Circular RNAs as novel mediators of cardiac repair

项目总结 心血管疾病是主要的死亡原因，药物治疗策略 改善心血管结局和存活率。然而，受影响个人的预后仍然存在。 很差；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。我们建议的研究集中在CircRNA作为未被探索的成分 心血管系统为心肌梗死的治疗提供了新的认识和工具。这个 本修订申请的首要目标是揭示环状RNA(CircRNAs)如何 最近发现的一类由许多蛋白质编码基因产生的RNA，Impact小鼠 心肌梗死(MI)模型。为当前提案生成的初步数据显示， 含3B(FNDC3b)基因的纤维连接蛋白III型结构域特异性CircRNA的调控 缺血心肌中的(CircFNDC3b)对小鼠心肌梗死后的心脏修复有调节作用。 特别是，我们发现：1)心肌梗死后小鼠心脏和左侧心脏中FNDC3b的表达减少 缺血性心肌病患者的心室组织，2)内皮细胞和心肌细胞 3)AAV9介导的CircFNDC3b过表达促进血管内皮细胞 血管生成和抑制体外低氧诱导的心肌母细胞凋亡，4)和改善左 心肌梗死后小鼠的心功能、重构和新生血管；5)FNDC3b结合RNA 内皮细胞和心肌母细胞中肉瘤结合蛋白(FUS-1)的表达及其调控 1级。我们的中心假设是，挽救CircFNDC3b促进了积极的心脏重构 通过FUS-1促进心肌梗死后新生血管和改善心肌细胞存活 抑制，从而改善心脏功能。这项研究将为未来打造一个多模式的平台 工作，加速这一领域的进展，因为它涉及治疗目标和基本机制。 这些假设将在以下3个具体目标下进行检验：具体目标1：确定 CircFNDC3b在小鼠心肌梗死后心肌损伤修复中的生理作用具体目标2： 阐明CircFNDC3b调控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以促进小鼠心肌梗死后的心肌损伤修复。成功完成 将可能确定CircRNA作为潜在的新的治疗靶点 心肌缺血修复。

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.