Elucidation of molecualr mechanism underlying maintenance of living body homeostasis by mechano-activated molecules and establishment of a strategy for exercise-mimetic drug development
| Project/Area Number |
16H05092
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pharmacology in pharmacy
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| Research Institution | Center for Novel Science Initatives, National Institutes of Natural Sciences (2017-2018)
Okazaki Research Facilities, National Institutes of Natural Sciences (2016) |
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Principal Investigator |
Motohiro Nishida 大学共同利用機関法人自然科学研究機構(新分野創成センター、アストロバイオロジーセンター、生命創成探究, 生命創成探究センター, 教授 (90342641)
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| Co-Investigator(Kenkyū-buntansha) |
西山 和宏 九州大学, 薬学研究院, 特任助教 (60810116)
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| Research Collaborator |
Tomita Takuro (Numaga Takuro)
Nishimura Akiyuki
Shimauchi Tsukasa
Oda Sayaka
Tanaka Tomohiro
Shimoda Kakeru
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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 |
¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2017: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2016: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
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| Keywords | イオンチャネル / 心血管 / 活性酸素 / メカノバイオロジー / 運動模倣薬 / TRPC / P2Y6R / 心血管疾患 / 薬理学 / 薬学 / 膜タンパク質 / シグナル伝達 / 循環器 / 運動 / 情報伝達 / 循環器学 / 線維化 / 運動療法 / メカノセンサー / 受容体 / 心血管病 |
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| Outline of Final Research Achievements |
Moderate exercise is good for our health. In this study, to aim the development of a new drug that can mimick moderate exercise, we investigated the pathophysiological roles of mechano-activated membrane proteins that could be a drug target of exercise-mimetic therapy, and examined whether inhibition of these proteins actually improved cardiovascular diseases. We found that transient receptor potential canonical (TRPC) 3 channel protein formed a stable complex with NADPH oxidase 2 (Nox2), a reactive oxygen species-generating enzyme, and caused oxidative stress in mouse heart, resulting in myocardial atrophy and interstitial fibrosis (i.e., cardiac stiffness). In contrast, increased TRPC6 channel activity in peripheral vascular smooth muscle cells contributed to retardation of blood-flow recovery after hindlimb ischemia. We also demonstrated that inhibition of TRPC3/6 channels enhanced the ischemic resistance in the cardiovascular system.
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| Academic Significance and Societal Importance of the Research Achievements |
TRPチャネル研究は世界中で活発に研究されているものの、多くは構造生物学的研究であり、医療応用を指向した研究は停滞気味であった。本研究は心血管疾患におけるTRPC3/6チャネルの重要性を膜タンパク質間相互作用という新しい視点から解明したユニークな研究成果であり、TRPC3/6チャネルが運動療法を模倣する分子標的となり、これを阻害する化合物が運動模倣薬として循環器疾患に適応できる可能性をマウスで実証できたことは臨床的に意義深い。
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Report
(4 results)
Research Products
(91 results)
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[Journal Article] Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence.2018
Author(s)
Nishimura A, Shimauchi T, Tanaka T, Shimoda K, Toyama T, Kitajima N, Ishikawa T, Shindo N, Numaga-Tomita T, Yasuda S, Sato Y, Kuwahara K, Kumagai Y, Akaike T, Ide T, Ojida A, Mori Y, Nishida M.
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Journal Title
Sci Signal
Volume: 11
Issue: 556
Pages: 5185-5195
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] MiR30-GALNT1/2 Axis-Mediated Glycosylation Contributes to the Increased Secretion of Inactive Human Prohormone for Brain Natriuretic Peptide (proBNP) From Failing Hearts.2017
Author(s)
Nakagawa Y, Nishikimi T, Kuwahara K, Fujishima A, Oka S, Tsutamoto T, Kinoshita H, Nakao K, Cho K, Inazumi H, Okamoto H, Nishida M, Kato T, Fukushima H, Yamashita JK, Wijnen WJ, Creemers EE, Kangawa K, Minamino N, Nakao K, Kimura T.
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Journal Title
J Am Heart Assoc.
Volume: 6
Issue: 2
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis.2016
Author(s)
Numaga-Tomita T., Kitajima N., Kuroda T., Nishimura A., Miyano K., Yasuda S., Kuwahara K., Sato Y., Ide T., Birnbaumer L., Sumimoto H., Mori Y. and Nishida M.
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Journal Title
Scientific Reports
Volume: 6
Issue: 1
Pages: 39383-39383
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling.2016
Author(s)
Kitajima N., Numaga-Tomita T., Watanabe M., Kuroda T., Nishimura A., Miyano K., Yasuda S., Kuwahara K., Sato Y., Ide T., Birnbaumer L., Sumimoto H., Mori Y. and Nishida M
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Journal Title
Scientific Reports
Volume: 6
Issue: 1
Pages: 37701-37701
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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