Regulation of mRNA stability in Kidney epithelia

描述(由申请人提供)：项目摘要：在所有急性肾功能衰竭病例中，大约50%是以缺血性损伤为中心的。缺血的一个特征是细胞ATP水平的严重下降，这促进了细胞功能的许多变化，包括对转录和翻译活动的广泛抑制。为了在这种能量耗尽的后果中生存下来，细胞必须保持一个转录库，该转录库编码关键细胞过程中涉及的蛋白质。对RNA稳定蛋白Hur在体外肾缺血损伤模型中作用的研究表明，在细胞ATP耗竭期间，它是维持特定mRNAs适当表达所必需的。HUR可以结合成百上千个不同的mRNA转录本，在缺血应激期间从细胞核穿梭到细胞质，在那里它能够防止这些mRNAs的降解。此外，ATP耗竭触发了应激诱导的Hur翻译的变化，而ATP水平的恢复则触发了新的Hur mRNA转录。这些数据表明，HUR可能在促进肾细胞在缺血损伤中的存活方面发挥重要作用。对受损肾上皮细胞HUR的检测表明，HUR的表达和分布具有小管段特异性调节，潜在地反映了对这种类型应激的不同反应。该项目的目标是弄清由缺血损伤引发的HUR表达增强的机制，并更准确地定义该蛋白的管段特异性调控。由于HUR可能在稳定数千个关键的mRNAs方面发挥作用，这项工作应该为了解细胞在缺血应激期间存活的关键方面提供重要的见解。相关性：肾血流丧失是肾功能衰竭的常见原因。无论是由疾病、创伤或移植引起的，这种循环问题都会导致细胞死亡和肾功能丧失。这项拟议工作的目的是确定肾脏细胞用来保护自己免受这种类型损伤的一些机制，希望创造出干预这一过程并促进细胞存活的能力。

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.