Regulation of Cardiac Fibroblast Function by MicroRNAs

心脏纤维化是结构重塑的一个重要特征，它是响应多种心肺疾病而发生的，并且可能是内皮损伤的结果。它会损害心室功能，增加心律失常的风险，并导致心力衰竭的发展。心脏成纤维细胞是重要的治疗靶点，因为它们在应激反应中被激活，并在纤维化发展中发挥关键作用。开发专门针对成纤维细胞的疗法仍处于早期阶段。与传统的药物靶标相比，microRNA (miRNA) 提供了新颖的机制可能性。到目前为止，人们对它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过程中的动态调节。 miRNA-1 是一种富含肌肉的 miRNA，迄今为止已在心肌细胞中进行了广泛研究，显示其在心脏成纤维细胞中表达，并在激活后显着下调。我的初步数据还显示，参与细胞周期调节和纤维化发展的几个预测的 miRNA-1 靶标的成纤维细胞增殖、转化和蛋白质表达存在 miRNA-1 依赖性负调节。我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在心脏成纤维细胞中的功能作用和作用机制。具体目标是： i) 鉴定体外和体内成纤维细胞激活后表达发生变化的 miRNA，并根据其表达谱和靶点预测选择候选 miRNA 进行进一步研究； 2) 使用功能获得和丧失的方法描述成体心脏成纤维细胞中 miRNA-1 和其他 miRNA 的功能效应和作用机制； 3) 确定成纤维细胞限制性 miRNA 操作对预防和/或逆转体内心脏纤维化发展的影响。该项目将为心脏成纤维细胞中的 miRNA 提供新颖且全面的见解。这些发现将为未来的资助申请提供一个平台，旨在充分描述体内成纤维细胞限制的 miRNA 操作的效果，这可能提供新的治疗策略。

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.