Efficient chemical library screening for WNK signaling inhibitors byinhibiting WNK-SPAK interaction
| Project/Area Number |
23659439
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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 |
UCHIDA Shinichi 東京医科歯科大学, 大学院・医歯学総合研究科, 准教授 (50262184)
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| Project Period (FY) |
2011 – 2012
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| Project Status |
Completed (Fiscal Year 2012)
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| Budget Amount *help |
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 水 / 電解質代謝学 / リン酸化酵素 / ケミカルライブラリー / 高血圧 / キナーゼ |
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| Research Abstract |
We focused on the With-no-lysine kinases (WNK) signaling cascade which has a pivotal role in regulating blood pressure. Agents that inhibit this signal cascade could be a new class of antihypertensive drugs. We sought to discover inhibitors of WNK-SPAK binding by screening chemical compounds that disrupt the binding. For this purpose, we developed a high-throughput screening method using fluorescent correlation spectroscopy. As a result of screening 17,000 compounds, we discovered two novel compounds that reproducibly disrupted the binding of WNK to SPAK. We then performed the modification of the seed compounds, and obtained novel compounds that exhibit the higher inhibitory activity.
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Report
(3 results)
Research Products
(80 results)
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[Journal Article] Phosphorylation of Na-Cl cotransporter by OSR1 and SPAK kinases regulates itsubiquitination2012
Author(s)
Hossain Khan MZ, Sohara E, Ohta A, Chiga M, Inoue Y, Isobe K, Wakabayashi M, Oi K, Rai T, Sasaki S, Uchida S
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Journal Title
Biochem. Biophys. Res. Commun
Volume: 425
Pages: 456-61
Related Report
Peer Reviewed
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[Journal Article] A new role for aquaporin 7 in insulinsecretion2012
Author(s)
Louchami K, Best L, Brown P, Virreira M, Hupkens E, Perret J, Devuyst O, Uchida S, Delporte C, Malaisse WJ, Beauwens R, Sener A
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Journal Title
Cell Physiol. Biochem
Volume: 29
Pages: 65-74
Related Report
Peer Reviewed
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[Journal Article] ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney2012
Author(s)
Naguro I, Umeda T, Kobayashi Y, Maruyama J, Hattori K, Shimizu Y, Kataoka K, Kim-Mitsuyama S, Uchida S, Vandewalle A, Noguchi T, Nishitoh H, Matsuzawa A, Takeda K, Ichijo H
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Journal Title
Nat. Commun
Volume: 3
Pages: 1285-1285
Related Report
Peer Reviewed
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[Journal Article] Accumulation of autofluorescent storage material in brain is accelerated by ischemia in chloride channel 3 gene-deficient mice2012
Author(s)
Ohtaki H, Ohara K, Song D, Miyamoto K, Tsumuraya T, Yofu S, Dohi K, Tanabe S,Sasaki S, Uchida S, Matsunaga M, Shioda S
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Journal Title
J. Neurosci. Res
Volume: 90
Pages: 2163-72
Related Report
Peer Reviewed
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[Journal Article] Impaired phosphorylation of Na(+)-K(+)-2Cl(-) cotransporter by oxidative stress-responsive kinase-1deficiency manifests hypotension and Bartter-like syndrome2011
Author(s)
Lin SH, Yu IS, Jiang ST, Lin SW, Chu P, Chen A, Sytwu HK, Sohara E, Uchida S, Sasaki S, Yang SS
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Journal Title
Proc. Natl. Acad. Sci. U S A
Volume: 108
Pages: 17538-43
Related Report
Peer Reviewed
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[Journal Article] Generation and analyses of R8L barttin knockin mouse2011
Author(s)
Nomura N, Tajima M, Sugawara N, Morimoto T, Kondo Y, Ohno M, Uchida K, Mutig K, Bachmann S, Soleimani M, Ohta E, Ohta A, Sohara E, Okado T, Rai T, JentschTJ, Sasaki S, Uchida S
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Journal Title
Am. J. Physiol. Renal. Physiol
Volume: 301
Related Report
Peer Reviewed
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[Journal Article] Acute insulin stimulation induces phosphorylation of the Na-Cl cotransporter in cultured distal mpkDCT cells and mouse kidney2011
Author(s)
Sohara E, Rai T, Yang SS, Ohta A, NaitoS, Chiga M, Nomura N, Lin SH, VandewalleA, Ohta E, Sasaki S, Uchida S
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Journal Title
Related Report
Peer Reviewed
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[Presentation] Phosphorylation of Na-Cl cotransporter by OSR1 and SPAK kinases regulates its ubiquitination2012
Author(s)
Hossain Khan MZ, Sohara E, Ohta A, Chiga M, Inoue Y, Isobe K, Wakabayashi M, Naito S, Oi K, Rai T, Sasaki S, Uchida S
Organizer
The 45th Annual meeting of American Society of Nephrology
Place of Presentation
San Diego (USA)
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