Molecular and Metabolic phenotype of Impaired AdipoR1 in the Heart

心脏中 AdipoR1 受损的分子和代谢表型

• 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
• 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

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.

心力衰竭仍然是地球仪的主要死因。许多因素促成了 心力衰竭的发病率和上升，但糖尿病和遗传性疾病的患病率不断增加， 重要贡献者。我们已经确定了一个新的突变脂联素受体1（AR 1）基因， 肥厚型心肌病和糖尿病患者。特别是，筛查的患者为阴性 其他31种不同的肌节和代谢基因的突变， 肥厚型心肌病代谢综合征对AR 1基因的测序鉴定出G>A 在第146位将氨基酸缬氨酸（GUA）替换为甲硫氨酸（AUG）的转变（V146 M）。 初步数据表明，该突变改变了心肌细胞的收缩力，增加了心脏的收缩力。 肥大、心肌纤维化和体内心脏功能受损以及心脏胰岛素受损 响应能力。这项提案的目标是进一步剖析这种疾病的直接病理功能影响。 人类基因突变对心脏结构和功能的影响，分子发病机制和信号机制。 使用腺病毒基因转移策略和心脏特异性过表达的转基因小鼠 人AR 1V 146 M和人工程化心脏组织，该提议将测试以下假设： AR 1 V 146 M突变干扰脂联素生物学作用; B）AR 1 V 146 M突变有助于 心脏功能受损，增加肥厚型心肌病发作的脆弱性 和心力衰竭，特别是在存在修饰因子或二次打击如糖尿病的情况下; c） AR 1V 146 M突变损害心肌能量底物并消除脂联素介导的心肌细胞凋亡 心脏保护AR 1V 146 M突变诱导的疾病表型和信号通路的定位 可能揭示预防肥大性和糖尿病性心肌病的新的药理学靶点。