| Project/Area Number |
17K09578
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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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| Research Field |
Cardiovascular medicine
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| Research Institution | Osaka University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
西田 優也 大阪大学, 医学系研究科, 招へい教員 (10793440)
新谷 泰範 大阪大学, 生命機能研究科, 准教授 (20712243)
朝野 仁裕 大阪大学, 医学系研究科, 講師 (60527670)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 心不全 / ミオシン調節軽鎖キナーゼ / サルコメア / ｃMLCK / キナーゼ活性化機構 / cardiac MLCK |
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| Outline of Final Research Achievements |
We investigated the physiological, molecular and structural regulatory mechanism of cMLCK activity. cMLCK is activated by mechanical stresses and phosphorylates myosin regulatory light chain to promote the sarcomere assembly. N-terminus of cMLCK is not essential for its kinase activity and C-terminus regulatory domain of cMLCK contributes to the recognition of the substrate. In addition, we successfully obtained the X-ray co-crystal structure of cMLCK and calmodulin.
Next, we investigated the contribution of the dysregulation of cMLCK activity to the development of heart failure in clinical practice, and we identified that depressed cMLCK activity could result in systolic heart failure or dilated cardiomyopathy in human. Furthermore, we tried to develop the methods to regulate cMLCK activity. The psudo-nature peptides that specifically binds to cMLCK and the AAV vector that can express cMLCK were developed to inhibit or activate cMLCK, respectively.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究によりcMLCK の生理学的、分子構造学的な活性制御機構が解明された。また、cMLCK活性の異常がヒトの心不全および拡張型心筋症の発症に関与することが明らかとなり、cMLCK活性の正常化が心不全治療に成り得る可能性を示すことが出来た。さらにcMLCKの結晶構造解析にも成功したことで、その構造情報を基にしてcMLCK 活性を制御する化合物の開発の基盤になると考えられる。将来的にはcMLCK 活性の制御剤の開発やAAV9 ベクターによるcMLCK を標的とした心不全治療法に繋がる可能性が考えられる。本邦で医学的かつ社会的問題である高齢者の心不全治療に新たな選択肢を与えることが出来る。
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