MicroRNA Control of Dilated Cardiomyopathy

扩张型心肌病的microRNA调控 扩张型心肌病是心力衰竭的主要原因，大约20%-35%的 这些病例有遗传原因。遗传学与疾病进展之间的联系 尽管是当前研究的主要焦点，但人们对此仍知之甚少。MicroRNAs 已经成为心脏病的重要调节者。其中大约有2000个 短的、非编码的RNA分子在体内通过抑制稳定性和 翻译蛋白质编码的mRNAs。MiRNAs调控几乎所有的生物过程 通常通过抑制一条路径中的多个点来产生相干的 对刺激的生物反应。我们最近使用了全身性功能筛查 合成miRNAs的基因组集合，以识别抑制 心肌细胞的体外收缩能力，并表明阻断其中之一，miR-25， 改善心力衰竭模型的心功能(自然，2014年，DOI：10.1038)。 我们应用高通量筛选来识别调节细胞周期下降的miRNAs。 使用患者特异性HiPSCs的家族性DCM患者的心肌细胞功能。机械式 压力和慢性肾上腺素能刺激诱导了许多这样的miRNAs。同舟共济 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miRNA对家族性扩张性心肌病的控制。目标1 和2将确定有可能抑制DCM收缩的miRNAs，使用 病人HiPSC-心肌细胞(cTn-T R173W和R141W)和小鼠DCM模型 对应于DCM患者HiPSC模型之一(cTn-T R173W)；AIM 3将 确定被miRNAs抑制以影响疾病的蛋白质，目的 4将确定miRNAs如何调节对病理性刺激增加的反应 导致疾病进展的室壁张力和慢性肾上腺素能刺激。 总而言之，这项研究解决了家族性DCM涉及的假设 MiRNAs的失调，损害了钙离子的处理、收缩和肌节的完整性。 阐明miRNAs及其蛋白靶标有助于深入了解疾病 进展和指向新的治疗靶点。

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.