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Mechanisms of Successful vs. Failed Kidney Repair

肾脏修复成功与失败的机制

基本信息

批准号：
10614480
负责人：
BENJAMIN D. HUMPHREYS
金额：
$ 38.22万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614480
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Adult Automobile Driving Back Binding Cell Cycle Cell Cycle Arrest Cell Cycle Progression Cell Proliferation Cells Chronic Kidney Failure Complex Data Defect Down-Regulation Epithelial Cells Epithelium Event Fibrosis G2/M Arrest Genes Genetic Transcription Goals Growth Factor Receptors Hospitalization In Vitro Inhibition of Cell Proliferation Injury Injury to Kidney Investigation Kidney Laboratories M cell Mediating Medicare Mitosis Modeling Molecular Nuclear Outcome Pathway interactions Patients Phosphotransferases Probability Process Proliferating Proteins Proto-Oncogene Proteins c-akt Proximal Kidney Tubules Publishing Receptor Activation Recovery Recurrence Regulator Genes Reperfusion Injury Role Signal Transduction Tea Testing Therapeutic Intervention Up-Regulation Work aged constitutive expression epithelial repair falls forkhead protein improved in vivo injured kidney repair knock-down mouse model novel therapeutic intervention prevent profibrotic cytokine programs recruit repaired response to injury transcription factor

项目摘要

ABSTRACT Outcomes after acute kidney injury (AKI) cover a wide spectrum ranging from full recovery to failed repair and transition to chronic kidney disease. Medicare patients aged 66 years and older who were hospitalized for AKI had a 35% cumulative probability of a recurrent AKI hospitalization within one year and 28% developed chronic kidney disease (CKD) in the year following hospitalization (the “AKI to CKD transition”). Work from our laboratory and others has demonstrated that proximal tubule repairs through injury-induced dedifferentiation of mature proximal tubule cells. A cardinal feature of proximal tubule dedifferentiation is increased proliferative capacity, but the mechanisms governing this process are incompletely understood. Moreover, in cases of severe or repetitive injury, proximal tubule epithelia become arrested in the G2/M phase of the cell cycle, leading to profibrotic cytokine secretion, tubulointerstitial fibrosis and CKD. The long term goal of this application is to define the molecular mechanisms of proximal tubule cell cycle progression and test whether this can be manipulated to promote successful repair. We have identified the specific and strong upregulation of the transcription factor forkhead box protein M1 (FoxM1) in injured proximal tubule after injury with subsequent downregulation by day 14. FoxM1 drives transcription of proliferation-related genes, and regulates both G1/S and G2/M phases of the cell cycle. We show that the epithelial growth factor receptor (EGFR) regulates FoxM1 expression both in vitro and in vivo, and knockdown of FoxM1 in primary renal proximal tubule epithelial cells (RPTECs) inhibits cell proliferation. EGFR activation in proximal tubule is also known to activate Yes-Associated Protein (Yap) and Tea Domain transcription factors (TEAD) which in turn regulates cell proliferation after AKI. Based on published and preliminary data, we propose that AKI leads to EGFR- dependent upregulation of FoxM1 via AKT and Yap/TEAD, causing pro-repair proximal tubule proliferation. We further hypothesize that failed repair and profibrotic G2/M arrest in proximal tubule can be prevented by inducible FoxM1 expression, driving a G2 transcriptional program, cell cycle progression and successful repair. In Aim 1 we examine the roles of EGFR, Hippo and FoxM1 signaling networks in proximal tubule epithelia. In Aim 2, we define the role of FoxM1 in successful repair after ischemia-reperfusion injury using a conditional deletion strategy. In Aim 3 we ask whether tubule-specific, transient expression of constitutively active FoxM1 (FoxM1∆N) can rescue pro-fibrotic G2/M cell cycle arrest and failed repair.

摘要急性肾损伤(AKI)的预后包括从完全恢复到修复失败和过渡到慢性肾脏疾病。因AKI住院的66岁及以上的医疗保险患者有35%的累积概率在一年内复发AKI住院，28%发展为慢性住院后一年的肾病(CKD)(“AKI向CKD过渡”)。从我们的工作实验室和其他人已经证明，近端小管通过损伤诱导的去分化修复成熟的近端小管细胞。近端小管去分化的一个主要特征是增殖性增加能力有限，但管理这一进程的机制还不完全清楚。此外，在以下情况下严重或重复损伤，近端小管上皮细胞停滞在细胞周期的G2/M期，导致促纤维化细胞因子分泌、肾小管间质纤维化和慢性肾脏病。这样做的长期目标是其应用是确定近端小管细胞周期进展的分子机制，并测试这可以被操纵来促进成功的修复。我们已经确定了具体和强烈的上调转录因子叉头盒蛋白M1在损伤近端小管中的表达随后在第14天下调。FOXM1驱动增殖相关基因的转录，并调节细胞周期的G1/S和G2/M期。我们发现上皮生长因子受体(EGFR) 调节FOXM1在体外和体内的表达以及对原发肾近端FOXM1的抑制作用肾小管上皮细胞(RPTECs)抑制细胞增殖。近端小管中EGFR的激活也是已知的激活YAP和茶区转录因子(TEAD)，进而调节 AKI后细胞增殖。根据已发表的和初步的数据，我们认为AKI导致EGFR- 依赖通过AKT和YAP/TEAD上调FOXM1，导致促进修复的近端小管增殖。我们进一步假设修复失败和近端小管纤维化G2/M期停滞可通过以下方法预防可诱导FOXM1表达，驱动G2转录程序，细胞周期进展和成功修复。在目标1中，我们研究了EGFR、HIPPO和FOXM1信号网络在近端小管上皮细胞中的作用。在……里面目的2，我们确定FOXM1在缺血再灌注损伤成功修复中的作用删除策略。在目标3中，我们询问结构活性FOXM1的瞬时表达是否是小管特异的 (FOXM1∆N)可以挽救促纤维化的G2/M期细胞周期停滞和修复失败。