The Role of circ-Cdr1as in monocyte/macrophage mediated cardiac injury and repair.

摘要 心肌梗死是心力衰竭引起的最常见的急性心脏损伤形式。虽然 尽管目前的治疗方法取得了显著的进步，但死亡率和发病率仍然很高。在回应心脏 损伤时，巨噬细胞大量募集到梗死心肌并控制启动， 维持和消除炎症反应。血液来源和组织驻留巨噬细胞 表现出在促炎和抗炎表型之间表型转换的独特特征 产生一系列细胞因子、趋化因子和生长因子，发挥促和抗肿瘤作用， 炎症效应。尽管有这样的理解，但关于大脑的可塑性还有很多东西需要了解。 组织修复过程中的巨噬细胞和调节巨噬细胞功能的因子。监管潜力 环状RNA（circRNA）在心血管疾病中作为一个很大程度上未探索的主题已经开始引起人们的兴趣。 环状RNA是近年来发现的一类广泛存在于蛋白质编码基因中的非编码RNA 在哺乳动物组织中表达，在物种间高度保守，最近被认为可能与 调节巨噬细胞活化。然而，目前还没有关于circRNA在细胞凋亡中的作用的报道。 巨噬细胞的生物学和功能。我们的中心假设是circRNA可能调节 单核细胞/巨噬细胞生物学在心脏损伤和治疗性调节损伤后心脏 炎症初步数据确定了在促炎和抗炎中差异表达的circRNA。 巨噬细胞，包括circRNA CDR 1as（circ-CDR 1as）。本项目旨在确定circ的具体作用- CDR 1as在促进单核细胞/巨噬细胞类别转换中的作用以及circ-CDR 1as如何调节 心肌损伤后单核细胞的功能。此外，我们计划测试circ-CDR 1as对心脏移植的功效。 使用小鼠MI模型通过功能丧失/获得方法进行体内修复。最后，研究机制 通过该循环，circ-CDR 1as在稳态和稳态下引起巨噬细胞的生理变化， 受伤的心总的来说，我们的目标是确定和建立circ-CDR 1as作为潜在治疗药物的作用。 用于解决心脏损伤后的炎症，促进心脏修复和重塑。

ABSTRACT Myocardial infarction is the most common form of acute cardiac injury attributing to heart failure. While there have been significant advances in current therapies, mortality and morbidity remain high. In response to cardiac injury, macrophages are recruited in high numbers to the infarcted myocardium and act to control the initiation, maintenance, and resolution of the inflammatory response. Blood-derived and tissue-resident macrophages exhibit the unique characteristic to phenotypically switch between a pro-and anti-inflammatory phenotype producing a sequential spectrum of cytokines, chemokines, and growth factors exerting both pro-and anti- inflammatory effects. Despite this understanding, much remains to be learned about the plasticity of macrophages during tissue repair and the factors that regulate macrophage function. The regulatory potential of circular RNAs (circRNA) in cardiovascular disease has begun to garner interest as a largely unexplored topic. Circular RNAs are newly discovered non-coding RNA generated from protein-coding genes ubiquitously expressed in mammalian tissue, highly conserved among species, and recently implicated in the possible regulation of macrophage activation. However, there are currently no reports on the role of circRNAs in macrophage biology and function during cardiac ischemia. Our central hypothesis is that circRNA may modulate monocyte/macrophage biology during cardiac injury and therapeutically regulate post-injury cardiac inflammation. Preliminary data identified circRNAs differentially expressed in pro-and anti-inflammatory macrophages, including circRNA CDR1as (circ-CDR1as). This project aims to determine the specific role of circ- CDR1as in the promotion of monocyte/macrophage class switching and how circ-CDR1as modulates the functions of monocytes post-cardiac injury. Further, we plan to test the efficacy of circ-CDR1as for cardiac repair in vivo using a mouse MI model by loss/gain of function approaches. Lastly, investigate the mechanism by which circular circ-CDR1as invokes physiological changes in macrophages in both the steady-state and injured heart. Collectively, our goal is to identify and establish the role of circ-CDR1as as a potential therapeutic for the resolution of inflammation after cardiac injury to promote cardiac repair and remodeling.