The Role of miR-17~92 in Nephron Progenitors

描述(申请人提供)：肾发育不良/发育不全是导致儿童肾功能衰竭的主要原因，导致与移植计划和透析相关的显著发病率和死亡率。慢性肾脏疾病的风险与肾脏储备减少有关，这是肾脏发育过程中肾单位减少和/或异常的结果。虽然人们对肾单位发育的遗传控制知之甚少，但对microRNAs(MiRNAs)的作用知之甚少。microRNAs是一种非编码的小RNA分子，可以负向调节基因的表达。本实验室已有数据表明miR-17~92miRNA簇在调节肾单位数量和形成中起关键作用。肾单位前体细胞miR-17~92的条件性缺失可导致成年小鼠肾发育不良、肾小球损伤和肾功能障碍。此外，我们在肾脏前体细胞miR-17~92杂合性缺失的动物中观察到了中间表型，提示miR-17~92的基因剂量是关键。人类正源基因(MIR17HG)的杂合突变导致了人类第一个已知的与miRNA突变相关的发育缺陷，包括肾脏异常。我们推测，在肾脏发育过程中，miR-17~92簇的缺失会导致固有的肾脏祖细胞缺陷，从而导致肾脏发育过程中肾单位数量和形态的异常。目的1.明确miR-17~92基因剂量在确定肾单位数目和类型中的作用。目的2.鉴定miR-17~92缺失肾小球祖细胞的固有缺陷。目的3.验证下游miR-17~92靶点，阐明miR-17~92簇调控肾单位数目和构型的机制(S)。

DESCRIPTION (provided by applicant): Renal dysplasia/hypoplasia is a leading cause of renal failure in children, leading to significant morbidity and mortality associated with transplan and dialysis. The risk of chronic kidney disease is linked to decreased renal reserve as a result of the formation of fewer and/or abnormal nephrons during kidney development. While much is known about the genetic control of nephron development, very little is known about the role of microRNAs (miRNAs), small, non-coding RNA molecules that negatively regulate gene expression. Our laboratory has data demonstrating that the miR-17~92 miRNA cluster is crucial to regulating nephron number and formation. Conditional loss of miR-17~92 in nephron progenitors results in renal hypodysplasia, glomerular injury and renal dysfunction in adult mice. Moreover, we observe an intermediate phenotype in animals with heterozygous loss of miR-17~92 in nephron progenitors, suggesting that the gene dosage of miR- 17~92 is key. Heterozygous mutations in the orthologous human gene (MIR17HG) results in the first known developmental defects associated with a miRNA mutation in humans, including renal anomalies. We hypothesize that loss of the miR-17~92 cluster in nephron progenitors results in an intrinsic nephron progenitor defect, and therefore abnormal nephron number and pattern during kidney development. Aim 1. Define the role of miR-17~92 gene dosage in establishing nephron number and pattern. Aim 2. Characterize the intrinsic defect in miR-17~92 null nephron progenitors. Aim 3. Validate downstream miR-17~92 targets to elucidate mechanism(s) by which the miR-17~92 cluster regulates nephron number and patterning.