Development of novel preventive drugs for lifestyle disease by inhibiting WNK4 signaling
Project/Area Number |
18K19534
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Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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Allocation Type | Multi-year Fund |
Review Section |
Medium-sized Section 53:Organ-based internal medicine and related fields
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Research Institution | Tokyo Medical and Dental University |
Principal Investigator |
Shinichi Uchida 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (50262184)
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Project Period (FY) |
2018-06-29 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
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Keywords | WNKシグナル / 生活習慣病 / 塩分感受性高血圧 / メタボリック症候群 / 創薬 / 炎症性サイトカイン / TNFα / WNK4 / 3T3-L1 / CRISPR/Cas9 / 質量分析 |
Outline of Final Research Achievements |
We focused on the role of WNK kinase signaling, which plays an important role in sodium handling and blood pressure control, and tried to seek the substrate of WNK4 in adipocytes, but no promising candidate was so far obtained unfortunately. Subsequently, we hypothesized that WNK kinase is a factor that links increased inflammatory cytokines and salt-sensitive hypertension in metabolic syndrome (MetS) or chronic kidney disease (CKD), and examined three types of CKD model mice. As a result, the WNK signal was observed to be enhanced in these kidneys and to be activated by TNFα. This was considered to be responsible for part of the mechanism of salt sensitive hypertension in MetS or CKD. The result was reported in Kidney International (IF: 8.4).
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Academic Significance and Societal Importance of the Research Achievements |
これまでの我々の研究成果から、WNKシグナル伝達系の制御は塩分感受性高血圧症にとどまらず肥満、耐糖能異常といったメタボリック症候群(MetS)に対する包括的治療標的となり得る可能性が期待される。今回明らかにした炎症性サイトカインとWNKシグナル伝達系との相関関係は、創薬ターゲットとしてのWNKシグナル制御の妥当性をさらに支持するものであり、有用な知見と考えられる。
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Report
(3 results)
Research Products
(33 results)
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[Journal Article] Renal TNFα activates the WNK phosphorylation cascade and contributes to salt-sensitive hypertension in chronic kidney disease2020
Author(s)
Furusho T, Sohara E, Mandai S, Kikuchi H, Takahashi N, Fujimaru T, Hashimoto H, Arai Y, Ando F, Zeniya M, Mori T, Susa K, Isobe K, Nomura N, Yamamoto K, Okado T, Rai T, Uchida S
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Journal Title
Kidney International
Volume: 97
Issue: 4
Pages: 713-727
DOI
Related Report
Peer Reviewed
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[Journal Article] Failure to sense energy depletion may be a novel therapeutic target in chronic kidney disease2019
Author(s)
Kikuchi H, Sasaki E, Nomura N, Mori T, Minamishima YA, Yoshizaki Y, Takahashi N, Furusho T, Arai Y, Mandai S, Yamashita T, Ando F, Maejima Y, Isobe K, Okado T, Rai T, Uchida S, Sohara E
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Journal Title
Kidney international
Volume: 95
Issue: 1
Pages: 123-137
DOI
Related Report
Peer Reviewed
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[Journal Article] Decreased KLHL3 expression is involved in the pathogenesis of pseudohypoaldosteronism type II caused by cullin 3 mutation in vivo2018
Author(s)
Yoshida S, Araki Y, Mori T, Sasaki E, Kasagi Y, Isobe K, Susa K, Inoue Y, Bomont P, Okado T, Rai T, Uchida S, Sohara E
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Journal Title
Clinical and experimental nephrology
Volume: 22
Issue: 6
Pages: 1251-1257
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Presentation] Renal TNFα activates WNK phosphorylation cascade and contributes to salt-sensitive hypertension in CKD2019
Author(s)
Furusho T, Mandai S, Kikuchi H, Takahashi N, Fujimaru T, Hashimoto H, Arai Y, Ando F, Mori T, Susa K, Isobe K, Nomura N, Okado T, Rai T, Yamamoto K, Uchida S, Sohara E
Organizer
ASN Kidney Week 2019
Related Report
Int'l Joint Research
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[Presentation] AMPK activation bypassing AMP sensing mechanism is a novel therapeutic strategy for chronic kidney disease2019
Author(s)
Kikuchi H, Sohara E, Nomura N, Mori T, Minamishima YA, Takahashi N, Furusho T, Ando F, Isobe K, Susa K, Rai T, Uchida S
Organizer
ASN Kidney Week 2019
Related Report
Int'l Joint Research
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[Presentation] NCX1を介したNCCの脱リン酸化と尿中カリウム排泄機構の解明2019
Author(s)
正田若菜, 野村尚弘, 安藤史顕, 田頭秀章, 岩本隆宏, 太田哲人, 磯部清志, 森崇寧, 須佐紘一郎, 蘇原映誠, 頼建光, 内田信一
Organizer
第62回日本腎臓学会学術総会
Related Report
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[Presentation] TNFαは腎臓でのWNK1分解を抑制して塩分感受性を亢進させる2019
Author(s)
古荘泰佑, 蘇原映誠, 萬代新太郎, 菊池寛昭, 新井洋平, 安藤史顕, 銭谷慕子, 森崇寧, 須佐絋一郎, 磯部清志, 野村尚弘, 岡戸丈和, 頼建光, 内田信一
Organizer
第62回日本腎臓学会学術総会
Related Report
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[Presentation] WNK1キナーゼはFOXO4の細胞核内局在,転写活性を調節し,骨格筋肥大を制御する2018
Author(s)
萬代 新太郎, 森 崇寧, 野村 尚弘, 古荘 泰佑, 新井 洋平, 菊池 寛昭, 佐々木 絵美, 蘇原 映誠, 頼 建光, 内田 信一
Organizer
第61回日本腎臓学会学術総会
Related Report
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[Presentation] Amelioration of Renal Fibrosis and Tubulointerstitial Damage in Fat-1 Transgenic CKD Mice by Compensation of Decreased Omega-3 Fatty Acids in the Kidney2018
Author(s)
Takahashi N, Kikuchi H, Ishihara T, Arita M, Furusho T, Ando F, Mori T, Isobe K, Susa K, Nomura N, Rai T, Uchida S, Sohara E
Organizer
The 52nd Annual Meeting of American Society of Nephrology, Kidney Week 2018
Related Report
Int'l Joint Research
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[Presentation] WNK1-SPAK-NCC signaling cascade is involved in salt sensitive hypertension induced by aristolochic acid nephropathy.2018
Author(s)
Furusho T, Sohara E, Mandai S, Kikuchi H, Ando F, Zeniya M, Mori T, Nomura N, Rai T, Uchida S
Organizer
The 52nd Annual Meeting of American Society of Nephrology, Kidney Week 2018
Related Report
Int'l Joint Research
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[Presentation] Genomic Background of Adults with Suspected Ciliopathy on Renal Biopsy.2018
Author(s)
Fujimaru T, Mori T, Mandai S, Chiga M, Kikuchi H, Ando F, Mori Y, Susa K, Isobe K, Iimori S, Nomura N, Naito S, Okado T, Rai T, Nagatsuji K, Nagahama K, Mishima E, Mochizuki T, Sekine A, Hoshino J, Ubara Y, Uchida S, Sohara E
Organizer
The 52nd Annual Meeting of American Society of Nephrology, Kidney Week 2018
Related Report
Int'l Joint Research
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