Muscle-dominant wild-type TDP-43 transgenic mice as a novel model of sporadic inclusion body myositis
Project/Area Number |
16K09674
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Neurology
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Research Institution | Kumamoto University |
Principal Investigator |
YAMASHITA Satoshi 熊本大学, 大学院生命科学研究部(医), 准教授 (20457592)
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Research Collaborator |
ANDO yukio
TAKEDA naoki
TAWARA nozomu
DOKI tsukasa
MATSUO yoshimasa
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Project Period (FY) |
2016-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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Keywords | 封入体筋炎 / TDP-43 / Tubular aggregate / NT5C1A / ミトコンドリア / 小胞体ストレス / IL-6 / 脳神経疾患 / 神経科学 |
Outline of Final Research Achievements |
Muscle histology of inclusion body myositis (IBM) demonstrates inflammatory findings and degenerative features including accumulation of TDP-43. However, whether sarcoplasmic accumulation of TDP-43 is a primary trigger of muscle degeneration or a secondary event resulting from muscle degeneration in IBM remained unclear. Our study aimed to discover whether muscle-dominant expression of TDP-43 is a primary cause of muscle degeneration. We generated wild-type TDP-43 transgenic mice driven by a creatine kinase 8 promoter. The mice showed increased serum levels of myogenic enzymes. Muscle histology demonstrated myopathic changes including fiber size variation, abundant tubular aggregates, and TDP-43 aggregation. Proteomic analysis identified increased SR/ ER-resident proteins as well as cytosolic 5'-nucleotidase 1A. Muscle-dominant wild-type TDP-43 expression indeed caused myotoxicity featuring tubular aggregates and TDP-43-positive inclusions.
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Academic Significance and Societal Importance of the Research Achievements |
封入体筋炎(IBM)は高齢者に好発する筋疾患であり、加齢に伴って起こる筋症=サルコぺニアのモデルとなる点でも今後注目すべき疾患である。本疾患の骨格筋では、筋萎縮性側索硬化症などの神経変性疾患に共通してTDP-43が沈着しており、TDP-43プロテイノパチーの一型でもある。本マウスを用いて、TDP-43の筋線維内凝集を抑制する低分子化合物スクリーニングシステムを構築し、IBMの根治的治療法を探索することは、高齢者の運動機能を著しく低下させるサルコぺニアやALSなどの神経変性疾患の治療法開発に展開可能であると期待される。
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Report
(4 results)
Research Products
(54 results)
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[Journal Article] Mitochondrial localization of PABPN1 in oculopharyngeal muscular dystrophy.2019
Author(s)
Tsukasa Doki, Satoshi Yamashita, Fan-Yan Wei, Kentaro Hara, Takahiro Yamamoto, Ziwei Zhang, Xiao Zhang, Nozomu Tawara, Hirotake Hino, Eiichiro Uyama, Takashi Kurashige, Hirofumi Maruyama, Kazuhito Tomizawa, Yukio Ando.
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Journal Title
Laboratory Investigation
Volume: 印刷中
Pages: 印刷中
DOI
Related Report
Peer Reviewed
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[Journal Article] Pathomechanisms of anti-cytosolic 5'-nucleotidase 1A autoantibodies in sporadic inclusion body myositis.2017
Author(s)
Tawara N, Yamashita S, Zhang X, Korogi M, Zhang Z, Doki T, Matsuo Y, Nakane S, Maeda Y, Sugie K, Suzuki N, Aoki M, Ando Y.
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Journal Title
Ann Neurol.
Volume: 81
Pages: 512-525
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Multicenter questionnaire survey for sporadic inclusion body myositis in Japan.2016
Author(s)
Suzuki N, Mori-Yoshimura M, Yamashita S, Nakano S, Murata KY, Inamori Y, Matsui N, Kimura E, Kusaka H, Kondo T, Higuchi I, Kaji R, Tateyama M, Izumi R, Ono H, Kato M, Warita H, Takahashi T, Nishino I, Aoki M.
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Journal Title
Orphanet J Rare Dis.
Volume: 11
Pages: 146
DOI
Related Report
Peer Reviewed
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[Journal Article] Hereditary amyloidosis with cardiomyopathy caused by the novel variant transthyretin A36D.2016
Author(s)
Yamashita T, Ueda M, Saga N, Nanto K, Tasaki M, Masuda T, Misumi Y, Oda S, Fujimoto A, Amano T, Takamatsu K, Yamashita S, Obayashi K, Matsui H, Ando Y.
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Journal Title
Amyloid
Volume: 23
Pages: 207-208
DOI
Related Report
Peer Reviewed
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[Journal Article] Lateral Asymmetry and Spatial Difference of Iron Deposition in the Substantia Nigra of Patients with Parkinson Disease Measured with Quantitative Susceptibility Mapping.2016
Author(s)
Azuma M, Hirai T, Yamada K, Yamashita S, Ando Y, Tateishi M, Iryo Y, Yoneda T, Kitajima M, Wang Y, Yamashita Y.
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Journal Title
AJNR Am J Neuroradiol.
Volume: 37
Pages: 782-788
DOI
Related Report
Peer Reviewed
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[Journal Article] Long-term outcome of patients with hereditary transthyretin V30M amyloidosis with polyneuropathy after liver transplantation.2016
Author(s)
Okumura K, Yamashita T, Masuda T, Misumi Y, Ueda A, Ueda M, Obayashi K, Jono H, Yamashita S, Inomata Y, Ando Y.
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Journal Title
Amyloid
Volume: 23
Pages: 39-45
DOI
Related Report
Peer Reviewed
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[Presentation] Mitochondrial dysfunction in the pathogenesis of oculopharyngeal muscular dystrophy.2016
Author(s)
Tsukasa Doki, Satoshi Yamashita, Ziwei Zhang, Xiao Zhang, Nozomu Tawara, Yasushi Maeda, Hirotake Hino, Eiichiro Uyama, Kimi Araki, Yukio Ando.
Organizer
21st International Congress of the World Muscle Society
Place of Presentation
Congress Palace, Granada, Spain
Year and Date
2016-10-05
Related Report
Int'l Joint Research
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