Genetic Analysis of microRNAs Function in Diabetic Cardiomyopathy

糖尿病心肌病中 microRNA 功能的遗传分析

基本信息

批准号：
8284424
负责人：
DJAMEL LEBECHE
金额：
$ 41.95万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-05 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8284424
关键词：
Ablation Accounting Animal Model Animals Binding Sites Bioinformatics Biological Calcium Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Abnormalities Cardiovascular Diseases Cell Culture System Clinical Computer Analysis Congenital Heart Defects Congestive Heart Failure Coronary artery Custom Defect Dependovirus Depressed mood Development Diabetes Mellitus Disease Ensure Epidemic Experimental Models Functional disorder Gene Expression Gene Targeting Gene Transfer Genes Goals Heart Heart Diseases Heart Hypertrophy Heart failure Homeostasis Human Hypertrophy Immunity Individual Insulin Insulin Resistance Luciferases Mass Spectrum Analysis Metabolic Metabolism MicroRNAs Molecular Morbidity - disease rate Mus Myocardial Non-Insulin-Dependent Diabetes Mellitus Obesity Pathogenesis Pathway interactions Patients Physiological Play Porifera Prevalence Primary Cell Cultures Proteins Proteomics Rattus Regulation Reporter Risk Factors Role Signal Pathway Stroke Therapeutic Transgenic Mice Untranslated Regions Up-Regulation Ventricular Work base cDNA Arrays diabetic diabetic cardiomyopathy diabetic patient diabetic rat early onset gain of function genetic analysis genome-wide glucose uptake hemodynamics in vitro Assay in vivo interest loss of function mortality mouse model nanoparticle new therapeutic target novel novel strategies overexpression public health relevance response stem therapeutic development transcriptomics type I and type II diabetes vector

项目摘要

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.

描述（由申请人提供）：心血管异常是糖尿病的重要表现，也是糖尿病患者死亡率增加的主要原因。众所周知，在缺乏已知心脏危险因素的情况下，糖尿病患者经常发生心肌病。尽管已经提出了几种机制，但糖尿病心肌病的发病机制尚不清楚，而且该疾病的整体复杂性表明还有待确定其他调节机制。最近，出现了一种关于 microRNA (miRNA) 在心脏功能中的作用的新范例。基于众多 miRNA 对病理性心脏肥大和发育的深刻影响，我们假设糖尿病心肌病与导致疾病发病机制的特定 miRNA 的改变有关。我们最近的工作发现 miR-152 在人类和大鼠糖尿病衰竭心脏中显着上调。因此，我们假设 miR-152 调节与糖尿病心肌病相关的心功能障碍相关的基因，并且体内沉默 miR-152 可以保留这种异常。我们本提案的目的是识别、分析和功能性阐明 miR-152 及其生理靶标和信号通路在糖尿病引起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 的疗法来治疗人类心力衰竭的新方法。阐明心脏 miRNA 表达如何促进糖尿病心肌病的发展对于干扰疾病相关途径非常重要，并且可能被证明作为潜在的治疗方法有价值。公共卫生相关性：糖尿病是世界上增长最快的疾病，发病率和死亡率很高，主要是由心脏病引起的。我们最近的工作发现了一组 microRNA，它们在人类和大鼠糖尿病衰竭心脏中发生了差异性改变；目前尚不清楚心脏中因糖尿病而出现的这种 microRNA 表达失调是否会导致该疾病的发病机制。因此，阐明 microRNA 在糖尿病心肌病病理生理机制中的作用将有助于我们设计新的疗法，旨在遏制胰岛素抵抗及其代谢和心脏并发症的流行趋势。