Circular RNAs as novel mediators of cardiac repair

项目摘要 心血管疾病是死亡的主要原因，药物治疗策略 改善心血管结局和生存率。然而，受影响的个人的痛苦仍然存在， 因此，需要阐明潜在的机制，并开发更好的治疗方法， 心血管疾病我们提出的研究集中在circRNA作为一个未探索的组成部分， 心血管系统产生新的理解和工具，用于治疗心肌梗死。的 当前修订申请的首要目标是揭示环状RNA（circRNA）， 最近发现的一类RNA是由许多蛋白质编码基因产生的， 心肌梗死（MI）模型。为当前提案生成的初步数据显示， 来自含纤连蛋白III型结构域3B（FNDC 3b）基因的特异性circRNA的调节 （circFNDC 3b）可以调节小鼠心肌梗死后的心脏修复。 特别是，我们发现：1）心肌梗死后小鼠心脏和左心室中circFNDC 3b表达减少， 缺血性心肌病患者的心室组织，2）以及内皮细胞和心肌细胞 3）AAV 9介导的circFNDC 3b过表达增强内皮细胞增殖; 血管生成和抑制缺氧诱导的心肌细胞凋亡，4）并改善左心室功能， 小鼠MI后心室功能、重塑和新血管形成; 5）circFNDC 3b结合RNA 在内皮细胞和心肌母细胞中的肉瘤融合结合蛋白（FUS-1），并调节FUS-1的表达。 1级。我们的中心假设是，拯救circFNDC 3b促进积极的心脏重塑 通过FUS-1增强新生血管形成并改善心肌细胞存活 抑制，从而改善心脏功能。这项研究将为未来的多模式平台 工作，加快这一领域的进展，因为它涉及到治疗目标和潜在的机制。 将根据以下3个具体目标对假设进行检验：具体目标1：确定 circFNDC 3b对小鼠MI后心肌损伤修复的生理作用。具体目标2： 阐明circFNDC 3b调节心肌细胞存活的分子机制， 增强内皮细胞功能。具体目标3：开发新的治疗策略， 操纵其他circRNA以促进小鼠MI后心肌损伤修复。成功完成 拟议的研究将有可能确定circRNA作为潜在的新型治疗靶点， 缺血性心肌修复

PROJECT SUMMARY Cardiovascular disease is the leading cause of death and pharmacologic treatment strategies have improved cardiovascular outcomes and survival. However, the prognoses of affected individuals remain poor; hence, the need to elucidate underlying mechanisms and develop better therapies for cardiovascular diseases. Our proposed studies focus on circRNA as an unexplored component of the cardiovascular system to yield new understanding and tools for treatment of myocardial infarction. The overarching objective of this current revised application is to reveal how circular RNAs (circRNAs), a recently identified class of RNAs that are generated from many protein-coding genes, impact mouse models of myocardial infarction (MI). Preliminary data generated for the current proposal shows that modulation of a specific circRNA from the Fibronectin Type III Domain Containing 3B (FNDC3b) gene (circFNDC3b) in ischemic myocardium can modulate cardiac repair after myocardial infarction in mice. In particular, we found: 1) decreased circFNDC3b expression in post-MI mouse hearts and in left ventricular tissues of ischemic cardiomyopathy patients, 2) and in endothelial cells and cardiomyocytes in post-MI mouse hearts; 3) AAV9 mediated circFNDC3b overexpression enhances endothelial cell angiogenesis and inhibits hypoxia-induced cardiomyoblast apoptosis in vitro, 4) and improves left ventricular function, remodeling and neovascularization post-MI in mice; 5) circFNDC3b bind RNA binding protein fused in sarcoma (FUS-1) in endothelial cells and cardiomyoblasts and regulate FUS- 1 levels. Our central hypothesis is that rescue of circFNDC3b promotes positive cardiac remodeling after MI by enhancing neovascularization and improves cardiomyocyte cell survival through FUS-1 inhibition, thus improving cardiac function. This research will create a multi-modal platform for future work, accelerating progress in this field as it relates to therapeutic targets and underlying mechanisms. The hypotheses will be tested under the following 3 specific aims: Specific Aim 1: To determine the physiological role of circFNDC3b on myocardial injury repair post-MI in mice. Specific Aim 2: To elucidate the molecular mechanism by which circFNDC3b regulates cardiomyocyte cell survival and enhances endothelial cell function. Specific Aim 3: To develop novel therapeutic strategies to manipulate other circRNAs to promote myocardial injury repair post-MI in mice. Successful completion of the proposed research will potentially identify circRNAs as potentially novel therapeutic targets for ischemic myocardial repair.