| Project/Area Number |
26460340
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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 |
General pharmacology
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| Research Institution | Kobe University |
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Principal Investigator |
Ueyama Takehiko 神戸大学, バイオシグナル総合研究センター, 准教授 (80346254)
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| Co-Investigator(Kenkyū-buntansha) |
坂口 博史 京都府立医科大学, 医学(系)研究科(研究院), 准教授 (00515223)
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| Co-Investigator(Renkei-kenkyūsha) |
SAITO Naoaki 神戸大学, バイオシグナル総合研究センター, 教授 (60178499)
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| Project Period (FY) |
2014-04-01 – 2017-03-31
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| Project Status |
Completed (Fiscal Year 2016)
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| Budget Amount *help |
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 聴覚 / 平衡覚 / 低分子量G蛋白質 / 聴毛 / 耳石 / DIA1 / DFNA1 / 感音難聴 / 遺伝性難聴 / Cdc42 / RhoA / DIAPH1 / アクチン / Rho-family GTPase / Rac / 内耳有毛細胞 / 聴力 / 活性酸素種 |
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| Outline of Final Research Achievements |
(1) We generated inner ear hair cell (HC)-specific KO mice to analyze the role of Cdc42 in HCs. HCs of Cdc42-KO mice developed normally but progressively degenerated after maturation, resulting in progressive hearing loss particularly at high frequencies. Adenovirus-encoded GFP-Cdc42 expression in HCs and fluorescence resonance energy transfer (FRET) imaging of HCs from transgenic mice expressing Cdc42-FRET biosensor indicated Cdc42 presence/activation at stereociliary membranes in cochlear HCs.
(2) We found that the amount of active RhoA (GTP-form) is increased in Cdc42-KD cells. DIA1 is a downstream molecule of RhoA signaling pathways, and nucleates and elongates unbranched/straight actin. We discovered a novel patient-derived DIAPH1 mutation (c.3610C>T) in two unrelated Japanese families. Mice expressing the DIA1(R1204X) mutant experienced progressive deafness beginning at high frequencies and HC loss with various morphological abnormalities in stereocilia at the basal turn.
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