The Role of miR-17~92 in Nephron Progenitors

描述（由申请人提供）：肾发育不良/发育不全是儿童肾衰竭的主要原因，导致与移植和透析相关的严重发病率和死亡率。慢性肾脏疾病的风险与肾脏发育期间形成较少和/或异常肾单位导致的肾储备减少有关。虽然对肾单位发育的遗传控制了解很多，但对microRNA（miRNAs）的作用知之甚少，miRNAs是一种负调控基因表达的小的非编码RNA分子。我们实验室有数据表明miR-17~92 miRNA簇对调节肾单位数量和形成至关重要。肾单位祖细胞中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，我们观察到在肾单位祖细胞中miR-17~92杂合缺失的动物中的中间表型，表明miR- 17~92的基因剂量是关键。人类正向基因（MIR 17 HG）的杂合突变导致了人类中与miRNA突变相关的第一个已知发育缺陷，包括肾脏异常。我们推测，肾单位祖细胞中miR-17~92簇的缺失导致内在的肾单位祖细胞缺陷，从而导致肾脏发育过程中肾单位数量和模式的异常。目标1。确定miR-17~92基因剂量在建立肾单位数量和模式中的作用。目标二。描述miR-17~92缺失的肾单位祖细胞中的内在缺陷。目标3。研究miR-17~92的下游靶点，以阐明miR-17~92簇调控肾单位数量和模式的机制。

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.