Elucidation of molecular pathomechanism and development of therapy for collagen VI deficiency

• Project/Area Number: 26293214
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: NISHINO Ichizo 国立研究開発法人国立精神・神経医療研究センター, 神経研究所 疾病研究第一部, 部長 (00332388)
• Co-Investigator(Kenkyū-buntansha): 野口 悟 国立研究開発法人国立精神・神経医療研究センター, 神経研究所 疾病研究第一部, 室長 (00370982) ; 西川 敦子 国立研究開発法人国立精神・神経医療研究センター, 神経研究所 疾病研究第一部, 研究員 (70737262)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2016: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2015: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2014: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: 遺伝病 / 骨格筋 / 治療 / コラーゲン / 間質前駆細胞

Outline of Final Research Achievements

Congenital muscular dystrophies with collagen VI deficiency are inherited muscle disorders are caused by mutations in one of COL6A1-3 genes. Muscle pathology is characterized by fiber size variation and increased interstitial fibrosis and fat infiltration. In this study, we define critical events that contribute to muscle weakness and fibrosis in mouse models with collagen VI deficiency. The Col6a1 mutant mice develop non-progressive weakness from younger age, accompanied by stunted muscle growth due to reduced IGF-1 signaling activity. In addition, these mutant mice have high numbers of interstitial mesenchymal progenitor cells, which dramatically increase with repeated myofiber necrosis/regeneration. Our results suggest that impaired neonatal muscle growth and the activation of the mesenchymal cells in skeletal muscles contribute to the pathology of collagen VI-deficient muscle diseases, and more importantly, provide the insights on the therapeutic strategies for the disease.

Research Products

• [Int'l Joint Research] NHGRI, HIN(米国)
• [Journal Article] Muscle Weakness and Fibrosis Due to Cell Autonomous and Non-cell Autonomous Events in Collagen VI Deficient Congenital Muscular Dystrophy (2017)
  • Author(s): Noguchi S, Ogawa M, Malicdan MC, Nonaka I, Nishino I
  • Journal Title: EBioMedicine Volume: 15(2017) Pages: 193-202
  • DOI: 10.1016/j.ebiom.2016.12.011
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Biallelic TBCD mutations cause early-onset neurodegenerative encephalopathy (2017)
  • Author(s): Miyake N, Fukai R, Ohba C, ... Shiina M, Ogata K, Okuno-Yuguchi J, Fueki N, Ogiso Y, Suzumura H, Watabe Y, Imataka G, Leong HY, Fattal-Valevski A, Kramer U, Miyatake S, Kato M, Okamoto N, Sato Y, Mitsuhashi S, Nishino I, Kaneko N, Nishiyama A, Tamura T, Mizuguchi T, Nakashima M, Tanaka F, Saitsu H, Matsumoto N
  • Journal Title: American Journal of Human Genetics Volume: 99 Issue: 4 Pages: 950-961
  • DOI: 10.1016/j.ajhg.2016.08.005
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Perifascicular necrosis in anti-synthetase syndrome beyond anti-Jo-1 (2016)
  • Author(s): Uruha A, Suzuki S, Suzuki N, Nishino I
  • Journal Title: Brain Volume: 139(Pt 9) Issue: 9 Pages: e50-e50
  • DOI: 10.1093/brain/aww125
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Beevor’s sign: a potential clinical marker for GNE myopathy (2016)
  • Author(s): Preethish-Kumar V, Pogoryelova O, Polavarapu K, Gayathri N, Seena V, Hudson J, Nishino I, Prasad C, Lochmuller H, Nalini A
  • Journal Title: Eur J Neurol. Volume: 23(8) Issue: 8
  • DOI: 10.1111/ene.13041
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Milder forms of muscular dystrophy associated with POMGN2 mutations. (2015)
  • Author(s): Endo Y, Dong M, Noguchi S, Ogawa M, Hayashi YK, Kuru S, Sugiyama K, Nagai S, Ozasa S, Nonaka I, Nishino I
  • Journal Title: Neurol Genet. Volume: 1(4) Issue: 4
  • DOI: 10.1212/nxg.0000000000000033
  • Peer Reviewed / Open Access
• [Journal Article] Plasma IP-10 level distinguishes inflammatory myopathy (2015)
  • Author(s): Uruha, A., S. Noguchi, W. Sato, H. Nishimura, S. Mitsuhashi, T. Yamamura, and I. Nishino
  • Journal Title: Neurology Volume: 85 Issue: 3 Pages: 293-294
  • DOI: 10.1212/wnl.0000000000001767
  • Peer Reviewed
• [Journal Article] Allele-specific Gene Silencing of Mutant mRNA Restores Cellular Function in Ullrich Congenital Muscular Dystrophy Fibroblasts. (2014)
  • Author(s): Noguchi S, Ogawa M, Kawahara G, Malicdan MC, Nishino I
  • Journal Title: Mol Ther Nucleic Acids Volume: 3 Pages: e171-e171
  • DOI: 10.1038/mtna.2014.22
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Muscle Weakness and Fibrosis Due to Cell Autonomous and Non-cell Autonomous Events in Collagen VI Deficient Congenital Muscular Dystrophy (2017)
  • Author(s): Satoru Noguchi
  • Organizer: International Conference on Collagen VI Disorders
  • Place of Presentation: Washington, U.S.A.
  • Year and Date: 2017-02-24
  • Int'l Joint Research / Invited
• [Presentation] ジストロフィン－結合糖タンパク質複合体研究の最近の展開 (2016)
  • Author(s): 野口 悟
  • Organizer: 第2回日本筋学会学術集会記念講演
  • Place of Presentation: 東京都小平市(国立精神・神経医療研究センター)
  • Year and Date: 2016-08-05
  • Invited
• [Presentation] KGS analysis in hereditary muscle disease. (2015)
  • Author(s): Nishino I
  • Organizer: 10th Japanese-French Workshop
  • Place of Presentation: Paris, France(Institute of Myology)
  • Year and Date: 2015-07-02
  • Invited
• [Presentation] Two events in the pathogenesis of congenital muscular dystrophy with collagen VI deficiency. (2015)
  • Author(s): Noguchi S
  • Organizer: 10th Japanese-French Workshop
  • Place of Presentation: Paris, France(Institute of Myology)
  • Year and Date: 2015-07-02
  • Invited
• [Presentation] 皮膚筋炎の筋病理診断におけるMxA染色の有用性． (2015)
  • Author(s): 西川敦子，西野一三
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 新潟(朱鷺メッセ(新潟コンベンションセンター))
  • Year and Date: 2015-05-20
  • Int'l Joint Research
• [Presentation] Activation of mesenchymal progenitor cells in skeletal muscles of Collagen VI deficient mice. (2014)
  • Author(s): Noguchi S, Ogawa M, Nishino I:
  • Organizer: 19th International Congress of the World Muscle Society
  • Place of Presentation: Berlin, Germany (福岡国際会議場)
  • Year and Date: 2014-10-07 – 2014-10-11
• [Remarks] 国立研究開発法人 国立精神・神経医療研究センター 疾病研究第一部
• [Remarks] http://www.ncnp.go.jp/nin/guide/r1/papers.html#top