Project/Area Number |
16K19496
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Research Category |
Grant-in-Aid for Young Scientists (B)
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Allocation Type | Multi-year Fund |
Research Field |
Kidney internal medicine
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Research Institution | Keio University |
Principal Investigator |
Hayashi Kaori 慶應義塾大学, 医学部(信濃町), 助教 (60445294)
|
Research Collaborator |
ITOH Hiroshi
HISHIKAWA Akihito
|
Project Period (FY) |
2016-04-01 – 2019-03-31
|
Project Status |
Completed (Fiscal Year 2018)
|
Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
|
Keywords | 慢性腎臓病 / エピゲノム変化 / DNA損傷修復 / ポドサイト / エピゲノム / 糖尿病性腎症 / 蛋白尿 / KAT5 / エピジェネティクス |
Outline of Final Research Achievements |
Recently we have reported the association of KLF4-mediated epigenetic regulation in glomerular podocytes with sustained regression of proteinuria by renin-angiotensin system (RAS) inhibitors (JCI 2014, KI 2015). This study revealed that the epigenetic alteration in chronic kidney disease (CKD) was partly associated with impaired DNA damage repair in podocytes. Histone acetyltransferase KAT5 plays an essential role of DNA double strand break (DSB) repair in podocytes with physiological conditions, which is decreased in diabetic nephropathy. KAT5 expression caused decreased DNA methylation and decreased DNA DSBs in the same nephrin promoter region (Cell Rep 2019). This study indicates a novel concept that an environment of DNA damage repair, such as decreased KAT5 expression in diabetic podocytes, may cause altered DNA methylation. Further study is necessary to investigate the relationship between RAS activation and DNA damage repair.
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Academic Significance and Societal Importance of the Research Achievements |
近年、エピゲノム変化と様々な疾患の関連が報告されており、慢性腎臓病との関連も多数報告されている。申請者はこれまで慢性腎臓病病態におけるエピゲノム変化の関連について特に糸球体ポドサイトに注目して検討してきたが、エピゲノム変化形成プロセスは不明な点が多かった。本研究の結果KAT5を介したDNA修復がポドサイト維持に必須であり、糖尿病性腎症におけるDNAメチル化変化形成に関与している可能性が明らかとなった。本結果は、DNA損傷修復環境がエピゲノム変化形成に関与している可能性を示唆しており、腎臓のDNA損傷修復環境の制御因子が新たな腎臓病治療標的となる可能性があり学術的・社会的意義が大きいと考える。
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