The role of miR-210 in cardiomyocyte metabolism following myocardial infarction

miR-210在心肌梗死后心肌细胞代谢中的作用

• 批准号: 7913139
• 负责人: Daniel Simon Quiat
• 金额: $ 2.78万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913139
• 关键词: Acute myocardial infarction; Adult; Affect; American; Cardiac; Cardiac Myocytes; Cell Survival; Cessation of life; Collection; Dilated Cardiomyopathy; Exhibits; Gene Expression; Gene Expression Regulation; Genetic; Genomics; Goals; Healthcare; Heart; Heart failure; Hour; Hypoxia; Infarction; Injury; Knockout Mice; Metabolic; Metabolism; MicroRNAs; Molecular; Mus; Muscle Cells; Myocardial Infarction; Nucleic Acids; Pathway interactions; Patients; Regulation; Reporter; Research Infrastructure; Role; Testing; Therapeutic Agents; Therapeutic Intervention; Transgenic Mice; Transgenic Organisms; in vitro Assay; in vivo; insight; interest; mortality; novel; prevent; public health relevance; response

DESCRIPTION (provided by applicant): Myocardial infarction (MI) and its sequelae are a significant burden on healthcare infrastructure worldwide. The number of therapeutic agents that target the pathological response to myocardial infarction are limited, thus a broad understanding of the intrinsic cell survival mechanisms that are activated following infarction could have important implications for developing new strategies to treat MI patients. MicroRNAs are small regulatory nucleic acids that exhibit a robust influence on gene expression. Recently, microRNAs have been identified as integral components in the pathological response to myocardial infarction. Our long-term goal is to understand mechanisms of gene regulation that are activated shortly following acute myocardial infarction, and how such genetic regulation might affect cell survival. Specifically, we are interested in the role of microRNA-210, a hypoxia associated microRNA (miR), in the myocyte following infarction. MiR-210 is up-regulated in the infarcted heart within 24 hours and is induced in cultured cardiomyocytes by hypoxia. Constitutive over-expression of miR-210 in the adult mouse heart results in dilated cardiomyopathy and death within 4 weeks, possibly due to metabolic derangement. First, we aim to understand the pathways that are important for the induction of miR-210 in response to hypoxia. We will use transgenic reporter mouse lines to delineate the genomic regions that govern miR-210 expression, as well as in vitro assays to test for transcriptional regulators of miR-210. We will then study the effects of miR-210 on metabolism in transgenic mice and in cultured cardiomyocytes. Last, we will generate a conditional knockout mouse for miR-210 in order to study its function following MI in vivo. This collection of studies will provide insight into the molecular response to myocardial infarction and possibly indentify novel points of therapeutic intervention. ) PUBLIC HEALTH RELEVANCE: Greater than 1 million Americans suffer from a heart attack (myocardial infarction) each year [5], and many of these patients will eventually progress to heart failure. We aim to study the cardiac response to myocardial infarction at the molecular level, with the hope that the insight we gain can be used to develop treatments that prevent injury and mortality that result myocardial infarction. )

描述（由申请人提供）：心肌梗死（MI）及其后遗症是全球医疗基础设施的重大负担。靶向心肌梗死病理反应的治疗药物的数量有限，因此对梗死后激活的内在细胞存活机制的广泛理解可能对开发治疗MI患者的新策略具有重要意义。microRNA是对基因表达表现出强大影响的小的调节核酸。最近，microRNA已被确定为心肌梗死病理反应的组成部分。我们的长期目标是了解急性心肌梗死后不久激活的基因调控机制，以及这种基因调控如何影响细胞存活。具体而言，我们感兴趣的是microRNA-210，缺氧相关的microRNA（miR），在心肌梗死后的心肌细胞中的作用。miR-210在24小时内在梗死心脏中上调，并在培养的心肌细胞中通过缺氧诱导。成年小鼠心脏中miR-210的组成性过表达导致扩张型心肌病和4周内死亡，可能是由于代谢紊乱。首先，我们的目标是了解在缺氧时诱导miR-210的重要途径。我们将使用转基因报告小鼠系来描绘控制miR-210表达的基因组区域，以及体外试验来测试miR-210的转录调节因子。然后，我们将研究miR-210对转基因小鼠和培养的心肌细胞代谢的影响。最后，我们将产生miR-210的条件性敲除小鼠，以研究其在体内MI后的功能。这些研究将提供对心肌梗死分子反应的深入了解，并可能确定新的治疗干预点。) 公共卫生相关性：每年有超过100万美国人患有心脏病发作（心肌梗死）[5]，其中许多患者最终会进展为心力衰竭。我们的目标是在分子水平上研究心肌梗死的心脏反应，希望我们获得的见解可以用于开发预防心肌梗死导致的损伤和死亡的治疗方法。)