Matrix metalloproteinases as a therapeutic target of sarcoglycan-deficient muscular dystrophy

• Project/Area Number: 21591101
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Kawasaki Medical School
• Principal Investigator: SUNADA Yoshihide 川崎医科大学, 医学部, 教授 (00240713)
• Co-Investigator(Kenkyū-buntansha): OHSAWA Yutaka 川崎医科大学, 医学部, 講師 (80246511) ; MURAKAMI Tatsufumi 川崎医科大学, 医学部, 准教授 (30330591)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2010: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2009: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 神経分子病態学1 / 筋ジストロフィー / 再生医療 / シグナル伝達 / 発生・分化 / 神経科学

Research Abstract

Processing of β-dystroglycan(β-DG) by matrix metalloproteinases(MMPs) has been considered to play a fundamental role in muscle degeneration in sarcoglycan(SG)-deficient muscular dystrophy. Here we generate triple knockout(TKO) mice deficient to MMP-2, MMP-9, and γ-SG to investigate in vivo processing of β-DG by MMP-2, MMP-9.Muscle pathology of TKO mice was comparable to that of γ-SG-knockout mice. Unexpectedly, the 30-kDa-processed form of β-DG was present in TKO mouse muscles likewise γ-SG-null mouse muscles. These findings indicate that MMPs other than MMP-2/9 participate in the molecular mechanism underlying the processing of β-DG in sarcoglycan-deficient muscular dystrophy.

Research Products

• [Journal Article] An inhibitor of transforming growth factor beta type I receptor ameliorates muscle atrophy in a mouse model of caveolin 3-deficient muscular dystrophy (2012)
  • Author(s): Ohsawa Y, Okada T, Nishimatsu SI, Ishizaki M, Suga T, Fujino M, Murakami T, Uchino M, Tsuchida K, Noji S, Hinohara A, Shimizu T, Shimizu K, Sunada Y
  • Journal Title: Lab Invest Volume: 78 Issue: 8 Pages: 1100-1114
  • DOI: 10.1038/labinvest.2012.78
  • Peer Reviewed
• [Journal Article] Endoplasmic reticulum stress response in P104L mutant caveolin-3 transgenic mice (2011)
  • Author(s): Kuga A, Ohsawa Y, Okada T, Kanda F, Kanagawa M, Toda T, Sunada Y.
  • Journal Title: Hum Mol Genet Volume: 20(15) Issue: 15 Pages: 2975-2983
  • DOI: 10.1093/hmg/ddr201
  • Peer Reviewed
• [Journal Article] Atelocollagen-mediated systemic administration ofmyostatin-targeting siRNA improves muscular atrophy in caveolin-3-deficient mice (2011)
  • Author(s): Kawakami E, Kinouchi N, Adachi T, Ohsawa Y, Ishimaru N, Ohuchi H, Sunada Y, Hayashi Y, Tanaka E, Noji S.
  • Journal Title: Dev Growth Differ Volume: 53 Issue: 1 Pages: 48-54
  • DOI: 10.1111/j.1440-169x.2010.01221.x
  • Peer Reviewed
• [Journal Article] Follistatin-derived peptide expression in muscle decreases adipose tissue mass and prevents hepatic steatosis (2011)
  • Author(s): Nakatani M, Kokubo M, Ohsawa Y, Sunada Y, Tsuchida K.
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 300 Issue: 3 Pages: 543-553
  • DOI: 10.1152/ajpendo.00430.2010
  • Peer Reviewed
• [Journal Article] Follistatin-derived peptide expression in muscle decreases adiposetissue mass and prevents hepatic steatosis. (2011)
  • Author(s): Nakatani M, Kokubo M, Ohsawa Y, Sunada Y, Tsuchida K.
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 300(3)
  • Peer Reviewed
• [Journal Article] Atelocollagen-mediated systemic administration of myostatin-targeting siRNA improves muscular atrophy in caveolin-3-deficient mice. (2011)
  • Author(s): Kawakami E, Kinouchi N, Adachi T, Ohsawa Y, Ishimaru N, Ohuchi H, Sunada Y, Hayashi Y, Tanaka E, Noji S.
  • Journal Title: Dev Growth Differ Volume: 53(1) Pages: 48-54
  • NAID: 10027899274
  • Peer Reviewed
• [Journal Article] Rapid screening for Japanese dysferlinopathy by fluorescent primer extension (2010)
  • Author(s): Hayashi S, Ohsawa Y, Takahashi T, Suzuki N, Okada T, Rikimaru M, Murakami T, Aoki M, Sunada Y.
  • Journal Title: Intern Med Volume: 49 Pages: 2693-2696
  • NAID: 130000413429
  • Peer Reviewed
• [Journal Article] The transthyretin gene is expressed in Schwann cells of peripheral nerves (2010)
  • Author(s): Murakami T, Ohsawa Y, Zhenghua L, Yamamura K, Sunada Y.
  • Journal Title: Brain Res Volume: 1348 Pages: 222-225
  • DOI: 10.1016/j.brainres.2010.06.017
  • Peer Reviewed
• [Journal Article] Hereditary sensory ataxic neuropathy associated with proximal muscle weakness in the lower extremities (2010)
  • Author(s): Murakami T, Fukai Y, Rikimaru M, Henmi S, Ohsawa Y, Sunada Y.
  • Journal Title: J Neurol Sci Volume: 291 Issue: 1-2 Pages: 121-123
  • DOI: 10.1016/j.jns.2009.12.011
  • Peer Reviewed
• [Journal Article] Rapid Screening for Japanese Dysferlinopathy by Fluorescent Primer Extension. (2010)
  • Author(s): Hayashi S, Ohsawa Y, Takahashi T, Suzuki N, Okada T, Rikimaru M, Murakami T, Aoki M, Sunada Y.
  • Journal Title: Int Med Volume: 49 Pages: 2693-2696
  • NAID: 130000413429
  • Peer Reviewed
• [Presentation] TGF-betaシグナルナル制御による筋疾患治療法の開発 (2011)
  • Author(s): 大澤裕、砂田芳秀、岡田只士、西松伸一郎、林良雄、土田邦博、野地澄晴
  • Organizer: 平成23年度厚生労働省精神・神経疾患研究委託費筋ジストロフィー「西野班」班会議
  • Place of Presentation: 東京
  • Year and Date: 2011-12-06
• [Presentation] 筋ジストロフィーの新時代の治療 (2011)
  • Author(s): 砂田芳秀
  • Organizer: 第29回日本神経治療学会総会
  • Place of Presentation: ホテルフジタ福井(招待講演)
  • Year and Date: 2011-11-17
• [Presentation] Sarcolemmal nNOS prevents muscular wasting in a caveolin-3-deficeint muscular dystrophy 1C model (2011)
  • Author(s): Ohsawa, Sunada Y, et al
  • Organizer: International Congress of Muscle Wasting 2011
  • Place of Presentation: Centro Stefano Franscini Monte Verita, Switzerland
  • Year and Date: 2011-09-21
• [Presentation] Wound-healing MRL-MpJ phenotype improves outcome of dystrophin deficient mdx mice (2011)
  • Author(s): Sunada Y, Ohsawa Y, Fujino M, Okada T, Hayashi S, Rikimaru M, Murakami T, Nishimatsu SI, Nohno T, Nagao M
  • Organizer: XII. International Congress on Neuromuscular Diseases
  • Place of Presentation: Naples, Italy
  • Year and Date: 2011-07-21
• [Presentation] シンポジウム:筋疾患に対する抗マイオスタチン抗体療法の開発と応用 (2011)
  • Author(s): 砂田芳秀
  • Organizer: 2011年日本神経学会学術大会シンポジウム
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-20
• [Presentation] シンポジウム32:神経疾患に対する抗体療法:筋疾患に対する抗マイオスタチン抗体療法の開発と応用 (2011)
  • Author(s): 砂田芳秀
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋国際会議場(招待講演)
  • Year and Date: 2011-05-20
• [Presentation] Caveolin-3高発現マウス骨格筋の解析 (2011)
  • Author(s): 砂田芳秀
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2011-05-20
• [Presentation] シンポジウム:骨格筋再生療法 (2011)
  • Author(s): 大澤裕
  • Organizer: 2011年日本神経学会学術大会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-19
• [Presentation] Sarcolemmal nNOS prevents muscular wasting in a caveolin-3-deficient limb-girdle muscular dystrophy 1C model (2011)
  • Author(s): Ohsawa Y, Fujino M, Okada S, Nishimatsu SI, Rikimaru M, Hayashi S, Nohno T, Sunada Y.
  • Organizer: International congress of muscle wasting
  • Place of Presentation: Ascona, Switzerland
• [Presentation] Reprogrammed fibroblasts as a feasible source of cell-based therapy for muscular duystrophy (2010)
  • Author(s): Ohsawa Y, Okada T, Fujii I, Nishimatsu SI, Fujino M, Hayashi S, Rikimaru M, Murakami T, Nohno T, Sunada Y.
  • Organizer: 15th International Congress of World Muscle Society
  • Place of Presentation: Kumamoto, Japan
  • Year and Date: 2010-12-10
• [Presentation] 筋ジストロフィーに対する抗myostatin治療薬の開発,厚生労働省精神・神経疾患研究開発費「筋ジストロフィーおよびその関連疾患の分子病態解明、診断法確立と薬物治療の開発に関する研究」 (2010)
  • Author(s): 砂田芳秀、大澤裕、岡田只士、西松伸一郎、石崎雅俊、菅智宏、内野誠、濃野勉、野地澄晴、土田邦博
  • Organizer: 平成22年度「砂田班」班会議
  • Place of Presentation: 東京
  • Year and Date: 2010-12-03
• [Presentation] Wound-healing MRL-MpJ phenotype improves outcome of dystrophin deficient mdx mice. (2010)
  • Author(s): Yoshihide Sunada, et al.
  • Organizer: XII International Congress on Neuromuscular Diseases
  • Place of Presentation: Naples, Italy
  • Year and Date: 2010-07-21
• [Presentation] 筋ジストロフィーの分子病態 (2010)
  • Author(s): 砂田芳秀
  • Organizer: 第28回日本神経治療学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2010-07-16
• [Presentation] nNOSはcaveolin-3欠損症の病態を抑制する (2010)
  • Author(s): 砂田芳秀
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2010-05-21
• [Presentation] 線維芽細胞のdirectによる筋ジストロフィーの細胞治療 (2010)
  • Author(s): 砂田芳秀、大澤裕、岡田只士、藤野雅広、力丸満惠、林紗織、村上龍文、藤井績
  • Organizer: 平成21年度厚生労働省精神・神経疾患研究委託費筋ジストロフィー総合班会議
  • Place of Presentation: 東京
  • Year and Date: 2010-01-09
• [Presentation] Reprogrammed fibroblasts are a source of cell therapy for caveolin-3-deficient and laminin α-2-deficient muscular dystrophies (2010)
  • Author(s): Ohsawa Y, Fujii I, Okada T, Nishimatsu SI, Hayashi S, Rikimaru M, Murakami T, Nohno T, Sunada Y.
  • Organizer: 2010 FASEB Summer Research Conferences : Skeletal Muscle Satellite and Stem Cells
  • Place of Presentation: Arizona, USA
• [Presentation] 線維芽細胞のdirect reprogrammingによる筋ジストロフィーの細胞治療 (2009)
  • Author(s): 砂田芳秀、大澤裕、岡田只士、藤野雅広、力丸満惠、林紗織、村上龍文、藤井績
  • Organizer: 平成21年度「砂田班」班会議
  • Place of Presentation: 東京
  • Year and Date: 2009-12-11
• [Presentation] Introduction of wound-healing MRL-MpJ phenotype improves skeletal muscle pathology in mdx mouse (2009)
  • Author(s): Ohsawa Y, Fujino M, Okada T, Kuga A, Hayashi S, Rikimaru M, Sunada Y.
  • Organizer: 14th International Congress of The World Muscle Society
  • Place of Presentation: Geneve, Switzerland
  • Year and Date: 2009-09-11
• [Presentation] TGF-βタイプIセリンスレオニンキナーゼ受容体阻害剤による筋ジストロフィー治療法の開発(第2報) (2009)
  • Author(s): 大澤裕、久我敦、林紗織、力丸満恵、村上龍文、砂田芳秀
  • Organizer: 第27回日本神経治療学会総会
  • Place of Presentation: 熊本
  • Year and Date: 2009-06-11
• [Book] Fifty Years of Neuromuscular Disorder Research after Discovery of Creatine Kinase as a Diagnostic Marker of Muscular Dystrophy-Development and application of anti-myostatin therapy for muscular dystrophy- (2011)
  • Author(s): 砂田芳秀
  • Publisher: 医学書院出版サービス,医学書院