The Role of miR-17~92 in Nephron Progenitors

描述（由申请人提供）：肾脏发育不良/发育不全是儿童肾功能衰竭的主要原因，导致移植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/或异常形成的结果。虽然人们对肾元发育的遗传控制了解很多，但对microRNAs （miRNAs）的作用知之甚少，microRNAs是一种小的、非编码的RNA分子，可以负性地调节基因表达。我们实验室的数据表明，miR-17~92 miRNA簇对调节肾细胞数量和形成至关重要。肾元祖细胞中miR-17~92的条件性缺失导致成年小鼠肾发育不良、肾小球损伤和肾功能障碍。此外，我们在肾元祖细胞中miR-17~92杂合缺失的动物中观察到一种中间表型，表明miR-17~92的基因剂量是关键。同源人类基因（MIR17HG）的杂合突变导致人类中第一个已知的与miRNA突变相关的发育缺陷，包括肾脏异常。我们假设肾素祖细胞中miR-17~92簇的缺失会导致肾素祖细胞内在缺陷，从而导致肾脏发育过程中肾素数量和模式异常。目的1。明确miR-17~92基因剂量对肾细胞数量和模式的影响。目标2。表征miR-17~92空肾元祖细胞的内在缺陷。目标3。验证下游miR-17~92靶点，以阐明miR-17~92集群调节肾细胞数量和模式的机制。

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.