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: 10387884
• 负责人: Carolina Gonzalez
• 金额: $ 3.31万
• 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/10387884
• 关键词: Accounting; Acute; Affect; Anti-Inflammatory Agents; Antiinflammatory Effect; Apoptosis; Biogenesis; Biology; Blood; Bone Marrow; Cardiac; Cardiovascular Diseases; Cause of Death; 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; Inflammation; Inflammatory; Inflammatory Response; Label; Left Ventricular Function; Macrophage Activation; Maintenance; Mediating; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocarditis; Myocardium; Phenotype; Physiological; Play; Population; Porifera; Process; Production; Proteins; Publishing; RNA; RNA-Binding Proteins; Regulation; Regulator Genes; Reporting; Resolution; Role; Sorting - Cell Movement; Testing; Therapeutic; Tissues; Toxicology; Translations; United States; Untranslated RNA; Western Blotting; base; cardiac repair; chemokine; circular RNA; cytokine; differential expression; efficacy testing; gain of function; healing; heart function; improved; in vivo; injured; injury and repair; interest; locked nucleic acid; loss of function; macrophage; monocyte; mortality; neovascularization; new therapeutic target; overexpression; prediction algorithm; recruit; repair function; 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.

摘要 心肌梗死是由心力衰竭引起的最常见的急性心脏损伤形式。在那里的时候 虽然目前的治疗方法取得了重大进展，但死亡率和发病率仍然居高不下。对心脏疾病的反应 损伤时，巨噬细胞被大量招募到梗死心肌并控制其启动， 维持和消解炎症反应。血源性和组织驻留的巨噬细胞 表现出在促炎和抗炎表型之间切换的独特特征 产生一系列细胞因子、趋化因子和生长因子，既有促进作用，也有反对作用 发炎效应。尽管有了这样的理解，但关于塑料的可塑性仍有许多需要了解的地方 组织修复过程中的巨噬细胞和调节巨噬细胞功能的因素。监管的潜力 环状RNA(CircRNA)在心血管疾病中的作用已经开始引起人们的兴趣，这在很大程度上是一个尚未探索的话题。 环状RNA是新发现的由蛋白质编码基因产生的非编码RNA，广泛存在于 在哺乳动物组织中表达，在物种中高度保守，最近与可能的 巨噬细胞活化的调节。然而，目前还没有关于CircRNAs在 心肌缺血时巨噬细胞的生物学和功能。我们的中心假设是CircRNA可能调节 心脏损伤中的单核/巨噬细胞生物学及其对损伤后心脏的治疗调节 发炎。初步数据确定在促炎和抗炎中差异表达的CircRNA 巨噬细胞，包括CircRNA CDR1as(CIRC-CDR1as)。本项目旨在确定中国保监会的具体角色- CDR1as在促进单核/巨噬细胞类别转换中的作用以及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对心脏疾病的疗效 通过功能丧失/功能获得的方法，使用小鼠MI模型进行体内修复。最后，对其机理进行了探讨。 环状CIRC-CDR1as在稳态和非稳态时均可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确定CIRC-CDR1as作为一种潜在的治疗手段的作用 用于消解心脏损伤后的炎症，促进心脏修复和重塑。