| Project/Area Number |
16K09620
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | The University of Tokushima |
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Principal Investigator |
KISHI Seiji 徳島大学, 病院, 助教 (10519507)
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| Co-Investigator(Kenkyū-buntansha) |
長井 幸二郎 徳島大学, 病院, 講師 (40542048)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2016: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
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| Keywords | DNA損傷応答 / 急性腎障害 / 慢性腎臓病 / 線維化 / 臓器老化 / DNA損傷 / 虚血再灌流 / DNA障害 / 腎線維化 / 腎臓病 / 尿細管間質 |
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| Outline of Final Research Achievements |
Renal proximal tubular epithelial cells (RPTECs) are the primary target of insults to the kidney. Maladaptive repair of RPTECs has been implicated in kidney fibrosis through induction of cell cycle arrest at G2/M. The role of DNA damage response (DDR) in the progression of kidney disease remains unknown.
We found that humans with CKD have activation of Ataxia telangiectasia and Rad3-related (ATR), a master regulator of DDR and DNA damage in RPTECs. Following injury by cisplatin, ATR was expressed in 70% of PTECs in kidney organoids. RPTECs specific ATR knockout mice <ATRRPTC-/-mice> exhibited greater kidney functional impairment, DNA damage, and fibrosis in response to kidney injury by either bilateral ischemia reperfusion, cisplatin or unilateral ureteral obstruction. ATRRPTC-/-mice had increased G2/M arrested cells after injuries. ATR plays a protective role against tubular cell injury and fibrosis. Regulation of ATR may be a therapeutic target against human kidney disease.
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| Academic Significance and Societal Importance of the Research Achievements |
これから我々人類は超高齢化社会を迎えるが、慢性腎臓病が糖尿病よりも患者数が多いことが明らかになっただけでなく、急性腎障害も高齢化に加えて医療の高度化を背景に増加している。
これまでDNA損傷の修復機構は主としてがん治療の標的として考えられてきたが、我々の得られた結果により、DNA損傷応答機構の調節は、腎臓病の進展に影響することが明らかとなった。今後、DNA損傷応答機構に着目した腎臓病治療法開発が期待できる。
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