Genetic Risk Factors of Myocyte Contractility in Human Heart Failure

描述（由申请人提供）：在美国大约有500万患者患有心力衰竭，每年有超过50万的新患者被诊断出来。个体与最晚期的心力衰竭不响应最佳的药物治疗。这一发现R21应用的目的是利用一种创新的方法来绘制破坏microRNA （miRNA）结合位点的单核苷酸多态性（snp），以识别心力衰竭患者中一类新的调控突变。这些snp可能抑制miRNA结合或产生新的miRNA结合位点。待验证的假设是，调节心肌细胞收缩和舒张的基因miRNA结合位点的snp与早发扩张型心肌病和晚期心力衰竭的风险增加有关。这些实验利用了来自接受心室辅助装置（VAD）或心脏移植的患者的独特的储存和新鲜人体组织资源。这种策略的一个优势是高概率同时确定通过已确定的snp影响遗传风险的生物学机制。获得新获得的人体组织允许测量心肌细胞收缩性。我们提出以下具体目标：具体目标1 .在早发扩张型心肌病和晚期心力衰竭患者中，确定与肌节功能和钙处理相关基因miRNA结合位点的新SNP关联。具体目标二。鉴定与肌节功能和钙处理相关的基因的miRNA结合位点的snp对分离心肌细胞的收缩性和舒张性的作用。

DESCRIPTION (provided by applicant): Approximately 5 million patients in the United States have heart failure and over 500,000 new patients are diagnosed each year. Individuals with the most advanced stage of heart failure do not respond to optimal medical therapy. The purpose of this discovery R21 application is to identify a new class of regulatory mutations in individuals with heart failure using an innovative approach to map single nucleotide polymorphisms (SNPs) that disrupt microRNA (miRNA) binding sites. These SNPs may inhibit miRNA binding or create new miRNA binding sites. The hypothesis to be tested is that SNPs in miRNA binding sites of genes that regulate myocyte contractility and relaxation are associated with increased risk of early onset dilated cardiomyopathy and advanced heart failure. These experiments leverage a unique resource of banked and fresh human tissue from patients receiving a ventricular assist device (VAD) or heart transplant. A strength of this strategy is the high probability of simultaneously identifying the biological mechanism through which the identified SNPs influence genetic risk. Access to newly procured human tissue permits measurements of myocyte contractility. We propose the following specific aims: Specific Aim I. Identify new SNP associations in miRNA binding sites of genes associated with sarcomere function and calcium handling in individuals with early onset dilated cardiomyopathy and advanced heart failure. Specific Aim II. Identify the role of SNPs in miRNA binding sites of genes associated with sarcomere function and calcium handling on myocyte contractility and relaxation in isolated cardiac myocytes from core biopsies. PUBLIC HEALTH RELEVANCE: Experiments outlined in this proposal will test an innovative approach to identify a new class of regulatory mutations in microRNA binding sites in individuals with heart failure. These mutations may disrupt microRNA binding or create new microRNA binding sites.