MicroRNAs in kidney progenitor cells.

描述（由申请人提供）：MicroRNAs （miRNAs）是一组新型小rna，通过转录后抑制特定靶mrna来调节基因表达。作为一个群体，mirna在多种发育过程中发挥关键作用，是胚胎干细胞分化所必需的；然而，mirna在肾脏发育过程中的功能在很大程度上仍未确定。我们的初步工作表明，在发育中的肾脏的肾元祖腔室中，mirna的丢失会导致这个群体的过早消耗，因此，肾元数量显著减少。此外，这还伴随着促凋亡蛋白Bim（也称为Bcl-2L11）在肾细胞祖细胞中的表达升高，以及该细胞群中凋亡的增加。我们提出，特定的mirna通过调节Bim的表达来促进肾元祖细胞的存活，这一机制代表了正常肾脏发育过程中决定先天性肾元禀性的一种手段。具体目的1：表征Bim （Bcl-2L11）在肾脏发育过程中肾素祖细胞存活中的作用。具体目的2：确定miRNA簇mmu- mir -106b~25和mmu- miR-17~92在调节Bim表达和肾细胞祖细胞中的功能。特异性目的3：确定mmu-miR-10a在肾脏发育中的功能作用。在这项拨款中提出的工作将作为PI过渡到一个独立的职业生涯的基础，作为一个学术儿科肾脏部门的内科科学家。辅导阶段（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。

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.