Elucidation of molecular mechanisms of defective neuromuscular signal transmission as a primary cause of sarcopenia
| Project/Area Number |
19K22802
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 59:Sports sciences, physical education, health sciences, and related fields
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| Research Institution | Nagoya University |
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Principal Investigator |
Ohno Kinji 名古屋大学, 医学系研究科, 教授 (80397455)
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| Project Period (FY) |
2019-06-28 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2020: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | サルコペニア / 廃用性筋萎縮 / 神経筋接合部 / リボタグマウス / 遺伝子発現プロファイル / 神経筋信号伝達障害 |
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| Outline of Research at the Start |
サルコペニアと廃用性筋萎縮における神経筋接合部(NMJ)信号伝達障害が一次的な原因として注目されている。サルコペニアモデルマウスの脊髄運動神経細胞とNMJ筋終板(endplate)において、RiboTag mouseを用いた網羅的遺伝子発現プロファイリング解析とSPPLAT法によるproximity proteomics解析を行い、サルコペニアの原因に関わるSMN分子・endplate分子を同定し、CRISPR/Cas9によるノックアウトiPS細胞・ノックアウトマウスの解析により、サルコペニアにおけるNMJ病態を明らかにし新規治療法開発につなげる。
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| Outline of Final Research Achievements |
Accumulating knowledge points to the notion that defects in the neuromuscular signal transmission are potentially the primary cause of amyotrophy including sarcopenia and muscle disuse atrophy. To explore NMJ-specific genes that are responsible for sarcopenia, we performed extensive gene expression profiling of the mouse motor endplate using RiboTag mouse that enables Cre-mediated HA-tagging to a ribosomal protein, RPL22. Analysis of genes expressed at the motor endplate showed that the phosphatidylinositol signaling system and the extracellular matrix receptor interaction, the roles of which at the neuromuscular junction remain to be elucidated, were highly expressed at the motor endplate. Analysis of subsets of these gene sets further revealed that diacylglycerol kinases, phosphatidylinositol kinases, phospholipases, integrins, laminins were enriched at the motor endplate.
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| Academic Significance and Societal Importance of the Research Achievements |
サルコペニアは世界で男女とも10%の有病率と推定されており高齢者のフレイルの最大要因となっている。しかし、サルコペニアは対症療法以外の薬物療法が存在しない「一般的な病気（common disease）」の代表疾患になっている。近年、サルコペニアに認められる神経筋接合部信号伝達障害はサルコペニアに伴う二次的な現象ではなくサルコペニアの一次的な原因の可能性が指摘されてきた。サルコペニアにともなう神経筋接合部の信号伝達障害の病態を明らかにすることによりサルコペニアの新規治療法開発につながることが期待される。
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Report
(4 results)
Research Products
(33 results)
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[Journal Article] Meta‐Analysis of Gut Dysbiosis in Parkinson's Disease2020
Author(s)
Nishiwaki Hiroshi、Ito Mikako、Ishida Tomohiro、Hamaguchi Tomonari、Maeda Tetsuya、Kashihara Kenichi、Tsuboi Yoshio、Ueyama Jun、Shimamura Teppei、Mori Hiroshi、Kurokawa Ken、Katsuno Masahisa、Hirayama Masaaki、Ohno Kinji
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Journal Title
Movement Disorders
Volume: 35
Issue: 9
Pages: 1626-1635
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Ubiquitination of DNA Damage-Stalled RNAPII Promotes Transcription-Coupled Repair2020
Author(s)
Nakazawa Y, Hara Y, Oka Y, Komine O, van den Heuvel D, Guo C, Daigaku Y, Isono M, He Y, Shimada M, Kato K, Jia N, Hashimoto S, Kotani Y, Miyoshi Y, Tanaka M, Sobue A, Mitsutake N, Suganami T, Masuda A, Ohno K, Nakada S, Mashimo T, Yamanaka K, Luijsterburg MS, Ogi T
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Journal Title
Cell
Volume: 19
Issue: 6
Pages: 1228-1244
DOI
NAID
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Congenital myasthenic syndrome-associated agrin variants affect clustering of acetylcholine receptors in a domain-specific manner2020
Author(s)
Ohkawara B, Shen X-M, Selcen D, Nazim M, Bril V, Tarnopolsky MA, Brady L, Fukami S, Amato AA, Yis U, Ohno K, Engel AG
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Journal Title
Related Report
Peer Reviewed / Int'l Joint Research
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