| Project/Area Number |
18H02735
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 52010:General internal medicine-related
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| Research Institution | Yokohama City University |
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Principal Investigator |
TAMURA Kouichi 横浜市立大学, 医学研究科, 教授 (40285143)
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| Co-Investigator(Kenkyū-buntansha) |
涌井 広道 横浜市立大学, 医学部, 准教授 (10587330)
山下 暁朗 横浜市立大学, 医学研究科, 客員教授 (20405020)
小林 竜 横浜市立大学, 医学研究科, 客員研究員 (60805612)
畝田 一司 横浜市立大学, 医学研究科, 客員研究員 (90780370)
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| Project Period (FY) |
2018-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2021: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2020: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2019: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2018: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
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| Keywords | 情報伝達系 / 受容体 / 腎臓病・高血圧 / 病態解明 / 治療標的 / 高血圧 / 腎性老化 / 新規治療 |
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| Outline of Final Research Achievements |
Pathological activation of kidney AT1R signaling stimulates tubular sodium transporters, including epithelial sodium channels, to increase sodium reabsorption and blood pressure. During a search for a means to functionally and selectively modulate AT1R signaling, a molecule directly interacting with the carboxyl-terminal cytoplasmic domain of AT1R was identified and named AT1R-associated protein (ATRAP). We showed that ATRAP promotes constitutive AT1R internalization to inhibit pathological AT1R activation in response to certain stimuli. In the kidney, ATRAP is abundantly distributed in epithelial cells along the proximal and distal tubules. Results from genetically engineered mice with modified ATRAP expression show a pivotal role of ATRAP in pathological BP regulation and suggest that the function of kidney tubule ATRAP may be different between distal tubules and proximal tubules, implying that ATRAP is a target of interest in hypertension, aging, and several aging-related diseases.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究の結果、全身性ATRAP-KOマウスを用いての検討では未解明であった、近位尿細管と遠位尿細管の区分特異的なATRAPの腎尿細管機能制御作用の一端が明らかにされた。また、近位尿細管において、ATRAPがAng II-AT1受容体シグナル伝達経路と非依存的にSIRT1タンパク質の発現を調節していることが示唆された。SIRT1は加齢に伴う慢性腎臓病の病因に関与するKeyとなる分子である。今回の研究は、研究代表者らのこれまでの研究報告と合わせて、ATRAPがSIRT1タンパク質発現を調節し、加齢に伴う高血圧や慢性腎臓病の発症機序にどのように関与しているかのメカニズム解析の一助になると考えられる。
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