Molecular and Metabolic phenotype of Impaired AdipoR1 in the Heart

心脏中 AdipoR1 受损的分子和代谢表型

基本信息

批准号：
9902515
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：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902515
关键词：
Address Adenoviruses Adipocytes Affect Amino Acids Animal Model Antiatherogenic Antidiabetic Drugs Attenuated Biological Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cause of Death Cell surface Complex Data Defect Diabetes Mellitus Disease Etiology Exons FRAP1 gene GTP-Binding Protein alpha Subunits, Gs Gene Targeting Gene Transfer Genes Genetic Diseases Goals Growth Heart Heart Diseases Heart Hypertrophy Heart failure Homeostasis Human Human Engineering Hypertrophic Cardiomyopathy Impairment Individual Inherited Insulin Insulin Resistance Lead Ligand Binding Ligands Link Mechanics Mediating Metabolic Metabolic Diseases Metabolic syndrome Metabolism Methionine Molecular Muscle Cells Mutation Myocardial Pathogenesis Pathologic Pathology Pathway interactions Patients Performance Pharmacology Phenotype Physiological Physiology Play Population Positioning Attribute Prevalence Prevention Property Role Signal Pathway Signal Transduction Signaling Protein Species Specificity Structure System Testing Transgenic Mice Valine Variant Ventricular adiponectin cardiac tissue engineering cardiometabolism cardioprotection clinical phenotype clinically translatable coronary fibrosis cytokine diabetes mellitus genetics diabetic diabetic cardiomyopathy diabetic patient disease phenotype glucose uptake heart function heart metabolism in silico in vivo insulin sensitivity lipid biosynthesis metabolic phenotype molecular phenotype mutant novel overexpression patient screening protein expression protein function receptor response screening

项目摘要

Heart failure remains the leading cause of death around the globe. Numerous factors contribute to the onset and rise of heart failure, but the increasing prevalence of diabetes and genetic disorders are important contributors. We have identified a novel mutation in the adiponectin receptor 1 (AR1) gene in patients with hypertrophic cardiomyopathy and diabetes. Particularly, the screened patients were negative for mutations in 31 other different sarcomeric and metabolic genes known to be associated with hypertrophic cardiomyopathy metabolic syndrome. Sequencing of the AR1 gene identified a G>A transition at 146th position that replaced the amino acid valine (GUA) into methionine (AUG) (V146M). Pilot data demonstrate that the mutation altered cardiomyocyte contractility, increased cardiac hypertrophy, myocardial fibrosis and compromised in vivo cardiac function, and impaired cardiac insulin responsiveness. The goal of this proposal is to further dissect the direct patho-functional impact of this human mutation on cardiac structure and function, molecular pathogenesis and signaling mechanisms. Using adenoviral gene transfer strategies and transgenic mice with cardiac-specific overexpression of the human AR1V146M and human engineered cardiac tissue, this proposal will test the hypotheses that: a) AR1V146M mutation interferes with adiponectin biological action; b) AR1V146M mutation contributes to impairment of cardiac function and increases vulnerability to the onset of hypertrophic cardiomyopathy and heart failure particularly in the presence of modifying factors or second hits such as diabetes; c) AR1V146M mutation impairs myocardial energy substrates and abrogates adiponectin-mediated cardioprotection. Mapping the disease phenotype and signaling pathway induced by AR1V146M mutation may reveal novel pharmacological targets for prevention of hypertrophic and diabetic cardiomyopathies.

心力衰竭仍然是全球死亡的主要原因。许多因素导致心力衰竭的发作和兴起，但是糖尿病和遗传疾病的患病率不断增加重要的贡献者。我们已经确定了在脂联素受体1（AR1）基因中的新型突变肥厚性心肌病和糖尿病患者。特别是，筛查的患者为阴性对于其他31种不同的肉瘤和代谢基因的突变，已知与肥厚的心肌病代谢综合征。 AR1基因的测序鉴定了A g> a 在第146位的过渡将氨基酸瓣膜（GUA）取代为蛋氨酸（Aug）（V146m）。试验数据表明，突变改变了心肌细胞的收缩力，心脏增加肥大，心肌纤维化和体内心脏功能受损和心脏胰岛素受损响应能力。该提议的目的是进一步剖析此提案的直接致病功能人体突变在心脏结构和功能，分子发病机理和信号传导机制上。使用具有心脏特异性过表达的腺病毒基因转移策略和转基因小鼠人类AR1V146M和人类工程性心脏组织，该提案将检验以下假设：a） AR1V146M突变会干扰脂联素生物学作用； b）AR1V146M突变有助于心脏功能障碍并增加了肥厚性心肌病的发作和心力衰竭，尤其是在有修改因素或第二次命中（例如糖尿病）的情况下； c） AR1V146M突变会损害心肌底物并消除脂联素介导的心脏保护。绘制AR1V146M突变诱导的疾病表型和信号传导途径可能揭示了预防肥厚和糖尿病心肌病的新型药理学靶标。