MicroRNAs in Kidney Progenitor Cells.

项目摘要/摘要 MicroRNAs(MiRNAs)是一组新型的小RNA，通过转录后调节基因表达。 转录抑制特定靶基因的mRNAs。作为一个群体，miRNAs在不同的 发育过程，是胚胎干细胞分化所必需的；然而 MiRNAs在肾脏发育过程中的作用在很大程度上仍不清楚。我们的初步工作表明， 发育中肾脏的肾单位祖细胞体内miRNAs的丢失导致早产 这一群体的枯竭，其结果是肾单位数量显著减少。此外，这一点 伴随着促凋亡蛋白Bim(也称为Bcl-2L11)的特异性表达增加 在肾单位祖细胞中，以及在这一细胞群体中的凋亡率增加。我们建议特定的miRNAs 通过调节Bim的表达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方法。 特异目的1：研究Bim(Bcl2L11)在肾小球祖细胞存活中的作用 发展。具体目标2：确定miRNA簇MMU-miR-106b~25和MMU-miR-106b~25的功能 MIR-17~92，调节Bim表达和肾单位祖细胞。具体目标3：确定 MMU-miR-10a在肾脏发育中的功能作用这项拨款中建议的工作将作为 为PI过渡到独立的职业生涯奠定基础，成为一名学术儿科的内科科学家 在接下来的两年里，肾脏部门。指导阶段(K99)将在波士顿儿童医院和 哈佛医学院在乔丹·克莱德伯格博士的指导下。

Project Summary/Abstract 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.