Regulation of Cardiac Fibroblast Function by MicroRNAs

MicroRNA 对心脏成纤维细胞功能的调节

基本信息

批准号：
8854114
负责人：
Peng Zhang
金额：
$ 26.25万
依托单位：
OCEAN STATE RESEARCH INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8854114
关键词：
Adult Angiotensin II Applications Grants Arrhythmia Base Sequence Biological Assay Biology Blood Vessels Body Weight Cardiac Cardiopulmonary Cell Cycle Regulation Centers of Research Excellence Collagen Data Dependovirus Development Drug Targeting Echocardiography Fibroblasts Fibrosis Future Gene Delivery Gene Targeting Goals HDAC4 gene Heart Heart failure Hypertrophy In Vitro Infusion procedures Injury Instruction Investigation Left Ventricular Function Luciferases Measurement Mediating MicroRNAs Modeling Molecular Profiling Muscle Muscle Cells Pattern Physiological Play Prevention Production Pulmonary Heart Disease Rattus Regulation Reporter Research Risk Role Seeds Signal Pathway Staging Stress Untranslated Regions Ventricular Ventricular Function base coronary fibrosis hemodynamics in vivo injury and repair insight interstitial knock-down loss of function mRNA Expression novel novel therapeutics overexpression periostin prevent promoter protein expression response subcutaneous targeted treatment therapeutic target therapy development

项目摘要

Cardiac fibrosis is an integral feature of structural remodeling that occurs in response to a variety of cardiopulmonary diseases and can be a consequence of endothelial injury. It can impair ventricular function, increase the risk for arrhythmias and contribute to heart failure development. Cardiac fibroblasts are important therapeutic targets because they become activated in response to stress and play a key role in fibrosis development. Efforts to develop therapies that specifically target fibroblasts are still at an early stage. Compared to traditional drug targets, microRNAs (miRNAs) offer novel mechanistic possibilities. So far, little is known about their role in cardiac fibroblasts. I have determined the miRNA expression pattern in adult rat ventricular fibroblasts and their dynamic regulation during fibroblast activation in vitro. MiRNA-1, a muscle-enriched miRNA that has so far been extensively studied in myocytes, is shown to be expressed in cardiac fibroblasts and markedly down-regulated upon activation. My preliminary data also show miRNA-ldependent negative regulation of fibroblast proliferation, transformation and protein expression of several predicted miRNA-1 targets that are involved in cell cycle regulation and fibrosis development. The long-term goal of my research is to gain a better understanding of the functional role and mechanisms of action of miRNAs in cardiac fibroblasts under physiological and pathophysiological conditions. The Specific Aims are: i) To identify miRNAs that are changed in their expression upon fibroblast activation in vitro and in vivo and to select candidate miRNAs for further investigation based on their expression profile and target predictions; 2) To delineate functional effects and mechanisms of action of miRNA-1 and other miRNAs in adult cardiac fibroblasts using gain- and loss-of-function approaches; 3) To determine the effects of fibroblast-restricted miRNA manipulation on prevention and/or reversal of cardiac fibrosis development in vivo. This project will provide novel and comprehensive insights into miRNAs in cardiac fibroblasts. The findings will provide a platform for future grant applications that will aim to fully delineate the effects of fibroblast-restricted miRNA manipulation in vivo, which may provide new therapeutic strategies.

心脏纤维化是结构重塑的组成部分，它是针对多种心肺疾病的响应而发生的，可能是内皮损伤的结果。它会损害心室功能，增加心律不齐的风险并导致心力衰竭发育。心脏成纤维细胞是重要的治疗靶标，因为它们会因压力而被激活并在纤维化发育中起关键作用。开发专门针对成纤维细胞的疗法的努力仍处于早期阶段。与传统的药物靶标相比，microRNA（miRNA）提供了新颖的机械可能性。到目前为止，他们在心脏成纤维细胞中的作用知之甚少。我已经确定了成年大鼠心室成纤维细胞中的miRNA表达模式及其在体外成纤维细胞激活期间的动态调节。 miRNA-1是一种富含肌肉的miRNA，迄今已在心肌细胞中进行了广泛研究，被证明在心脏成纤维细胞中表达，激活后明显下调。我的初步数据还表明，与细胞周期调节和纤维化发育有关的几个预测的miRNA-1靶标的成纤维细胞增殖，转化和蛋白质表达的负面调节。我的研究的长期目标是更好地了解miRNA在生理和病理生理条件下心脏成纤维细胞中的功能作用和作用机理。具体目的是：i）确定在体外和体内成纤维细胞激活后其表达中改变的miRNA，并选择候选miRNA以根据其表达谱和目标预测进行进一步研究； 2）使用功能丧失方法来描述成人心脏成纤维细胞中miRNA-1和其他miRNA的作用机理； 3）确定成纤维细胞限制的miRNA操纵对体内心脏纤维化发育的预防和/或逆转的影响。该项目将在心脏成纤维细胞中对miRNA提供新颖而全面的见解。这些发现将为未来的赠款应用程序提供一个平台，旨在充分描述体内成纤维细胞限制的miRNA操纵的影响，该效果可能提供新的治疗策略。