microRNA-210 regulation of kidney development

项目摘要/摘要： 低肾单位数会增加个人患高血压和慢性肾脏疾病的风险， 分别影响大约30%和15%的美国成年人。肾单位减少的个体 许多人对高盐和高脂肪饮食对肾脏健康的有害影响更加敏感。 在人类出生之前，肾单位的数量在很大程度上是由自我更新和 肾单位祖细胞的分化(分化形成大部分肾单位的细胞)。这一差额 在一定程度上受到来自分支输尿管芽(形成收集管道的细胞)的信号的影响，这种信号诱导 尼弗农。在空间上，肾单位祖细胞围绕在输尿管芽尖周围，并居住在肾形成区，这 是一个生理上的低氧环境。最近，有研究表明，血液流量和氧气的增加 向这个肾区的交付与肾单位祖细胞分化有关，与其相关 但低氧可能如何调节肾脏发生的潜在机制尚不清楚。 我的初步数据表明，microRNA-210(miR-210)是一种受缺氧调节的microRNA(MiRNA)，它 在肾脏发育过程中在肾单位祖细胞中表达，并且全局miR-210基因敲除导致 肾单位数显著减少(减少约45%)。MiRNAs是一种小的非编码RNA，有那么细- 通过转录后调节特定靶向的mRNAs来调节基因的表达，这对于 哺乳动物的正常发育。MiR-210是缺氧中诱导最稳定的miRNA，直接 受缺氧诱导因子(HIF)转录因子家族的调节。反过来，miR-210调节 新陈代谢、细胞凋亡、细胞周期进展和血管生成，所有这些都在肾单位受到严格调控。 祖先。最近发表的染色质免疫沉淀测序数据表明，miR-210可能 也受肾单位祖细胞特异性转录因子SIX2的调控。此外，我的初步数据 结果表明，miR-210基因敲除的肾脏有six2和β-catenin的过度表达，这两个基因都是预测的 促进肾单位祖细胞的早期分化。有趣的是，miR-210基因敲除的肾脏有~45% 肾单位数目减少。总而言之，这些数据表明miR-210在调节平衡方面发挥了作用 在自我更新和分化之间的肾单位祖细胞。 我的项目将1)确定miR-210基因敲除小鼠的肾脏发育表型和它的 对饮食诱导的应激反应；以及2)研究肾单位祖细胞miR-210的下游靶点。 总体而言，我的项目将是第一个定义miR-210如何在肾脏期间调节肾单位祖细胞行为的项目 发展以决定肾单位的形成和功能。

Project Summary/Abstract: Low nephron number increases an individual’s risk for developing hypertension and chronic kidney disease, which affect approximately 30% and 15% of American adults, respectively. Individuals with decreased nephron number are more sensitive to the detrimental effects that high salt and high fat diets have on kidney health. Nephron number is largely determined before birth in humans by the balance between self-renewal and differentiation of nephron progenitors (cells which differentiate to form the majority of the nephron). This balance is influenced, in part, by signals from the branching ureteric bud (cells that form the collecting ducts) that induce nephrons. Spatially, nephron progenitors surround ureteric bud tips and reside in the nephrogenic zone, which is a physiologically hypoxic environment. Recently, it has been shown that increased blood flow and oxygen delivery to this nephrogenic zone is associated with nephron progenitor differentiation are associated with their differentiation, but the mechanisms underlying how hypoxia may regulate nephrogenesis are unknown. My preliminary data demonstrates that microRNA-210 (miR-210) is a hypoxia-regulated microRNA (miRNA) that is expressed in nephron progenitors during kidney development, and that a global miR-210 knockout results in significantly reduced nephron number (~45% decrease). miRNAs are ~22nt small noncoding RNAs that fine- tune gene expression through post-transcriptional regulation of specific target mRNAs and are essential for proper mammalian development. miR-210 is the most consistently induced miRNA in hypoxia and is directly regulated by the Hypoxia Inducible Factor (HIF) transcription factor family. In turn, miR-210 regulates metabolism, apoptosis, cell cycle progression, and angiogenesis, all of which are tightly regulated in nephron progenitors. Recently published chromatin immunoprecipitation-sequencing data suggests that miR-210 may also be regulated by the nephron progenitor-specific transcription factor Six2. Furthermore, my preliminary data show that the miR-210 knockout kidneys have overexpression of Six2 and β-catenin, both of which are predicted to promote early differentiation of nephron progenitors. Interestingly, miR-210 knockout kidneys have ~45% reduction in nephron number. Together, these data suggest miR-210 plays a role in regulating the balance between self-renewal and differentiation of nephron progenitors. My project will 1) determine the kidney developmental phenotype of the miR-210 knockout mouse and its response to diet-induced stress; and 2) investigate the downstream targets of miR-210 in nephron progenitors. Overall, my project will be the first to define how miR-210 regulates nephron progenitor behavior during kidney development to dictate nephron formation and function.