MicroRNAs in kidney progenitor cells.

描述(申请人提供)：microRNAs(MiRNAs)是一组新的小RNA，通过转录后抑制特定目标mRNAs来调节基因表达。作为一个群体，miRNAs在不同的发育过程中发挥着关键作用，并且是胚胎干细胞分化所必需的；然而，miRNAs在肾脏发育中的功能在很大程度上仍不清楚。我们的初步工作表明，发育中的肾脏的肾单位祖室内miRNAs的丢失导致这一群体的过早枯竭，结果是肾单位数量显著减少。此外，伴随着促凋亡蛋白Bim(也称为Bcl2L11)在肾单位祖细胞中的表达增加，以及在该细胞群中的凋亡率增加。我们认为，特定的miRNAs通过调节Bim的表达来促进肾单位祖细胞的存活，这一机制代表了一种确定正常肾脏发育过程中先天性肾单位天赋的手段。具体目的1：研究Bim(Bcl2L11)在肾脏发育过程中对肾祖细胞存活的影响。目的2：明确miRNA簇MMU-miR-106b~25和MMU-miR-17~92在调节Bim表达和肾小球祖细胞中的作用。具体目的3：确定MMU-miR-10a在肾脏发育过程中的功能作用。这项拨款中提议的工作将作为未来两年内国际医学联合会过渡到一个独立的职业生涯的基础，成为一个学术儿科肾科的内科科学家。指导阶段(K99)将在波士顿儿童医院和哈佛医学院进行，由乔丹·克莱德伯格博士指导。 公共卫生相关性：总之，这些研究将进一步加深我们对分子和细胞过程的理解，这些分子和细胞过程调节肾单位祖细胞在肾脏发育过程中建立完整的肾单位。这最终将为先天性肾脏异常的病理生理学提供信息，先天性肾脏异常是幼儿肾功能衰竭的主要原因，以及决定先天性肾单位数量的机制，这对长期肾脏健康具有重要意义。

DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) are a group of novel small RNAs that regulate gene expression via the post- transcriptional repression of specific target mRNAs. As a group, miRNAs play a key role in diverse developmental processes, and are required for the differentiation of embryonic stem cells; however the function of miRNAs during kidney development remains largely undefined. Our preliminary work indicates that the loss of miRNAs within the nephron progenitor compartment of the developing kidney results in a premature depletion of this population, and as a consequence, a marked decrease in nephron number. Furthermore, this is accompanied by elevated expression of the pro-apoptotic protein Bim (also known as Bcl-2L11) specifically in nephron progenitors, and an increase in apoptosis in this cell population. We propose that specific miRNAs promote the survival of nephron progenitors by regulating the expression of Bim, and that this mechanism represents a means of determining congenital nephron endowment during normal kidney development. Specific aim 1: To characterize the role of Bim (Bcl-2L11) in the survival of nephron progenitors during kidney development. Specific aim 2: To define the function of the miRNA clusters, mmu-miR-106b~25 and mmu- miR-17~92, in regulating Bim expression and nephron progenitors. Specific aim 3: To determine the functional role of mmu-miR-10a during kidney development. The work proposed in this grant will serve as the foundation for the PI's transition into an independent career as a physician-scientist in an academic pediatric renal division over the next two years. The mentored phase (K99) will occur at Children's Hospital Boston and Harvard Medical School under the guidance of Dr. Jordan Kreidberg. PUBLIC HEALTH RELEVANCE: Together, these studies will further our understanding of the molecular and cellular processes that regulate nephron progenitors in establishing the full complement of nephrons during kidney development. This will ultimately inform the pathophysiology underlying congenital renal anomalies, the leading cause of renal failure in young children, and the mechanisms that determine congenital nephron number, which has important implications for long-term kidney health.