microRNA-210 regulation of kidney development

microRNA-210对肾脏发育的调节

• 批准号: 9811792
• 负责人: Shelby Lynn Hemker
• 金额: $ 3.47万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9811792
• 关键词: Adult; Affect; American; Apoptosis; Behavior; Birth; Blood flow; Cell Cycle Progression; Cells; ChIP-seq; Child; Chronic Kidney Failure; Data; Defect; Development; Diet; Disease; Duct (organ) structure; Environment; Equilibrium; Etiology; Family; Gene Expression; Gene Targeting; Genes; Health; High Fat Diet; Human; Hypertension; Hypoxia; Hypoxia Inducible Factor; In Vitro; Individual; Kidney; Kidney Diseases; Knock-out; Knockout Mice; Measures; Mediating; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Metanephric Diverticulum; MicroRNAs; Molecular; Nephrons; Oxidative Phosphorylation; Oxygen; Pathway interactions; Phenotype; Physiological; Play; Post-Transcriptional Regulation; Proteins; Publishing; Regulation; Renal function; Repression; Risk; Role; Signal Transduction; Sodium Chloride; Stem cells; Stress; Testing; Time; Untranslated RNA; angiogenesis; beta catenin; in vivo; nephrogenesis; normal aging; overexpression; premature; progenitor; response; self-renewal; transcription factor

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.

项目概要/摘要： 肾单位数量少会增加个体患高血压和慢性肾病的风险， 分别影响了大约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敏感。 肾单位数量在很大程度上取决于人类出生前自我更新和 肾单位祖细胞（分化形成大部分肾单位的细胞）的分化。这种平衡 部分受到来自分支输尿管芽（形成集合管的细胞）的信号的影响， 肾单位在空间上，肾单位祖细胞围绕输尿管芽尖，并居住在生肾区， 是一个生理缺氧的环境。最近，研究表明，增加血流量和氧气 向该生肾区的递送与肾单位祖细胞分化相关， 分化，但缺氧如何可能调节肾发生的潜在机制是未知的。 我的初步数据表明，microRNA-210（miR-210）是一种低氧调节的microRNA（miRNA）， miR-210在肾脏发育过程中在肾单位祖细胞中表达，并且整体miR-210敲除导致 显著减少肾单位数量（减少约45%）。miRNAs是一种约22个核苷酸的非编码小RNA， 通过特定靶mRNA的转录后调节来调节基因表达， 哺乳动物的正常发育miR-210是在缺氧中最稳定诱导的miRNA，并且直接被 由缺氧诱导因子（HIF）转录因子家族调节。反过来，miR-210调节 代谢、细胞凋亡、细胞周期进程和血管生成，所有这些都在肾单位中受到严格调控。 祖先最近发表的染色质免疫沉淀测序数据表明，miR-210可能 也受到肾单位祖细胞特异性转录因子Six 2的调节。此外，我的初步数据 显示miR-210敲除的肾脏有Six 2和β-catenin的过表达，这两者都是预测的。 促进肾单位祖细胞的早期分化。有趣的是，miR-210敲除的肾脏有约45%的 肾单位数量减少。总之，这些数据表明miR-210在调节平衡中起作用。 自我更新和肾单位祖细胞分化之间的关系。 我的项目将1）确定miR-210基因敲除小鼠的肾脏发育表型， 对饮食诱导的应激的反应;和2）研究miR-210在肾单位祖细胞中的下游靶点。 总的来说，我的项目将是第一个确定miR-210如何调节肾细胞祖细胞行为的项目。 发育决定肾单位的形成和功能。