MicroRNAs in kidney progenitor cells.

描述（由申请人提供）：微小RNA（miRNA）是一组新型小RNA，其通过特异性靶mRNA的转录后抑制来调节基因表达。作为一个群体，miRNAs在不同的发育过程中起着关键作用，并且是胚胎干细胞分化所必需的;然而，miRNAs在肾脏发育过程中的功能在很大程度上仍然不确定。我们的初步工作表明，在发育中的肾脏的肾单位祖细胞隔室中的miRNA的损失导致该群体的过早耗尽，并因此导致肾单位数量的显著减少。此外，这伴随着促凋亡蛋白Bim（也称为Bcl-2L 11）在肾单位祖细胞中特异性表达的升高，以及该细胞群中凋亡的增加。我们认为特定的miRNAs通过调节Bim的表达促进肾单位祖细胞的存活，并且这种机制代表了在正常肾脏发育过程中确定先天性肾单位禀赋的一种手段。具体目标1：描述Bim（Bcl-2L 11）在肾脏发育过程中肾单位祖细胞存活中的作用。具体目标2：目的：研究mmu-miR-106 b ~25和mmu-miR-17~92对Bim表达和肾单位祖细胞的调控作用。具体目标3：确定mmu-miR-10a在肾脏发育过程中的功能作用。这项拨款中提出的工作将作为PI在未来两年过渡到学术儿科肾脏部门的独立职业生涯的基础。指导阶段（K99）将在Jordan Kreidberg博士的指导下在波士顿儿童医院和哈佛医学院进行。 公共卫生相关性：总之，这些研究将进一步加深我们对在肾脏发育过程中调节肾单位祖细胞建立完整肾单位的分子和细胞过程的理解。这将最终告知先天性肾异常的病理生理学，这是幼儿肾衰竭的主要原因，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.