MicroRNA Control of Dilated Cardiomyopathy

MicroRNA 控制扩张型心肌病

基本信息

批准号：
9278284
负责人：
MARK MERCOLA
金额：
$ 55.09万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9278284
关键词：
ATP phosphohydrolase Accounting Address Adrenergic Agents Affect Biological Biological Process Calcium Cardiac Cardiac Myocytes Cause of Death Chronic Clinical Code Collection Contractile Proteins Data Dilated Cardiomyopathy Disease Disease Progression Disease susceptibility Drug Targeting Equilibrium Functional disorder Gene Mutation Genetic Genetic Predisposition to Disease Genotype Goals Heart Diseases Heart Transplantation Heart failure Hereditary Disease Human Impairment In Vitro Individual Knock-in Knock-in Mouse Laminin Link Mechanics Mediating Mediator of activation protein Messenger RNA MicroRNAs Modeling Mus Mutation Nature Nuclear Pathologic Pathway interactions Patients Pharmacology Phenotype Physiological Predisposition Proteins Pump Regulation Research SERCA2a Sarcomeres Sarcoplasmic Reticulum Signal Transduction Stimulus Stress Stretching Structural Protein Technology Testing Translational Repression Translations Untranslated RNA base biophysical analysis biophysical properties connectin cost desensitization disease phenotype disease-causing mutation drug candidate familial dilated cardiomyopathy heart function high throughput screening improved in vivo individual patient induced pluripotent stem cell insight mimetics mutant new therapeutic target prevent protein expression protein function response reuptake screening therapeutic target transcription factor whole genome

项目摘要

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.

microRNA 控制扩张型心肌病扩张型心肌病是心力衰竭的主要原因，大约 20-35% 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，但人们对它的了解仍然知之甚少。微小RNA 已成为心脏病的重要调节因素。其中大约有2000个短的非编码 RNA 分子在体内通过抑制稳定性和蛋白质编码 mRNA 的翻译。 miRNA 调节几乎所有的生物过程检查时，通常通过抑制通路中的多个点来产生连贯的对刺激的生物反应。我们最近使用了整个功能筛选合成 miRNA 的基因组集合，以识别抑制的 miRNA 体外心肌细胞收缩性并表明阻断其中之一 miR-25，改善心力衰竭模型中的心脏功能（Nature，2014，doi：10.1038）。我们应用高通量筛选来鉴定调节 miRNA 下降的 miRNA。使用患者特异性 hiPSC 来研究家族性扩张型心肌病 (DCM) 中的心肌细胞功能。机械的压力和慢性肾上腺素刺激会诱导大量此类 miRNA。一起我们的数据表明 miRNA 将生理压力与抑制联系起来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 DCM 的控制。目标1 2 将使用以下方法鉴定有可能抑制 DCM 收缩性的 miRNA 患者 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 miRNA 抑制以影响疾病的蛋白质，以及 AIM 4 将确定 miRNA 如何介导对病理刺激增加的反应导致疾病进展的壁张力和慢性肾上腺素刺激。总之，该研究提出了家族性 DCM 涉及的假设 miRNA 失调会损害 Ca2+ 处理、收缩性和肌节完整性。阐明 miRNA 及其蛋白质靶标应该有助于深入了解疾病进展并指出新的治疗靶点。