| Project/Area Number |
18K15996
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53040:Nephrology-related
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| Research Institution | Niigata University |
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Principal Investigator |
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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 |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
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| Keywords | ネフローゼ症候群 / FKBP12 / 糸球体上皮細胞 / タクロリムス / カルシニューリン阻害剤 / アクチン細胞骨格 / カルシニューリン |
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| Outline of Final Research Achievements |
FKBP12 was identified as a binding protein of tacrolimus (Tac). In this study, we investigated the expression and the role of FKBP12 in podocytes and analyzed the effect of Tac on FKBP12 in podocytes. We observed that FKBP12 is highly expressed in glomeruli, and the FKBP12 in glomeruli is restricted in podocytes. FKBP12 interacted with the actin-associated proteins 14-3-3 and synaptopodin (Synp) in podocytes. In injured podocyte, FKBP12 was downregulated, and the consequent disruption of the linkages of FKBP12 with 14-3-3 and Synp resulted in deranged F-actin structure. Tac enhanced the interactions of FKBP12 with 14-3-3 and Synp and suppressed the decrease of FKBP12. Tac treatment suppressed the decrease of process formation in podocyte injury by restoring FKBP12 at actin cytoskeleton. These observations suggested that FKBP12 at actin cytoskeleton participates in the maintenance of process, and Tac treatment ameliorates podocyte injury by restoring FKBP12 at actin cytoskeleton.
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| Academic Significance and Societal Importance of the Research Achievements |
免疫抑制剤として広く使われるタクロリムス(Tac)はネフローゼ症候群でT細胞非依存的に蛋白尿抑制効果を示す事が報告されているが、詳細な薬効機序は明らかでなかった。FKBP12はTacの結合蛋白質として同定された。FKBP12はTacに非依存的に生理的な細胞内シグナル調節因子としての機能も持つが、FKBP12の腎臓における発現と機能、TacのFKBP12の機能に与える影響は不明だった。本研究で、FKBP12のポドサイトにおける発現と局在、相互作用分子を同定し、アクチン細胞骨格の維持における機能を解明した。また、TacのFKBP12の機能維持を介した蛋白尿抑制効果の新規薬効機序を明らかにした。
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