MicroRNA Control of Dilated Cardiomyopathy

扩张型心肌病的microRNA调控 扩张性心肌病是心力衰竭的主要原因， 病例有遗传病因。遗传学与疾病进展之间的联系 尽管是当前研究的一个主要焦点，但仍然知之甚少。微rna 已经成为心脏病的重要调节因子。其中约2000人 短的非编码RNA分子在体内通过抑制稳定性和 蛋白质编码mRNA的翻译。miRNAs几乎调节所有的生物过程 通常通过抑制通路中的多个点来检查， 对刺激的生物反应我们最近使用功能筛选的整体 合成miRNAs的基因组集合，以鉴定抑制 体外心肌细胞收缩性研究表明，阻断其中之一，miR-25， 改善心力衰竭模型的心脏功能（Nature，2014，doi：10.1038）。 我们应用高通量筛选来鉴定调节细胞凋亡的miRNAs。 使用患者特异性hiPSC的家族性DCM中的心肌细胞功能。机械 紧张和慢性肾上腺素能刺激诱导许多这些miRNA。一起 我们的数据显示，miRNAs将生理应激与抑制 维持钙调节和肌节完整性的蛋白质。 在这里，我们建议系统地研究家族性DCM的miRNA控制。目标1 和2将鉴定具有抑制DCM收缩潜力的miRNA，使用 患者hiPSC-心肌细胞（cTn-T R173 W和R141 W）和小鼠DCM模型 对应于DCM患者hiPSC模型之一（cTn-T R173 W）; AIM 3将 确定被miRNAs抑制以影响疾病的蛋白质，以及AIM 4将建立miRNAs如何介导对病理刺激的反应， 血管壁张力和慢性肾上腺素能刺激，导致疾病进展。 总之，该研究提出了家族性DCM涉及 miRNAs的失调损害了Ca 2+处理、收缩性和肌节完整性。 阐明miRNAs及其蛋白质靶点将有助于深入了解疾病 进展并指出新的治疗靶点。

microRNA Control of Dilated Cardiomyopathy Dilated cardiomyopathy is a major cause of heart failure and approximately 20-35% of cases have genetic etiologies. The link between the genetics and disease progression remains poorly understood, despite being a major focus of current research. microRNAs have emerged as important regulators of heart disease. Approximately 2000 of these short, non-coding RNA molecules function in vivo by repressing the stability and translation of protein-coding mRNAs. miRNAs regulate nearly all biological processes examined, often by suppressing multiple points in a pathway produce a coherent biological response to stimuli. We have recently used functional screening of whole genome collections of synthetic miRNAs to identify miRNAs that suppress cardiomyocyte contractility in vitro and shown that blocking one of these, miR-25, improves heart function in a heart failure model (Nature, 2014, doi:10.1038). We applied high throughput screening to identify miRNAs that regulate the decline in cardiomyocyte function in familial DCM using patient-specific hiPSCs. Mechanical strain and chronic adrenergic stimulation induce a number of these miRNAs. Together our data have revealed that miRNAs connect physiological stress to suppression of proteins that maintain calcium regulation and sarcomeric integrity. Here we propose to systematically investigate miRNA control of familial DCM. AIMS 1 and 2 will identify miRNAs that have the potential to suppress contractility in DCM, using patient hiPSC-cardiomyocytes (cTn-T R173W and R141W) and a mouse DCM model corresponding to one of the DCM patient hiPSC models (cTn-T R173W); AIM 3 will determine the proteins that are repressed by the miRNAs to influence disease, and AIM 4 will establish how miRNAs midiate the response to pathological stimuli of increased wall tension and chronic adrenergic stimulation that contribute to disease progression. In summary, the research addresses the hypothesis that familial DCM involves dysregulation of miRNAs that impair Ca2+ handling, contractility and sarcomere integrity. Elucidating the miRNAs and their protein targets should provide insight into disease progression and point to novel therapeutic targets.