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

circ-Cdr1as 在单核细胞/巨噬细胞介导的心脏损伤和修复中的作用。

• 批准号: 10669558
• 负责人: Carolina Gonzalez
• 金额: $ 3.41万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2025-08-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669558
• 关键词: Accounting; Acute; Affect; Anti-Inflammatory Agents; Antiinflammatory Effect; Apoptosis; Biogenesis; Biology; Blood; Bone Marrow; Cardiac; Cardiovascular Diseases; Cause of Death; Cd68; Cell physiology; Cerebellar Degeneration Related 1 Antisense; Cessation of life; Characteristics; Code; Data; Dependovirus; Deterioration; Enzyme-Linked Immunosorbent Assay; Exhibits; Exposure to; Flow Cytometry; Gene Expression; Genes; Genetic Transcription; Goals; Growth Factor; Heart; Heart Injuries; Heart failure; Immunity; Immunoglobulin Class Switching; In Vitro; Infarction; Inflammation; Inflammatory; Inflammatory Response; Label; Learning; Left Ventricular Function; Macrophage; Macrophage Activation; Maintenance; Mediating; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocarditis; Myocardium; Phenotype; Physiological; Population; Porifera; Process; Production; Proteins; Publishing; RNA; RNA-Binding Proteins; Regulation; Regulator Genes; Reporting; Resolution; Role; Sorting; Testing; Therapeutic; Tissues; Toxicology; Translations; United States; Untranslated RNA; Western Blotting; cardiac repair; chemokine; circular RNA; cytokine; differential expression; efficacy evaluation; efficacy testing; gain of function; healing; heart function; improved; in vivo; injured; interest; locked nucleic acid; loss of function; monocyte; mortality; neovascularization; new therapeutic target; overexpression; prediction algorithm; recruit; repaired; response; tissue repair

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.

抽象的 心肌梗塞是心力衰竭引起的急性心脏损伤的最常见形式。在那里 目前的治疗已取得重大进展，但死亡率和发病率仍然很高。响应心脏 损伤后，巨噬细胞被大量募集到梗塞心肌并发挥控制起始作用， 维持和消除炎症反应。血液来源和组织驻留的巨噬细胞 表现出在促炎表型和抗炎表型之间进行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，发挥促和抗作用 炎症作用。尽管有这样的认识，但关于可塑性仍有很多需要了解的地方。 组织修复过程中的巨噬细胞以及调节巨噬细胞功能的因素。监管潜力 心血管疾病中的环状RNA（circRNA）作为一个很大程度上未被探索的话题已经开始引起人们的兴趣。 环状RNA是新发现的非编码RNA，由普遍存在的蛋白质编码基因产生 在哺乳动物组织中表达，在物种间高度保守，最近与可能的 巨噬细胞活化的调节。但目前尚无关于circRNA在中枢神经系统中的作用的报道。 心脏缺血期间巨噬细胞的生物学和功能。我们的中心假设是 circRNA 可能调节 心脏损伤期间的单核细胞/巨噬细胞生物学和治疗调节损伤后心脏 炎。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 CDR1as (circ-CDR1as)。该项目旨在确定循环的具体作用 CDR1as 促进单核细胞/巨噬细胞类别转换以及 circ-CDR1as 如何调节 心脏损伤后单核细胞的功能。此外，我们计划测试 circ-CDR1as 对心脏的功效 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，研究一下机制 通过这种方式，环状 circ-CDR1as 会引起巨噬细胞在稳态和稳态下的生理变化。 受伤的心。总的来说，我们的目标是确定并确定 circ-CDR1as 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。