| Project/Area Number |
24659412
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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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, 医歯(薬)学総合研究科, 准教授 (80334431)
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| Project Period (FY) |
2012-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
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| Keywords | WNKキナーゼ / OSR1 / SPAK / SLC12A輸送体 / NCC / NKCC1 / NKCC2 / 蛍光相関分光法 / Slc12a輸送体 / ELISA |
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| Outline of Final Research Achievements |
The WNK (with-no-lysine kinase) phosphorylation signal cascade plays an important role in blood pressure control through regulation of NaCl reabsorption and vasoconstriction. Therefore, agents that can modulate this signal cascade could be a new class of antihypertensive drugs with dual actions (i.e., NaCl diuresis and vasodilation). In this study, we organized two high-throughput drug-screening systems to find novel specific inhibitors of the WNK - OSR1 / SPAK - Slc12a cascade. First, fluorescent correlation spectroscopy was employed to detect inhibition of the binding of WNK and SPAK. Next, a new ELISA-based screening system was developed to find drugs that inhibit SPAK activity. As a result of screening over 20,000 compounds by these two methods, we discovered several compounds that could inhibit the WNK cascade activation, namely the activation of Slc12a transporters in vitro and in mice. These compounds could be promising seeds of new types of antihypertensive drugs.
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