| Project/Area Number |
16K09642
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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 |
Kidney internal medicine
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
Rai Tatemitsu 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座教授 (80334431)
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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 |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | KLHL3 / cullin3 / NKCC1 / NCC / FOXO4 / 偽性低アルドステロン症II型 / ユビキチン / 偽性低アルドステロン症II型（PHAII） / ループ利尿薬 / サルコペニア / Cullin3 / PHAII / 高血圧 / 内科 / 生理学 / トランスレーショナルリサーチ / シグナル伝達 |
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| Outline of Final Research Achievements |
(1) Pathogenesis of defective degradation of WNK kinases by KLHL-Cullin3 complex: By generation and analysis of KLHL3 knockout mice, the dominant-negative effect of mutant KLHL3 was found to be important for the pathogenesis of PHAII.
(2) Function of KLHL3/Cul3/WNK signal in extra-renal organs: By generation and analysis of WNK4 knockout mice, WNK4 was found to be a novel regulating factor of adipocyte differentiation. In addition, NKCC1 was shown to play an important role in muscle differentiation and hypertrophy. Thus, WNK1-FOXO4 signal was identified as a novel signaling system participating in the physiologic and pathogenic association of the muscle and kidney.
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| Academic Significance and Societal Importance of the Research Achievements |
KLHL3とKLHL2によるWNKシグナルの制御メカニズム、慢性腎臓病における塩分感受性高血圧の成立メカニズムについて重要な新知見を得ることができた。この成果は、新たな高血圧治療薬の創薬につながるものである。また腎臓以外の、脂肪組織や筋肉におけるWNKシグナル系の機能についても新規発見を得た。この成果により、WNKシグナル系が肥満やサルコペニアの新しい治療標的となる可能性があることが示された。
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