Updated on 2025/12/24

写真a

 
HIRAYAMA Haruko
 
Organization
Scheduled update Assistant Professor
Position
Assistant Professor
Homepage
http://www.cc.okayama-u.ac.jp/~animal/
External link

Degree

  • 博士（獣医学） ( 岐阜大学 )

Research Interests

  • 消化管運動

  • 消化管神経系

Research Areas

  • Life Science / Veterinary medical science

  • Life Science / Laboratory animal science

  • Life Science / Physiology

Education

  • Gifu University   連合獣医学研究科博士課程  

    2007.4 - 2011.3

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  • Gifu University   農学部   獣医学科

    1997.4 - 2003.3

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Research History

  • Okayama University   Department of Animal Resources, Advanced Science Research Center   Assistant Professor

    2012.4

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  • University of Melbourne   Department of Anatomy and Cell Biology   Research Assistant

    2012.1 - 2012.3

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  • University of Melbourne   Department of Anatomy and Cell Biology

    2011.6 - 2011.11

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  • Ai Animal Clinic

    2003.4 - 2007.3

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Papers

  • Bacterial DNA and serum IgG antibody titer assays for assessing infection of human-pathogenic and dog-pathogenic Porphyromonas species in dogs. Reviewed International journal

    Masako Tai-Tokuzen, Takashi Ito, Kazuya Tamura, Haruko Hirayama, Hirohito Ogawa, Shin Nakamura, Keisuke Okubo, Kazuhiro Omori, Tadashi Yamamoto, Katsumi Mominoki, Shogo Takashiba

    Heliyon   10 ( 11 )   e31872   2024.6

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    Language：English   Publishing type：Research paper (scientific journal)  

    Periodontal disease is highly prevalent in both humans and dogs. Although there have been reports of cross-infection of periodontopathic bacteria, methods for assessing it have yet to be established. The actual status of cross-infection remains to be seen. The purpose of this study was to evaluate the utility of bacterial DNA and serum immunoglobulin G (IgG) antibody titer assays to assess infection of human-pathogenic and dog-pathogenic Porphyromonas species in dogs. Four experimental beagles were used for establishing methods. Sixty-six companion dogs at veterinary clinics visiting for treatment and prophylaxis of periodontal disease were used and divided into healthy, gingivitis, and periodontitis groups. Periodontal pathogens such as Porphyromonas gingivalis and Porphyromonas gulae were investigated as target bacteria. DNA levels of both bacteria were measured using species-specific primers designed for real-time polymerase chain reaction (PCR). Serum IgG titers of both bacteria were measured by enzyme-linked immunosorbent assay (ELISA). PCR primers were confirmed to have high sensitivity and specificity. However, there was no relationship between the amount of bacterial DNA and the severity of the periodontal disease. In addition, dogs with periodontitis had higher IgG titers against both bacteria compared to dogs in the healthy and gingivitis groups; there was cross-reactivity between the two bacteria. Receiver operating characteristic (ROC) analysis of IgG titers against both bacteria showed high sensitivity (>90 %) and specificity (>75 %). Since both bacteria were distinguished by DNA assays, the combination of these assays may be useful in the evaluation of cross-infection.

    DOI： 10.1016/j.heliyon.2024.e31872

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  • Innovative submucosal injection solution for endoscopic resection with phosphorylated pullulan: a preclinical study. Reviewed International journal

    Takuya Satomi, Yukari Ochi, Takumi Okihara, Hiroki Fujii, Yasuhiro Yoshida, Katsumi Mominoki, Haruko Hirayama, Junki Toyosawa, Yasushi Yamasaki, Seiji Kawano, Yoshiro Kawahara, Hiroyuki Okada, Motoyuki Otsuka, Akihiro Matsukawa

    Gastrointestinal endoscopy   99 ( 6 )   1039 - 1047   2024.6

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    BACKGROUND AND AIMS: A submucosal injection solution is used to assist in endoscopic surgery. The high viscosity of current solutions makes them difficult to inject. In the present study, we developed an extremely low-viscosity, easy-to-use submucosal injection solution using phosphorylated pullulan (PPL). METHODS: The PPL solutions were prepared at different concentrations, and their viscosities were measured. The mucosal elevation capacity was evaluated using excised porcine stomachs. Controls included 0.4% sodium hyaluronate (SH), 0.6% sodium alginate (SA), and saline. To evaluate the practicality, the catheter injectability of 0.7% PPL was measured, and EMR and endoscopic submucosal dissection (ESD) were performed using the stomach and colorectum of live pigs. As controls, 0.4% SH and saline were used. RESULTS: The PPL solutions were of extremely low viscosity compared to the solutions of 0.4% SH and 0.6% SA. Nevertheless, the mucosal elevation capacity of PPL solutions for up to 0.7% concentration was similar to that of 0.4% SH, and 0.7% PPL was less resistant to catheter infusion than 0.4% SH and 0.6% SA. In live pig experiments with endoscopic mucosal resection and ESD, snaring after submucosal injection of 0.7% PPL was easier than with 0.4% SH, ESD with 0.7% PPL produced less bubble formation than with 0.4% SH, and the procedure time tended to be shorter with 0.7% PPL than with 0.4% SH because of the shorter injection time. CONCLUSIONS: The PPL solution is an innovative and easy-to-use submucosal injection solution.

    DOI： 10.1016/j.gie.2024.01.015

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  • Risk assessment for hepatitis E virus infection from domestic pigs introduced into an experimental animal facility in a medical school Reviewed

    Hirohito Ogawa, Haruko Hirayama, Satsuki Tanaka, Norio Yata, Hikaru Namba, Nobuko Yamashita, Kenzo Yonemitsu, Ken Maeda, Katsumi Mominoki, Masao Yamada

    Journal of Veterinary Medical Science   81 ( 8 )   1191 - 1196   2019

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    DOI： 10.1292/jvms.19-0086

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  • Effects of Endoprosthesis Head Material on Acetabular Cartilage Metabolism: An Animal Study Using Crossbred Pigs.

    Shuhei Matsui, Tokifumi Majima, Katsumi Mominoki, Haruko Hirayama, Yasushi Oshima, Kenji Takahashi, Shinro Takai

    Journal of Nippon Medical School = Nippon Ika Daigaku zasshi   85 ( 6 )   309 - 314   2018

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    Language：English   Publishing type：Research paper (scientific journal)  

    BACKGROUND: Hip endoprosthesis is one option for the treatment of displaced femoral neck fractures and avascular necrosis of the femoral head. Few reports are available describing acetabular cartilage metabolism after endoprosthesis surgery of the hip. The purpose of this study was to compare the biological effects on cartilage between cobalt-chrome (Co-Cr) and alumina ceramic heads wherein the cartilage articulates directly. METHODS: We used the acetabular cartilage from six hips of three immature crossbred pigs to examine the effects on cytokines, the amount of hyaluronic acid (HA), and cartilage mRNA expression of ceramic head and Co-Cr head endoprosthesis. Mechanical loading of materials of Co-Cr and ceramic heads was performed on the acetabular cartilage in culture media as an organ culture model. Thereafter, protein levels of cytokines (MMP-1, 3, TNF-alpha (α), Interleukin (IL)-1 alpha (α), and IL-1 beta (β)) and the amount of HA were measured from the culture media. Cartilage RNA extraction was performed, and quantitative reverse transcriptase-polymerase chain reaction was performed with primer sets for type I, II, and III collagens; aggrecan; MMP-1, 3, 13; TNF-α; and IL-1 α, IL-1 β. RESULTS: Protein level of IL-1 β and amount of HA in the Co-Cr group were significantly higher than those of the Ceramic group. Type II collagen mRNA expression in the Ceramic group was significantly higher than in the Co-Cr group. IL-1 β mRNA expression was significantly higher in the Co-Cr group than in the Ceramic group. CONCLUSIONS: The present study showed that ceramic bipolar produces smaller adverse effects on cartilage cells compared to Co-Cr bipolar. These results could have significant implications for implant usage not only in hip joints, but also in other joints, including the shoulder, talus and radial head.

    DOI： 10.1272/jnms.JNMS.2018_85-50

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  • Sites of action of ghrelin receptor ligands in cardiovascular control Reviewed

    Brid Callaghan, Billie Hunne, Haruko Hirayama, Daniela M. Sartor, Trung V. Nguyen, Fe C. Abogadie, Dorota Ferens, Peter McIntyre, Kung Ban, Jonathan Baell, John B. Furness, James A. Brock

    AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY   303 ( 8 )   H1011 - H1021   2012.10

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1152/ajpheart.00418.2012

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  • Identification of neurons that express ghrelin receptors in autonomic pathways originating from the spinal cord Reviewed

    John B. Furness, Hyun-Jung Cho, Billie Hunne, Haruko Hirayama, Brid P. Callaghan, Alan E. Lomax, James A. Brock

    CELL AND TISSUE RESEARCH   348 ( 3 )   397 - 405   2012.6

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1007/s00441-012-1405-9

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  • Extract of grains of paradise and its active principle 6-paradol trigger thermogenesis of brown adipose tissue in rats Reviewed

    Momoe Iwami, Fatma A. Mahmoud, Takahiko Shiina, Haruko Hirayama, Takeshi Shima, Jun Sugita, Yasutake Shimizu

    AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL   161 ( 1-2 )   63 - 67   2011.4

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.autneu.2010.11.012

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  • Intraluminal administration of zingerol, a non-pungent analogue of zingerone, inhibits colonic motility in rats Reviewed

    Momoe Iwami, Takahiko Shiina, Haruko Hirayama, Yasutake Shimizu

    BIOMEDICAL RESEARCH-TOKYO   32 ( 2 )   181 - 185   2011.4

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.2220/biomedres.32.181

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  • Extract of grains of paradise and its active principle 6-paradol trigger thermogenesis of brown adipose tissue in rats. Reviewed

    Iwami Momoe, Mahmoud Fatma A, Shiina Takahiko, Hirayama Haruko, Shima Takeshi, Sugita Jun, Shimizu Yasutake

    Autonomic neuroscience : basic&clinical   161 ( 1-2 )   63 - 67   2011.4

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    Language：English   Publishing type：Research paper (scientific journal)  

    Grains of paradise (GP) is a species of the ginger family, Zingiberaceae, extracts of which have a pungent, peppery taste due to an aromatic ketone, 6-paradol. The aim of this study was to explore the thermogenic effects of GP extracts and of 6-paradol. Efferent discharges from sympathetic nerves entering the interscapular brown adipose tissue were recorded. Intragastric injection of a GP extract or 6-paradol enhanced the efferent discharges of the sympathetic nerves in a dose-dependent manner. The enhanced nerve discharges were sustained for as long as 3h. The rats did not become desensitized to thestimulatory effects these compounds on sympathetic nerve activity. The tissue temperature of brown adipose tissue showed significant increase in rats injected with 6-paradol. These results demonstrate that GP extracts and 6-paradol activate thermogenesis in brown adipose tissue, and may open up new avenues for the regulation of weight loss and weight maintenance.

    DOI： 10.1016/j.autneu.2010.11.012

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  • Inhibitory effects of zingerone, a pungent component of Zingiber officinale Roscoe, on colonic motility in rats Reviewed

    Momoe Iwami, Takahiko Shiina, Haruko Hirayama, Takeshi Shima, Tadashi Takewaki, Yasutake Shimizu

    Journal of Natural Medicines   65 ( 1 )   89 - 94   2011.1

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1007/s11418-010-0463-0

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  • Inhibitory effects of zingerone, a pungent component of Zingiber officinale Roscoe, on colonic motility in rats. Reviewed

    Iwami Momoe, Shiina Takahiko, Hirayama Haruko, Shima Takeshi, Takewaki Tadashi, Shimizu Yasutake

    Journal of natural medicines   65 ( 1 )   89   2011.1

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    Language：English   Publishing type：Research paper (scientific journal)  

    Ginger (rhizome of Zingiber officinale Roscoe) is an herbal medicine for the treatment of gastrointestinal disorders including constipation and diarrhea. Zingerone is a likely active constituent responsible for the antidiarrheal activity of ginger. The current study was designed to characterize pharmacological actions of zingerone on colonic motility. To evaluate pharmacological effects of zingerone on colonic motility, we used isolated colonic segments from rats, in which mechanical responses were recorded in the longitudinal direction. In addition, we evaluated the effects on colonic motility in vivo by measuring intraluminal pressure changes and expelled fluid volume from the colon in anesthetized rats. Zingerone was applied to the lumen of the colon to allow the drug to access from the mucosal side. Zingerone inhibited spontaneous contractile movements in the isolated colonic segments in a dose-dependent manner. The inhibitory effects of zingerone on colonic movements were not affected by pretreatment with capsazepine, a typical antagonist of transient receptor potential vanilloid 1. In addition, tetrodotoxin, a blocker of voltage-dependent sodium channels on neurons, did not a

    DOI： 10.1007/s11418-010-0463-0

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  • Contrasting effects of ghrelin and des-acyl ghrelin on the lumbo-sacral defecation center and regulation of colorectal motility in rats. Reviewed

    Hirayama H, Shiina T, Shima T, Kuramoto H, Takewaki T, B Furness J, Shimizu Y

    Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society   22 ( 10 )   1124 - 1131   2010.10

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  • Contractile responses induced by physalaemin, an analogue of substance P, in the rat esophagus Reviewed

    Takahiko Shiina, Takeshi Shima, Haruko Hirayama, Hirofumi Kuramoto, Tadashi Takewaki, Yasutake Shimizu

    EUROPEAN JOURNAL OF PHARMACOLOGY   628 ( 1-3 )   202 - 206   2010.2

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    DOI： 10.1016/j.ejphar.2009.11.039

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  • Contractile responses induced by physalaemin, an analogue of substance P, in the rat esophagus. Reviewed

    Shiina Takahiko, Shima Takeshi, Hirayama Haruko, Kuramoto Hirofumi, Takewaki Tadashi, Shimizu Yasutake

    European journal of pharmacology   628 ( 1-3 )   202 - 206   2010.2

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    We examined the effects of physalaemin, an agonist of tachykinin receptors, on mechanical responses in the rat esophagus to clarify possible regulatory roles of tachykinins in esophageal motility. Exogenous application of physalaemin caused tonic contractions in rat esophageal segments when tension was recorded in the longitudinal direction but not when tension was recorded in the circular direction. The physalaemin-evoked contractions were blocked by pretreatment with nifedipine, a blocker of L-type calcium channels in both striated and smooth muscle cells. However, tetrodotoxin, a blocker of voltage-dependent sodium channels in striated muscle cells and neurons, did not affect the physalaemin-induced contractions. These results indicate that physalaemin might induce contractile responses in longitudinal smooth muscle of the muscularis mucosa via direct actions on muscle cells but not on neurons. Although pretreatment with a tachykinin NK(1) receptor antagonist, N-acetyl-l-tryptophan 3,5-bis (trifluoromethyl) benzyl ester (L-732,138), did not significantly affect the physalaemin-evoked contractions in rat esophageal segments, a tachykinin NK(2) receptor antagonist, (S)-N-methyl-N[

    DOI： 10.1016/j.ejphar.2009.11.039

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  • Contractile Properties of Esophageal Striated Muscle: Comparison with Cardiac and Skeletal Muscles in Rats Reviewed

    Takahiko Shiina, Takeshi Shima, Kazuaki Masuda, Haruko Hirayama, Momoe Iwami, Tadashi Takewaki, Hirofumi Kuramoto, Yasutake Shimizu

    JOURNAL OF BIOMEDICINE AND BIOTECHNOLOGY   2010   459789   2010

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    DOI： 10.1155/2010/459789

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  • Contractile properties of esophageal striated muscle: comparison with cardiac and skeletal muscles in rats. Reviewed

    Shiina Takahiko, Shima Takeshi, MasudaKazuaki, Hirayama Haruko, Iwami Momoe, Takewaki Tadashi, Kuramoto Hirofumi, Shimizu Yasutake

    Journal of biomedicine&biotechnology   2010   459789   2010

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    The external muscle layer of the mammalian esophagus consists of striated muscles. We investigated the contractile properties of esophageal striated muscle by comparison with those of skeletal and cardiac muscles. Electrical field stimulation with single pulses evoked twitch-like contractile responses in esophageal muscle, similar to those in skeletal muscle in duration and similar to those in cardiac muscle in amplitude. The contractions of esophageal muscle were not affected by an inhibitor of gap junctions. Contractile responses induced by high potassium or caffeine in esophageal muscle were analogous to those in skeletal muscle. High-frequency stimulation induced a transient summation of contractions followed by sustained contractions with amplitudes similar to those of twitch-like contractions, although a large summation was observed in skeletal muscle. The results demonstrate that esophageal muscle has properties similar but not identical to those of skeletal muscle and that some specific properties may be beneficial for esophageal peristalsis.

    DOI： 10.1155/2010/459789

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  • Extract from Calotropis procera latex activates murine macrophages Reviewed

    Abdel Iatif Shaker Seddek, Motamed Elsayed Mahmoud, Takahiko Shiina, Haruko Hirayama, Momoe Iwami, Seiji Miyazawa, Hideki Nikami, Tadashi Takewaki, Yasutake Shimizu

    JOURNAL OF NATURAL MEDICINES   63 ( 3 )   297 - 303   2009.7

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    DOI： 10.1007/s11418-009-0335-7

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  • Capsaicin pretreatment attenuates LPS-induced hypothermia through TRPV1-independent mechanisms in chicken Reviewed

    Hideki Nikami, Motamed Elsayed Mahmoud, Yasutake Shimizu, Takahiko Shiina, Haruko Hirayama, Momoe Iwami, Reem Mahmoud Dosoky, Moustafa Mohamed Ahmed, Tadashi Takewaki

    LIFE SCIENCES   82 ( 23-24 )   1191 - 1195   2008.6

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    DOI： 10.1016/j.lfs.2008.04.003

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  • Chicken B lymphoma DT40 cells as a useful tool for in vitro analysis of pathogenic infectious bursal disease virus Reviewed

    Kaori Terasaki, Haruko Hirayama, Christopher J. Kasanga, Min Thein Maw, Kenji Ohya, Tsuyoshi Yamaguchi, Hideto Fukushi

    JOURNAL OF VETERINARY MEDICAL SCIENCE   70 ( 4 )   407 - 410   2008.4

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    DOI： 10.1292/jvms.70.407

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  • Fatal necrotic enteritis associated with Clostridium perfringens in wild crows (Corvus macrorhynchos) Reviewed

    Y Asaoka, T Yanai, H Hirayama, Y Une, E Saito, H Sakai, M Goryo, H Fukushi, T Masegi

    AVIAN PATHOLOGY   33 ( 1 )   19 - 24   2004.2

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1080/03079450310001636228

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MISC

  • 実験動物の安楽死の課題 安楽死処置におけるセコバルビタールの有用性

    赤木佐千子, 平山晴子, 樅木勝巳

    Labio 21   ( 81 )   2020

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  • コモンマーモセットを育てる

    橋本春菜, 矢田範夫, 赤木佐千子, 平山晴子, 樅木勝巳

    日本実験動物技術者協会総会講演要旨集   53rd   2019

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  • Helicobacter hepaticusの検疫方法に関する検討

    石原すみれ, 平山晴子, 樅木勝巳

    日本実験動物技術者協会総会講演要旨集   53rd   2019

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  • 動物実験施設に搬入される家畜ブタにおけるE型肝炎ウイルスの遺伝子検出および血清学的解析

    小川 寛人, 難波 ひかる, 山下 信子, 山田 雅夫, 田中 爽暉, 矢田 範夫, 平山 晴子, 樅木 勝巳, 米満 研三, 前田 健

    臨床とウイルス   46 ( 2 )   S58 - S58   2018.4

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    Language：Japanese   Publisher：日本臨床ウイルス学会  

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  • 【消化器疾患の病態に関わる新たな展開】 グレリンの大腸運動促進作用

    平山 晴子, 樅木 勝巳, 椎名 貴彦, 志水 泰武

    日本薬理学雑誌   143 ( 6 )   270 - 274   2014.6

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  • ラットにおけるグレリンの大腸運動調節作用

    平山晴子, 樅木勝巳, 椎名貴彦, 志水泰武

    九州実験動物雑誌   29   3 - 7   2013

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  • 脊髄を介するグレリンの大腸運動促進作用

    平山晴子, 樅木勝巳, 椎名貴彦, 志水泰武

    岡山実験動物研究会報   29 ( 29 )   51 - 54   2013

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  • グレリンによる排便促進機構

    志水 泰武, 平山 晴子, 嶋 剛士, 椎名 貴彦

    自律神経   48 ( 2 )   86 - 88   2011

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  • グレリンによる大腸運動促進機構

    平山 晴子, 椎名 貴彦, 嶋 剛士, 石見 百江, 志水 泰武

    日本病態生理学会雑誌   19 ( 1 )   28 - 33   2010.5

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  • Neuronal controls and contractile properties of esophageal muscles in neonatal rats

    Takahiko Shiina, Chiaki Nakamori, Haruko Hirayama, Takeshi Shima, Hirofumi Kuramoto, Yasutake Shimizu

    JOURNAL OF PHYSIOLOGICAL SCIENCES   60   S173 - S173   2010

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  • MODULATORY ACTIONS OF TACHYKININS ON THE STRIATED AND SMOOTH MUSCLE MOTILITY IN THE RAT ESOPHAGUS

    Takahiko Shiina, Takeshi Shima, Haruko Hirayama, Ammar Boudaka, Juergen Woerl, Winfried L. Neuhuber, Tadashi Takewaki, Yasutake Shimizu

    JOURNAL OF PHYSIOLOGICAL SCIENCES   59   288 - 288   2009

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  • ENHANCEMENT OF COLORECTAL MOTILITY BY GHRELIN, BUT NOT DES-ACYL GHRELIN, THROUGH AN ACTIVATION OF LUMBO-SACRAL DEFECATION CENTER IN RATS

    Yasutake Shimizu, Haruko Hirayama, Takahiko Shiina, John B. Furness, Tadashi Takewaki

    JOURNAL OF PHYSIOLOGICAL SCIENCES   59   472 - 472   2009

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  • Acylated ghrelin, but not desacyl ghrelin, enhances colorectal motility by activating lumbo-sacral defecation center in rats

    Yasutake Shimizu, Haruko Hirayama, Takahiko Shiina, John Furness, Tadashi Takewaki

    JOURNAL OF PHARMACOLOGICAL SCIENCES   106   101P - 101P   2008

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Research Projects

  • 脊髄排便中枢におけるグレリン作動性大腸運動制御機構の解明

    Grant number：25K11226  2025.04 - 2030.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    平山 晴子, 美藤 純弘

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

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  • 筋組織欠損を再生および再建するための脱細胞化骨格筋組織の調整方法および移植片の開発

    2025.04 - 2026.03

    日本医療研究開発機構研究費  橋渡し研究プログラムシーズA  医療機器開発

    藤原智洋, 藤里俊哉, 澤田和也, 尾﨑敏文, 長谷川翼, 平山晴子

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    Authorship：Coinvestigator(s) 

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  • 歩行障害を示す二分脊椎モデル動物を用いた運動機能障害に関する基礎的研究

    Grant number：24K11045  2024.04 - 2025.11

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    樅木 勝巳, 平山 晴子

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    Authorship：Coinvestigator(s) 

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

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  • A novel mechanism for promoting osteoblast differentiation by mechanical stimulation -- Function of transcription cofactor VGLL3

    Grant number：22K06790  2022.04 - 2025.03

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

    池亀 美華, 岡村 裕彦, 平山 晴子, 福原 瑶子

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    Authorship：Coinvestigator(s) 

    Grant amount：\4030000 （ Direct expense: \3100000 、 Indirect expense：\930000 ）

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  • 歩行障害を示す二分脊椎モデル動物における運動機能障害の病態に関する基礎的研究

    Grant number：20K08230  2020.04 - 2024.03

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    樅木 勝巳, 藤原 隆, 平山 晴子

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

    椎弓の欠損を主徴とする非致死性脊髄奇形である二分脊椎症は，椎弓の欠損状態や奇形箇所の脊髄の状態から病形が区分される。本奇形は、椎弓欠損のみに奇形が限局しする潜在性型と椎弓欠損に髄膜あるいは脊髄と髄膜の両方が巻き込まれる嚢胞性型とに区分される。一般に潜在性型は無症状であるが，嚢抱性型は種々の程度の神経障害を示す。これまでの二分脊椎症に関連する研究では，この神経障害の病態は臨床知見に基づいたものがほとんどであり，実験に基づく知見は臨床知見に比べてはるかに少ない。特に、幼若年時に臨床症状を示さず、年齢進行に伴って神経症状を呈する場合がある潜在性型二分脊椎症においては、神経症状の発現に至る病態については不明な点が未だ多く残されている。
    我々はこれまでに二分脊椎症で見られる神経障害の病態を詳細に解析することを目的として，ヒト二分脊椎症患者に似た後肢運動障害を示す二分脊椎モデル動物を開発し，奇形領域の神経細胞の発生異常や神経伝導路形成異常が二分脊椎症で併発することが多い歩行障害を誘発する可能性を示してきた。すなわち、本モデルは、人為的に二分脊椎を引き起こすことから本奇形の病態解析に有用なモデル動物の可能性を示した。
    既報では二分脊椎症モデル動物が示す二分脊椎症の病型は、嚢胞型ではあるが最も重症例である脊椎裂に類似したものであり、ヒトにおいて最も発症例が多い病型を示さないという。一方、これまでに我々は、提示したモデルにおいて脊椎裂ではない嚢胞型や潜在型の病型を示すことを示し、モデル動物として高いポテンシャルを有することを確認した。令和3年度には、潜在型の二分脊椎を発生させるような処置を行い、初期胚を用いた解析を行ったが、嚢胞型のような発生遅延現象が認められなかった。

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  • 脊髄におけるグレリンの大腸運動亢進作用機構の解明

    Grant number：19K17492  2019.04 - 2024.03

    日本学術振興会  科学研究費助成事業  若手研究

    平山 晴子

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

    グレリンは、脊髄腰仙髄部の排便中枢に作用して、大腸運動を亢進する。しかしこの大腸運動亢進作用は主にin vivoの実験系で現象としてとらえられているのみであり、その詳細なメカニズムは不明である。本研究は、脊髄におけるグレリンの大腸運動亢進作用について、脊髄から大腸への経路における作用機序の詳細解明をすることを目的とする。本年度は前年度に引き続き、以下の実験を行った。
    （１）グレリンの大腸における作用部位を詳細に特定：麻酔下のラットを用い、グレリンを脊髄腔内に投与した際の大腸運動を測定した。本年度以前の実験により、グレリンは大腸の直腸領域の運動を亢進させることが明らかになっており、直腸から肛門の領域について同一個体で同時に複数箇所の内圧を測定し、グレリン投与時の大腸運動について確認した。
    （２）グレリンの作用発現時における神経の出力を確認：麻酔下ラットの骨盤神経に記録電極を留置し、グレリン投与時における神経の複合活動電位記録を試みた。長らく活動記録には至っていなかったが、本年度はようやく、神経活動電位と思われる記録に成功した。しかしながらまだ例数も少なく、現在、手技の安定化を目指し実験を重ねている。
    （３）脊髄神経細胞における作用を解析：パッチクランプ法を用いて、グレリンの作用点である脊髄において、ニューロンに惹起される変化を明らかにすることを試みた。神経標識色素を新生ラットの腹腔内に投与し、脊髄に存在する腹腔内臓器支配神経をあらかじめ逆行性に標識した脊髄スライス標本を作製し、パッチクランプ法により神経活動記録を行うことを目的とした。前年度の予備実験に続き、条件検討の実験を行っており、脊髄ニューロンが標識色素により染色されること、また染色される細胞の局在について確認したが、グレリン投与時の反応記録には至っていない。

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  • Development of periodontal tissue regeneration therapy for horizontal alveolar bone resorption with collagen-binding FGF-2

    Grant number：19H03831  2019.04 - 2023.03

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

    高柴 正悟, 松下 治, 平山 晴子, 山本 直史, 美間 健彦, 伊東 孝

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    Grant amount：\17030000 （ Direct expense: \13100000 、 Indirect expense：\3930000 ）

    本研究は，水平性骨吸収に対する歯周組織再生療法を実現するために，既に歯科臨床で応用されている塩基性線維芽細胞増殖因子（bFGF）と細菌由来のコラーゲン結合ドメイン（CBD）を組み合わせた融合タンパク質（CBFGF）を用いた研究である。本研究の目的は，CBFGFの最適化とイヌを用いた実験モデルによる非臨床試験データの取得である。2019年度は，認可済みのbFGF製剤に合わせて，CBFGFを組換融合型から架橋型へ変更するための実験とイヌの骨欠損モデルを用いた実験を実施した。まず，CBFGFの最適化について，架橋反応の比率・濃度などの反応条件を決定するために，多量のbFGFとCBDを要した。そこで，大腸菌生産系を用いてbFGFとCBDを精製し，実験効率の改善を図った。現在は，CBDとbFGFを架橋する適切な条件を探索しているところである。また，イヌを用いた実験モデルでは，歯周組織再生療法の適応症である垂直性骨欠損（2壁性）で組換融合型CBFGFの有効性を実証し，水平性骨欠損および垂直性骨欠損（1壁性）を作製して，組換融合型CBFGFを投与した。現在，動物へのタンパク質の投与は終了し，一部のサンプルはCT撮影まで行っている。
    また，組換融合型CBFGFについてこれまでに得られたデータについては，研究発表（Takashiba S, International Academy of Periodontology, 2019；Nakamura S, et al, International Association of Dental Research, General Session & Exhibition, 2019；岡本ら，日本歯科保存学会，2019；高柴，BioJapan 2019）を行って，今後の研究の進め方やCBFGFの製剤化に関して，様々な研究者や企業と情報交換を行った。

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  • Pathophysiological research on the neural development of the affected spinal cord using the animal model of spina bifida

    Grant number：17K11509  2017.04 - 2020.03

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

    Mominoki Katsumi

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

    This research using the animal model with spina bifida, which is one of the congenital malformation of a partial spinal cord, was operated to investigate the pathophysiology of the leg dysfunction in this model, using clues to understanding the nature of the neuronal development in the normal and/or abnormal the spinal cord region. On the other hand, in comparing the pathological condition of the spina bifida model animal, which is the final objective of this study, with the pathological condition of human spina bifida, the model used from the beginning caused inconvenience. Therefore, we decided to improve the method of creating the spina bifida model in this study. As a result, it has become possible to create a model that exhibits symptoms that are more similar to those of human spina bifida. It was suggested that the addition of this model to the experimental subjects may lead to more socially meaningful results.

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  • Regulatory mechanism for controlling colorectal motility via the spinal defecation center.

    Grant number：26292164  2014.04 - 2017.03

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

    Shimizu Yasutake, SHIINA Takahiko

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    Grant amount：\16380000 （ Direct expense: \12600000 、 Indirect expense：\3780000 ）

    The aim of this work was to clarify the regulatory mechanism for controlling colorectal motility via the spinal defecation center. By using in vivo experimental system in which gut motility can be assessed in the presence of intact neural connection between the central nervous system and gut, it has been demonstrated that noradrenalin, serotonin and dopamine injected into the spinal defecation center elicit large propulsive colorectal motility. These monoamines are transmitters associated with the descending pain inhibitory pathway. Considering that nociceptive stimuli including visceral pain activate the descending inhibitory pathway to suppress noxious input in the spinal cord, our results provide a rationale for the concurrent appearance of chronic abdominal pain and colonic dysmotility in patients with irritable bowel syndrome. These findings would provide a novel therapeutic strategy for stress-induced diarrhea and constipation.

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  • Basic research on the pathophysiological sequences of neural development on the affected spinal cord using the animal model of spina bifida aperta

    Grant number：25462774  2013.04 - 2016.03

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

    Mominoki Katsumi, HIRAYAMA HARUKO

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

    This research was carried out to determine whether the neural disruption in spina bifida model animals with the leg dysfunction was occurred or not. the research suggested that the affected spinal cord to create spina bifida in the model lead to the neural disruption, regardless of the normal appearance of the developed spinal cord on the surface.

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  • The spinal defecation center-mediated prokinetic effect of ghrelin and its involvement in dysmotility of the large intestine.

    Grant number：22380157  2010 - 2012

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

    SHIMIZU Yasutake, KURAMOTO Hiroshi, YAMAMOTO Yoshio, HIRAYAMA Haruko, SHIINA Takahiko

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    Grant amount：\19110000 （ Direct expense: \14700000 、 Indirect expense：\4410000 ）

    The aim of this work was to clarify the regulatory mechanism of the central nervous system on gut motility. By using in vivo experimental system in which gut motility can be assessed in the presence of intact neural connection between the central nervous system and gut, it has been demonstrated that ghrelin and dopamine injected into the spinal defecation center elicit large propulsive colorectral motility. In addition, neurons sensitive to ghrelin and dopamine have been identified in the spinal cord. These findings would provide a novel therapeutic strategy for stress-induced diarrhea and constipation.

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  • ストレスに伴う消化管運動異常に対する新規概念構築:排便中枢におけるグレリンの役割

    Grant number：09J04314  2009 - 2010

    日本学術振興会  科学研究費助成事業 特別研究員奨励費  特別研究員奨励費

    平山 晴子

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    Grant amount：\1400000 （ Direct expense: \1400000 ）

    グレリンは、胃から主に放出されるペプチドホルモンで、成長ホルモン分泌亢進など中枢に対する作用がよく知られている。作用発現には脂肪酸修飾が必要であることがグレリンの構造上の特徴であり、脂肪酸修飾を持たない型をデスアシルグレリンという。これまでに申請者の所属研究室では、中枢からの消化管運動への影響も検討できるin vivoの実験系を用い、非ペプチド性グレリン受容体アゴニストが脊髄排便中枢に作用し大腸運動を亢進させることを報告した。この結果に基づき申請者は、ペプチド性グレリンは脊髄排便中枢への投与により用量依存性に大腸運動を亢進させること、また、デスアシルグレリンは単独投与によっては大腸運動に変化は起こさないものの、グレリンの効果に対しては抑制効果をもつことをこれまでに明らかにした。さらに脊髄におけるグレリンおよびグレリン受容体のmRNA発現が確認され、グレリンが神経伝達物質として作用する可能性が示唆された。
    前述の結果をふまえ、申請者は当該年度、グレリンの大腸運動亢進作用をさらに詳細に検討し、脊髄から大腸運動を亢進させるに至る経路が骨盤神経であることを特定した。また、この脊髄を介するグレリンの大腸運動亢進作用は、大腸内腔圧を上昇させることにより誘発される蠕動亢進には必須ではないことを明らかにした。本研究の最終的な目的であるグレリンと病態との関与について検討するために、覚醒下の実験条件の検討を行い、無麻酔下のラットへのグレリンの脊髄腔内投与方法を確立した。また、ストレス下の状況は既存のコルチコトロピン放出ホルモン投与による手法を用いた。グレリンとストレス、そして消化管運動の相互関係について確定的な結論を導くまでの結果は得られなかったが、予備的な実験は進んでおり、近い将来に結論が導かれ、過敏性腸症候群などの消化管疾患の病態解明に寄与すると期待される。

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