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Regulation of mRNA stability in Kidney epithelia

肾上皮细胞 mRNA 稳定性的调节

基本信息

批准号：
7916094
负责人：
BETH S. LEE
金额：
$ 14.97万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7916094
关键词：
Acute Kidney Failure Be++ element Beryllium Binding Blood flow Cell Death Cell Nucleus Cell Survival Cell physiology Cells Cellular Stress Cytoplasm Cytoplasmic Granules Data Disease Drops Epithelial Cells Epithelium Event Future Gene Expression Profile Genetic Genetic Transcription Goals Growth Heart Heat shock proteins Histocompatibility Testing HuR protein Injury Investigation Ischemia Ischemic Preconditioning Kidney Kidney Failure Mammalian Cell Messenger RNA Nephrons Play Process Proteins Rattus Recovery Regulation Renal function Reperfusion Injury Reperfusion Therapy Role Stress Stress-Induced Protein Testing Transcript Transcriptional Regulation Translational Regulation Translational Repression Translations Transplantation Trauma Untranslated Regions Work in vitro Model injured insight interest kidney cell mRNA Expression mRNA Stability preconditioning prevent renal epithelium response

项目摘要

DESCRIPTION (provided by applicant): Project summary: Ischemic injury is at the heart of approximately 50% of all cases of acute renal failure. One hallmark of ischemia is a severe drop in cellular ATP levels, which promotes numerous changes in cellular functions, including broad suppression of transcriptional and translational activity. To survive this consequence of energy depletion, cells must maintain a pool of mRNA transcripts that encode proteins involved in critical cellular processes. Investigation into the role of the RNA-stabilizing protein HuR in an in vitro model of renal ischemic injury demonstrated that it is required for maintaining appropriate expression of select mRNAs during cellular ATP depletion. HuR, which may bind hundreds to thousands of distinct mRNA transcripts, shuttles from the nucleus to the cytoplasm during ischemic stress, where it is capable of preventing degradation of these mRNAs. Further, ATP depletion triggers stress-induced changes in translation of HuR, while recovery of ATP levels triggers new HuR mRNA transcription. These data suggest that HuR may play a large role in promoting kidney cell survival during ischemic injury. Examination of HuR in injured kidney epithelia demonstrates tubule segment-specific regulation of HuR expression and distribution, potentially reflecting different responses to this type of stress. The goal of this project is to discern the mechanisms behind enhanced HuR expression triggered by ischemic injury, and to more precisely define tubule segment-specific regulation of this protein. Because HuR may play a role in stabilizing thousands of critical mRNAs, this work should provide important insight into a critical aspect of cell survival during ischemic stress. Relevance: Loss of blood flow to the kidney is a common cause of renal failure. Whether induced by disease, trauma, or transplantation, this circulatory problem results in cell death and loss of kidney function. The object of the proposed work is to identify some of the mechanisms that kidney cells use to protect themselves from this type of injury, in hopes of creating the ability to intervene in this process and promote cell survival.

描述（由申请人提供）：项目总结：缺血性损伤是所有急性肾衰竭病例中约50%的核心。缺血的一个标志是细胞ATP水平的严重下降，这促进了细胞功能的许多变化，包括转录和翻译活性的广泛抑制。为了在这种能量耗尽的后果中生存下来，细胞必须维持一个mRNA转录物库，这些转录物编码参与关键细胞过程的蛋白质。对RNA稳定蛋白HuR在肾缺血性损伤的体外模型中的作用的研究表明，在细胞ATP耗竭期间，它是维持所选mRNA适当表达所必需的。HuR可以结合数百至数千种不同的mRNA转录物，在缺血应激期间从细胞核穿梭到细胞质，在细胞质中它能够防止这些mRNA的降解。此外，ATP耗竭触发应激诱导的HuR翻译变化，而ATP水平的恢复触发新的HuR mRNA转录。这些数据表明，HuR可能在促进缺血性损伤期间的肾细胞存活方面发挥重要作用。损伤的肾上皮细胞中的HuR的检查证明了HuR表达和分布的小管段特异性调节，可能反映了对这种类型的应激的不同反应。该项目的目标是识别由缺血性损伤引发的HuR表达增强背后的机制，并更精确地定义这种蛋白质的小管片段特异性调节。由于HuR可能在稳定数千种关键mRNA中发挥作用，因此这项工作应该为缺血应激期间细胞存活的关键方面提供重要见解。相关性：肾脏血流损失是肾衰竭的常见原因。无论是由疾病、创伤还是移植引起的，这种循环问题都会导致细胞死亡和肾功能丧失。这项工作的目的是确定肾细胞用来保护自己免受这种损伤的一些机制，希望创造干预这一过程并促进细胞存活的能力。