The role of miR-210 in cardiomyocyte metabolism following 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保健基础设施的重大负担。针对心肌梗死病理反应的治疗药物数量有限，因此广泛了解梗死后激活的内在细胞存活机制可能对开发治疗心肌梗死患者的新策略具有重要意义。MicroRNAs是一种小的调控核酸，对基因表达具有强大的影响。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。具体来说，我们对microRNA-210（一种缺氧相关的microRNA (miR)）在梗死后心肌细胞中的作用感兴趣。MiR-210在梗死心脏24小时内上调，并在缺氧培养的心肌细胞中诱导表达。miR-210在成年小鼠心脏中的组成性过表达导致扩张性心肌病和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反应中诱导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，并在体外测试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心肌细胞代谢的影响。最后，我们将生成miR-210的条件敲除小鼠，以研究其在MI后的体内功能。这些研究将为心肌梗死的分子反应提供见解，并可能确定新的治疗干预点。

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. )