Molecular and Metabolic phenotype of Impaired AdipoR1 in the Heart

心力衰竭仍然是全球主要的死亡原因。许多因素导致了 心力衰竭的发病和上升，但糖尿病和遗传性疾病的发病率不断增加 重要的贡献者。我们发现了一种新的脂联素受体1(AR1)基因突变。 肥厚型心肌病和糖尿病患者。特别是，筛查的患者是阴性的。 其他31个不同的肉瘤和代谢基因的突变与已知的 肥厚型心肌病代谢综合征。鉴定为G&gt；A的AR1基因的序列分析 第146位取代氨基酸缬氨酸(GUA)为蛋氨酸(AUG)(V146M)。 初步数据显示，突变改变了心肌细胞的收缩能力，增加了心脏 肥大、心肌纤维化和体内心功能受损，以及心脏胰岛素受损 响应性。这项建议的目标是进一步剖析这一疾病的直接病理功能影响 人类突变对心脏结构和功能、分子发病机制和信号转导机制的影响。 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 人类AR1V146M和人类工程心脏组织，这一提议将检验以下假设：a) AR1V146M突变干扰脂联素的生物学作用；b)AR1V146M突变有助于 心功能受损并增加肥厚型心肌病发病的易感性 和心力衰竭，特别是在存在修饰因素或二次发作时，如糖尿病；c) AR1V146M突变损伤心肌能量底物并阻断脂联素介导的作用 心脏保护。AR1V146M突变诱导的疾病表型和信号通路的定位 可能揭示预防肥厚性和糖尿病心肌病的新的药理靶点。

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.