The Role of miR-17~92 in Nephron Progenitors

miR-17~92在肾单位祖细胞中的作用

• 批准号: 8798885
• 负责人: JACQUELINE HO
• 金额: $ 33.92万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8798885
• 关键词: Adult; Animals; Bioinformatics; Child; Chronic Kidney Failure; Data; Defect; Development; Developmental Biology; Dialysis procedure; Disease; Dysplasia; Endowment; Functional RNA; Functional disorder; Gene Dosage; Gene Expression; Gene Expression Regulation; Genes; Genetic; Goals; Health; High-Throughput Nucleotide Sequencing; High-Throughput RNA Sequencing; Human; Hypertension; In Vitro; Injury; Kidney; Kidney Failure; Laboratories; Life Expectancy; Link; MicroRNAs; Molecular; Morbidity - disease rate; Mus; Mutation; Nephrons; Pathway interactions; Pattern; Phenotype; Psyche structure; Risk; Risk Factors; Role; Testing; Transplantation; Universities; in vivo; morphometry; mortality; mutant; nephrogenesis; pediatric department; progenitor; public health relevance; self-renewal

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.

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显着发病率和死亡率。慢性肾病的风险与肾储备减少有关，这是由于肾脏发育过程中肾单位形成较少和/或异常所致。虽然人们对肾单位发育的遗传控制了解甚多，但对 microRNA (miRNA) 的作用却知之甚少，microRNA 是一种负向调节基因表达的非编码小 RNA 分子。我们实验室的数据表明，miR-17~92 miRNA簇对于调节肾单位的数量和形成至关重要。肾单位祖细胞中miR-17~92的条件性缺失会导致成年小鼠肾发育不良、肾小球损伤和肾功能障碍。此外，我们在肾单位祖细胞中杂合丢失miR-17~92的动物中观察到中间表型，这表明miR-17~92的基因剂量是关键。人类直系同源基因 (MIR17HG) 的杂合突变导致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。我们假设肾单位祖细胞中 miR-17~92 簇的丢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异常。目的 1. 明确 miR-17~92 基因剂量在建立肾单位数量和模式中的作用。目标 2. 表征 miR-17~92 无效肾单位祖细胞的内在缺陷。目标 3. 验证下游 miR-17~92 靶点，以阐明 miR-17~92 簇调节肾单位数量和模式的机制。