA Tomoko, OHTSUKA Aiji

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    Grant amount:\14100000 ( Direct expense: \14100000 )

    We report the molecular cloning of a new member of the transmembrane-type immunoglobulin superfamily and designate the encoded protein as limitrin since it selectively localized to glia limitans in mouse brain. Limitrin cDNA was obtained using a subtractive hybridization procedure designed to identify molecules responsible for blood-brain barrier function. Western blots using a limitrin-specific antibody demonstrated that the gene product is expressed significantly in mouse brain and primary murine astrocytes, and is distributed in the plasma membrane. Immunohistochemical studies using confocal and electron microscopy clearly demonstrated highly polarized localization in astroglial endfeet in the perivascular region and under the pia mater in vivo. Limitrin is expressed in spinal cord and many areas of the brain but not in the median eminence or subfornical organ (the circumventricular organs) where the blood-brain barrier is lacking. Disruption of the blood-brain barrier by cold injury resulted in a drastic reduction in limitrin expression. Furthermore, during retrieval from cold injury the increased expression of limitrin in perivascular endfeet correlated with the recovery of angiogenesis in capillaries within the lesion margins. Our results suggest that limitrin is physically and functionally associated with the blood-brain barrier, implying that this protein may be useful as a diagnostic determinant of barrier integrity.

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  • Identifying new aggrecanase and producing antibody and gene-targeting mouse

    Grant number:13470312  2001 - 2002

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    HIROHATA Satoshi, YONEZAWA Tomoko, OOHASHI Toshitaka, NINOMIYA Yoshufumi, MOMOTA Ryusuke

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    Grant amount:\14000000 ( Direct expense: \14000000 )

    To investigate new aggrecanase, we have done the following experiments and got some data.
    1) Various ADAMTS-specific primers were designed and RT-PCR was performed. We cultured human chondrosarcoma cell lines OUMS-27 (Okayama University Medical School-27) and stimulated with interleukine-1 beta (IL-1β). To determine gene expression quantitatively, we employed real-time RT-PCR method. Briefly, total RNA was extracted and then DNAse treatmeat was done to eliminate contaminating genomic DNA. After reverse transcribed with random primers and enzymes, cDNA was served as a template for RT-PCR. GAPDH was used for the internal control.
    2) The expression and gene regulation by IL-1β was different amonf the ADAMTS-1,4, and -5, which were reported to have aggrecan cleaving property in vitro. We also investigated other ADAMTS gene expressions.
    3) We identified another up-regulating ADAMTS gene by IL-1β in OUMS-27 cells. We raised polyclonal antibody against this new ADAMTS gene using peptide sequence of this ADAMTS.
    4) We also started to making knock-out mouse for this gene. We screened mouse genomic library and identified several clones including this new ADAMTS gene. Under the collaboration with Dr. Apte's lab in the USA, we started to put our clones to ES cells.

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  • ADAMTSによるアミロイド前駆体蛋白のプロセッシングと細胞外基質への影響

    Grant number:13877097  2001 - 2002

    日本学術振興会  科学研究費助成事業  萌芽研究

    廣畑 聡, 米澤 朋子, 大橋 俊孝, 二宮 善文, 百田 龍輔

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    Grant amount:\2000000 ( Direct expense: \2000000 )

    ADAMファミリーのうち、ADM-10とADAM-17はαセクレターゼ機能を持つことが知られているが、ADAMTSが同様な機能を持つか検討した。
    まず、基礎的実験としてADAMTS-1はその遺伝子発現がリポポリサッカライド刺激により、各臓器において発現が上昇することから炎症において何らかの役割を持つことが示唆されている。そこで、ラット実験的心筋梗塞モデルを用いてADAMTS-1の発現形式をノーザンブロット法にて検討した。ADAMTS-1は非梗塞心臓では弱い発現しか認めなかったが、梗塞心においては、梗塞後6時間でその発現が大きく上昇していた。
    マウス脳におけるADAMTSの発現をADAMTS-1〜7において検討したが、いずれもそれほど強くなかった。海外共同研究として、アミロイド前駆体蛋白を強制発現し、恒常的に発現する細胞株を樹立している、アラバマ大学Fukuchi教授らと共同実験を開始した。同細胞株は、通常の神経系細胞よりも過剰にアミロイド前駆体蛋白を発現している。これまでの検討によって過剰なアミロイド蛋白前駆体が細胞表面及び培養上清中に存在することが確認された。この実験系において過剰なアミロイド前駆体の切断がαセクレターゼによって制御されているかどうかを検討する目的でこの細胞系におけるαセクレターゼ発現の検討を開始した。実験の条件検討が複雑であり、切断の確認は困難であった。今後は、In vivoの系における実験系の確立およびアルツハイマー脳におけるADAMTSの発現解析が重要と考えられた。

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  • Molecular biological studies of Ten-m2 gene function for the olfactory sensory neuron projections

    Grant number:12470356  2000 - 2001

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    OOHASHI Toshitaka, YONEZAWA Tomoko, NINOMIYA Yoshifumi

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    Grant amount:\14700000 ( Direct expense: \14700000 )

    To investigate the function of ten-m2/Neurestin gene for the olfactory sensory neuron projection, we have done the following experiments and got some data.
    Ten-m2 specific antibodies were raised using the C-terminal unique amino acid sequence among the ten-m family. The specific staining was confirmed in the mouse section and confirmed its embryonic expression in combination with in situ hybridization.
    Detection of Ten-m2 ligand: The extracellular domain of Ten-m2 protein was expressed in HEK293 cell culture system. We could detect specific protein band in the SDS-PAGE which bound to the ecto-domain. We are now identifying the protein.
    Chromosomal mapping of human ten-m2 gene. The ten-m2, 3, and 4 genes were mapped to the chromosome 5, 4and 11, respectively. There was no genetic disorder reported to the locus.
    Phenotypic analysis of the ten-m2 knockout mouse: By introducing a neomycin expression cassette in to the transmembrane exon of type II transmembrane protein, ten-m2, ten-m2 null mice were generated. There was no obvious phenotype so far. Ten-m2 null mice were viable and fertile, had a normal life span. There could be some compensation by another ten-m family members. The olfactory neuronal axon is now stained with MBP, marker of myelin and observed carefully.
    Another approach to look for the ligand for ten-m2: The ten-m protein seems to be quite unique for its protein structure. Structural analysis will become a very important information to search the ligands. Ultrastructural analysis of recombinants revealed the dimerfomation through the disufide-bond. The dimer could be formed between the different members of ten-m family in our reconstitution experiments. Since CSPGs are known to act for the axon guidance, and the versican is expressed in the olfactory bulb, we tried to clone some related genes. The Brain link protein is cloned and the expression pattern was analyzed. The data for the novel link protein is published (see references).

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  • Functional Analysis of Basement Membrane Collagen Genes

    Grant number:11694280  1999 - 2001

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    NINOMIYA Yoshifumi, YONEZAWA Tomoko, MOMOTA Ryusuke, OOHASHI Toshitaka

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    Grant amount:\8200000 ( Direct expense: \8200000 )

    By analyzing Col4a knockout mice, it is now possible to predict the biological function of α(IV) chains in vivo. We have now knockout mice of two strains: col4a3 and col4a6. Since we have evidence that there are major three molecular forms in basement membranes: (α1)2α2, α3α4α5, and (α5)2α6, it is now possible to set-up experiments to presume in vivo function of several α chains. We also set-up international collaboration to create another new project of gene targeting for col4α1 or col4α2, which makes it possible to make mice without type IV collagen.
    We have solved problems of which of the 6 α(IV) chains can make molecules. We raised monoclonal antibodies specific for α(IV) chains. By using these 6 antibodies, we came to the conclusion that there are at least three molecular forms as mentioned above: (α1)2α2, α3α4α5, and (α5)2α6. New biochemical analysis using antibodies that recognize native chains made possible to immunoprecipitate specific molecules when they are digested by pure bacterial collagenase. The products run on SDS-PAGE were analyzed by other monoclonal antibodies that recognize now denatured α-chains by Western blots. This now method concluded that our prediction from immunocytochemistry was indeed true. In other words, there were three (α1)2α2, α3α4α5, and (α5)2α6 molecules. By this method, we analyzed basement membranes from renal glomeruli and bladder and aortic smooth muscle cells.
    Specialized basement membrane from glomeruli was analyzed to contain supramolecular aggregates of (α1)2α2 and α3α4α5 molecules. The function of it is to filter blood to create urine. The similar phenomenon is found in choroid plexus in the brain. We analyzed it and found that it contains also the same compositions as glomerulus.

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  • Inhibitory mechanism of vascular endothelial cell proliferation by endostatin

    Grant number:11470274  1999 - 2001

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    NINOMIYA Yoshifumi, YONEZAWA Tomoko, MOMOTA Ryusuke, OOHASHI Toshitaka

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    Grant amount:\13900000 ( Direct expense: \13900000 )

    Under low oxygen condition, expression of collagen XVIII gene by cultured vascular endothelial cells reduced significantly. When it was analyzed by specific monoclonal antibodies, the collagen XVIII protein level was also reduced.
    Endostatin induced regression of chondrosarcoma growth and tumor angiogenesis in vivo. However, endostatin showed no effects on the proliferation and migration of chondrosarcoma cells in vitro. Next, we investigated the interactions between endostatin and endothelial cells in detail. Endostatin inhibited the migration and attachment on collagen I but did not affect proliferation of endothelial cells. Although the migration of endothelial cells was stimulated with angiogenic factors such as basic fibroblast growth factor and vascular endothelial growth factor, endostatin showed similar inhibitory effects on it in the presence or absence of stimulants.
    We came to the conclusion that non-vascular BMs contain predominantly one of the two types; I.e., subepithelial basement membranes contained type XVIII in general, whereas skeletal and cardiac muscles harbored prominently type XV. But basement membranes surrounding smooth muscle cells in vascular tissues contained one or both of them, depending on their locations. Interestingly, continuous or somatic capillaries contained both type XV and type XVIII collagens in their basement membranes; however, fenestrated or specialized capillaries such as glomeruli, liver sinusoids, lung alveoli, and splenic sinusoids expressed only type XVIII chains in their basement membranes, lacking type XV chain. This observation could imply different functions of basement membranes in various tissues and organs that use different mechanisms for the endogenous control of angiogenesis.

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  • 新生血管の構築と基底膜コラーゲンの新しい機能

    Grant number:11877121  1999 - 2000

    日本学術振興会  科学研究費助成事業  萌芽的研究

    二宮 善文, 米澤 朋子, 百田 龍輔, 大橋 俊孝, 植木 靖好

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    Grant amount:\2000000 ( Direct expense: \2000000 )

    1 血管系特に毛細血管全体におけるXVIIIコラーゲンおよびXVコラーゲン遺伝子の発現
    両コラーゲンは内皮細胞直下基底膜と血管壁に存在する平滑筋細胞周囲の基底膜であることがわかった。毛細血管内皮細胞下基底膜ではXVIII型とXV型を共通に発現するものが認められる.即ち腎や小腸粘膜、皮膚の毛細血管の内皮細胞下基底膜はXVIII型/XV型両者が共存する.しかしこれは組織臓器により異なり、肺胞壁、肝類洞、糸球体基底膜はXVIII型が主であり、他方胎盤、心臓、骨格筋、小腸筋層ではXV型が主であった.しかし、XVIII型/XV型両者の発現のない毛細血管は認められなかった.このように、毛細血管内皮細胞下基底膜のXVIII型とXV型の発現には多様性がある、XVIII型とXV型ともに発現するものが基本だが、類洞や糸球体基底膜のように特殊化した毛細血管ではXVIII型が優位に発現された.
    2 基底膜IV型コラーゲンの新しい機能
    IV型コラーゲンのα鎖は6種類あり、中央にコラーゲン部分、N末(NC2ドメイン)とC末(NC1ドメイン)に非コラーゲンドメインを有する。私達は、これらの6種類のα鎖のNC1ドメインをリコンビナントで作製し、これらを用いて血管内皮細胞の接着性と走化性をみたところ、α2、α3、α6鎖NC1ドメインにそれを抑制する活性が認められた。さらに、血管内皮細胞の接着と走化性はインテグリンαvβ1依存性であることが分かった。鶏胚の系(CAMアッセイ)でbFGFによって誘導された血管新生が、明らかにコントロールとくらべて優位に、リコンビナントα2、α3、α6鎖NC1ドメインによって抑制されるという結果を得た。このことは初めての報告であり、IV型コラーゲンの断片に新しい機能があることが明らかになったという意味で意義のある発見である。

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  • Reconstruction of basement membranes aiming at artificial organs

    Grant number:10557113  1998 - 2000

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B).

    NINOMIYA Yoshifumi, YONEZAWA Tomoko, MOMOTA Ryusuke, OOHASHI Toshitaka

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    Grant amount:\12900000 ( Direct expense: \12900000 )

    Ultimate goal of the research project is to make artificial organs to insert basement membrane materials between epithelial layers and extracellular matrix. In order to make type IV collagen molecules in vitro, we we did the following investigations :
    * Molecular composition of basement membranes underneath smooth muscle cells varies in different organs, which could be related to specific function of the individual organs.
    * We first isolated and characterized genomic DNA fragments that cover the 5'flanking sequences of COL4A3 and COL4A4 genes, which provided information to delineate the promoter activity for the tissue-specific expression of the six type IV collagen genes.
    * Molecular forms of collagen IV in follicle basement membranes are different in development.
    * We identified interactions between the α2(IV) and ProMMP-9 by immunoprecipitations and blotting.
    * Basement membrane collagen IV molecules diminish in parallel with malignancy and invasiveness when analyzed in tumor progression.
    * Although mRNA expression level of α5 decreased in kidney of a canine Alport case, that of α6 resulted in unchanged. But the protein level of both chains cannot be found any. These results suggest a possibility of a molecular form of α5/α6.
    * Differential expression of collagen IV genes in epithelial basement membranes was analyzed in detail.
    * Here we define a novel function for soluble non-collagenous (NC1) domains of the α2(IV), α3(IV), and α6(IV) chains of human collagen type IV in the regulation of angiogenesis and tumor growth. These NCI domains were shown to regulate endothelial cell adhesion and migration by distinct αv and β1 integrin-dependent mechanisms.
    * In Lmx1b(-/-) mice, expression of both α3 and α4 is strongly diminished in GBM, whereas that of α1, α2 and α5 is unchanged. Moreover, LMX1B binds specifically to a putative enhancer in intron 1 of mouse/human COL4A4 and upregulates reporter constructs containing the enhancer-like sequence.

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