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对扩张心肌病的控制扩张的心肌病是心力衰竭的主要原因，约为20-35％病例具有遗传病因。遗传学与疾病进展之间的联系尽管是当前研究的主要重点，但仍然知之甚少。 microRNA 已经成为心脏病的重要调节剂。其中约有2000个短而非编码的RNA分子在体内通过抑制稳定性和蛋白质编码mRNA的翻译。 miRNA几乎调节所有生物过程经常通过抑制途径中的多点产生连贯的检查来检查对刺激的生物反应。我们最近使用了整个功能筛选合成miRNA的基因组收集，以鉴定抑制的miRNA 体外心肌细胞收缩率，表明将其中一种阻止miR-25，改善心力衰竭模型中的心脏功能（自然，2014年，doi：10.1038）。我们应用了高吞吐量筛选，以识别调节下降的miRNA 使用患者特异性HIPSC在家族性DCM中的心肌细胞功能。机械的菌株和慢性肾上腺素能刺激诱导许多这些miRNA。一起我们的数据表明，miRNA将生理压力与抑制维持钙调节和肉瘤完整性的蛋白质。在这里，我们建议系统地研究家族性DCM的miRNA控制。目标1 2将确定有可能抑制DCM收缩性的miRNA，使用患者HIPSC-核腺癌细胞（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）；目标3意志确定受miRNA抑制以影响疾病的蛋白质，目标 4将确定miRNA如何中间对增加的病理刺激的反应壁张力和慢性肾上腺素能刺激，导致疾病进展。总而言之，该研究涉及家族性DCM涉及的假设损害Ca2+处理，收缩性和肌节完整性的miRNA失调。阐明miRNA及其蛋白质靶标应提供对疾病的见解进展并指向新的治疗靶标。