| Project/Area Number |
18K06872
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 48020:Physiology-related
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| Research Institution | University of Occupational and Environmental Health, Japan (2019-2020)
Kyoto University (2018) |
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Principal Investigator |
Mori Masayuki 産業医科大学, 医学部, 教授 (80342640)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | イオンチャネル / チャネロパシー / カルシウム依存的不活性化 / 糸球体硬化症 / TRPC6 / Calmodulin / ポドサイト / ネフローゼ症候群 / カルシウム依存的不活性化：CDI / 巣状分節性糸球体硬化症 / 電気生理 / 機能構造相関 / Ca2+依存的不活性化 / ストレスファイバー / FRET / カルシウムシグナル / 構造機能相関 / 腎疾患 |
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| Outline of Final Research Achievements |
TRPC6 is a nonselective cation channel, and mutations of this gene are associated with FSGS. These mutations are associated with TRPC6 current amplitude amplification and/or delay of the channel inactivation (gain-of-function phenotype). However, the mechanism of the gain-of-function in TRPC6 activity has not yet been clearly solved. We performed electrophysiologic, biochemical, and biophysical experiments to elucidate the molecular mechanism underlying calmodulin (CaM)-mediated Ca2+-dependent inactivation (CDI) of TRPC6. The FSGS-associated TRPC6 mutations within the coiled-coil severely delayed CDI and often increased TRPC6 current amplitudes. The gain-of-function mechanism found in FSGS-causing mutations, TRPC6 can be explained by impairments of the CDI, caused by disruptions of TRPC's coiled-coil assembly and CaM bridge binding. The resulting excess Ca2+ may contribute to structural damage in the podocytes.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究グループは、カルシウムチャネルの一つTRPC6の活性にブレーキをかける、Ca(2+)依存的不活性化（Ca(2+)-dependent inactivation：CDI）と呼ばれる機構に関する研究を行い、その分子的基盤を得た。解析した5種類のFSGS型TRPC6全てにおいて分子構造体の異常を伴ったCDIの破綻を認めた。これらは、TRPC6のCDI分子機構を明らかにすると共にこのブレーキ機構の破綻がFSGS発症原因であるという新しい概念を提唱するもので、TRPC6の分子基盤、FSGSの診断、治療へ向けた重要な足がかりになると考えられた。
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