| Project/Area Number |
19K17706
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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 | Kyoto University |
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Principal Investigator |
Toda Naohiro 京都大学, 医学研究科, 客員研究員 (30760615)
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| Project Period (FY) |
2019-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | 中皮細胞 / 腹膜透析 / 炎症細胞 / 蛋白分解酵素 / MMP-10 / 腹膜線維化 / p38MAPK |
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| Outline of Research at the Start |
長期間の腹膜透析により、腹膜の線維化が認められる。腹膜線維症マウスの網羅的遺伝子解析から、タンパク分解酵素であるmatrix metalloproteinase-10 (MMP-10)に着目した。MMP-10ノックアウトマウスに腹膜線維症を惹起し、腹膜線維症に及ぼす影響を検討する。また、MMP-10誘導にp38MAPKが関与することから、p38MAPKもノックアウトマウスを用いて解析を行う。培養中皮細胞を用いてMMP-10の過剰発現や欠損状態が、線維化と血管新生に及ぼす影響について解析する。
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| Outline of Final Research Achievements |
To elucidate the mechanism of peritoneal fibrosis caused by long-term peritoneal dialysis, we analyzed the role of matrix metalloproteinase-10 (MMP-10), which is upregulated in the peritoneum fibrosis. Intraperitoneal administration of chlorohexidine to MMP-10 knockout mice reduced peritoneal fibrosis compared to wild-type mice. TGF-β and Col1a1 were decreased in chlorohexidine MMP-10 knockout mice. Ccl2 and Emr1 expression, which are involved in inflammation, were also decreased. To investigate the effect of MMP-10 on peritoneal permeability, we performed a peritoneal equilibrium test and found no difference in peritoneal permeability and water removal between wild-type and MMP-10 knockout mice treated with chlorohexidine.
Furthermore, peritoneal mesothelial cells harvested from MMP-10 knockout mice as a primary culture system were examined with TNF-α stimulation. Expression of Ccl2 and TNF-α mRNA was decreased compared to wild-type mice, consistent with the in vivo results.
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| Academic Significance and Societal Importance of the Research Achievements |
腹膜透析の合併症である腹膜線維化進行機序解明を行った研究であり、透過性亢進に関与しないものの腹膜線維化に関連する液性因子を同定した。社会的意義としては腹膜透析長期継続へのバイオマーカー、標的因子の候補の一つである。
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