MicroRNAs in kidney progenitor cells.

肾祖细胞中的 MicroRNA。

• 批准号: 7871237
• 负责人: JACQUELINE HO
• 金额: $ 12.57万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7871237
• 关键词: Algorithms; Apoptosis; Bioinformatics; Biological Models; Boston; Cell physiology; Cells; Child; Childhood; Complement; Data; Developmental Process; Embryo; Endowment; Equilibrium; Foundations; Functional disorder; Gene Expression; Grant; Health; Individual; Jordan; Kidney; Kidney Failure; Knowledge; Mentors; MicroRNAs; Modeling; Molecular; Nephrons; Organ Culture Techniques; Pediatric Hospitals; Phase; Phenotype; Physicians; Play; Population; Research; Role; Scientist; Small RNA; Stem cells; Testing; Transcript; Transgenic Mice; Transgenic Organisms; Work; body system; career; embryonic stem cell; gain of function; gene repression; improved; interest; loss of function; medical schools; member; mouse model; nephrogenesis; novel; peptide analog; premature; pro-apoptotic protein; progenitor; public health relevance; self-renewal; small hairpin RNA

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.

描述（由申请人提供）：MicroRNA（miRNA）是一组新型小RNA，通过特定靶mRNA的转录后抑制来调节基因表达。作为一个群体，miRNA 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，miRNA 在肾脏发育过程中的功能在很大程度上仍不明确。我们的初步工作表明，发育中肾脏的肾单位祖细胞内 miRNA 的丢失导致该群体过早耗尽，从而导致肾单位数量显着减少。此外，这还伴随着促凋亡蛋白 Bim（也称为 Bcl-2L11）在肾单位祖细胞中的表达升高，以及该细胞群中细胞凋亡的增加。我们提出，特定的 miRNA 通过调节 Bim 的表达来促进肾单位祖细胞的存活，并且该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：表征 Bim (Bcl-2L11) 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：明确miRNA簇mmu-miR-106b~25和mmu-miR-17~92在调节Bim表达和肾单位祖细胞中的功能。具体目标 3：确定 mmu-miR-10a 在肾脏发育过程中的功能作用。这笔赠款中提出的工作将成为 PI 在未来两年内作为学术儿科肾脏科医师科学家过渡到独立职业的基础。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。 公共健康相关性：这些研究将进一步加深我们对调节肾单位祖细胞在肾脏发育过程中建立完整肾单位的分子和细胞过程的理解。这最终将揭示先天性肾异常的病理生理学（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。