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：
8107677
负责人：
DJAMEL LEBECHE
金额：
$ 42.38万
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/8107677
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显着表现，并解释了糖尿病患者死亡率增加的大部分。众所周知，在没有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，但是尚不清楚糖尿病心肌病的发病机理，并且该疾病的总体复杂性表明尚待确定其他调节机制。最近，出现了一种新颖的microRNA（miRNA）在心脏功能中的范例。基于众多miRNA在病理心脏肥大和发育发展中的深远影响，我们假设糖尿病心肌病与特定miRNA的改变有关，这有助于疾病的发病机理。我们最近的工作确定MiR-152在人和大鼠糖尿病失败的心脏中显着上调。因此，我们的假设是，miR-152调节涉及与糖尿病心肌病有关的心脏功能障碍的基因，并在体内沉默miR-152可以保留这种异常。我们在该建议中的目标是识别，分析和在功能上阐明miR-152及其生理靶标的潜在作用以及在糖尿病诱导的心脏功能障碍的情况下的潜在作用。我们的长期目标是使用基于miRNA的治疗剂提供新方法来治疗人类的心力衰竭。心脏miRNA表达如何有助于糖尿病心肌病的发展的阐明对于干扰与疾病相关的途径非常重要，并且可能被证明是有价值的。公共卫生相关性：糖尿病是世界上最快的疾病，其发病率和死亡率高，主要是由于心脏病。我们最近的工作确定了一组microRNA，这些microRNA在人类和大鼠糖尿病失败的心脏中有差异化。目前尚不清楚这种疾病的发病机理的microRNA表达的这种microRNA表达是否有助于疾病的发病机理。因此，阐明microRNA在糖尿病心肌病的病理生理机制中的作用将有助于我们设计旨在阻止胰岛素抵抗及其代谢和心脏并发症的新疗法。