Genetic Analysis of microRNAs Function in Diabetic Cardiomyopathy

描述（由申请人提供）：心血管异常是糖尿病的重要表现，是糖尿病患者死亡率增加的主要原因。众所周知，在没有已知心脏危险因素的情况下，心肌病经常发生在糖尿病患者中。虽然已经提出了几种机制，但糖尿病性心肌病的发病机制尚不清楚，并且该疾病的总体复杂性表明其他调节机制仍有待确定。最近，一种关于microRNAs （miRNAs）在心脏功能中的作用的新范式出现了。基于众多mirna对病理性心脏肥厚和发展的深远影响，我们假设糖尿病性心肌病与特定mirna的改变有关，这些改变有助于疾病的发病机制。我们最近的工作发现miR-152在人类和大鼠糖尿病心力衰竭中显著上调。因此，我们的假设是miR-152调节与糖尿病心肌病相关的心功能障碍相关的基因，在体内沉默miR-152可以保留这种异常。我们的目的是识别、分析和功能阐明miR-152及其生理靶点和信号通路在糖尿病诱导的心功能障碍中的潜在作用。我们的长期目标是提供使用基于mirna的治疗方法治疗人类心力衰竭的新方法。阐明心脏miRNAs表达如何促进糖尿病性心肌病的发展将对干扰疾病相关途径具有重要意义，并可能被证明是有价值的潜在治疗方法。

DESCRIPTION (provided by applicant): Cardiovascular abnormalities are significant manifestations of diabetes mellitus and account for much of the increased mortality in diabetic patients. It is well recognized that cardiomyopathy occurs frequently in diabetic patients in the absence of known cardiac risk factors. Although several mechanisms have been proposed, the pathogenesis of diabetic cardiomyopathy is not well understood, and the overall complexity of the disease suggests that additional regulatory mechanisms remain to be identified. Recently, a novel paradigm for the role of microRNAs (miRNAs) in cardiac function has emerged. Based on the profound influence of numerous miRNAs in the development of pathological cardiac hypertrophy and development, we hypothesize that diabetic cardiomyopathy is associated with alterations in specific miRNAs that contribute to the pathogenesis of the disease. Our recent work identified miR-152 to be significantly upregulated in human and rat diabetic failing hearts. It is therefore our hypothesis that miR-152 regulates genes involved in cardiac dysfunction associated with diabetic cardiomyopathy and silencing miR-152 in vivo can reserve such abnormalities. Our aim in this proposal is to identify, analyze and functionally elucidate the potential role of miR-152 and its physiological targets and signaling pathways in the setting of diabetes-induced cardiac dysfunction. Our long-term goal is to provide new approaches using miRNA-based therapeutics to treat heart failure in humans. The elucidation of how cardiac miRNAs expression contributes to the development of diabetic cardiomyopathy will be important to interfere with disease-related pathways and may prove valuable as potential therapeutics. PUBLIC HEALTH RELEVANCE: Diabetes is the world's fastest-growing disease with high morbidity and mortality rates, predominantly as a result of heart disease. Our recent work identified a set of microRNAs that are differentially altered in human and rat diabetic failing hearts; whether such dysregulation of microRNAs expression in the heart in response to diabetes contributes to the pathogenesis of the disease is currently unknown. Therefore, elucidating the role of microRNAs in the pathophysiological mechanisms underlying diabetic cardiomyopathy will help us devise new therapies aimed at stemming the tide of the epidemic of insulin resistance and its metabolic and cardiac complications.