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 心肌梗塞是归因于心力衰竭的最常见急性心脏损伤形式。那里 目前的疗法，死亡率和发病率仍然很高。回应心脏 损伤，巨噬细胞被大量招募到梗塞心肌，并控制起始， 维持和解决炎症反应。血液来源和组织居民巨噬细胞 表现出表型在专业和抗炎表型之间的独特特征 产生细胞因子，趋化因子和生长因子的顺序谱，既有抗抗 炎症作用。尽管有这样的理解，但仍有很多尚待了解的可塑性 组织修复过程中的巨噬细胞和调节巨噬细胞功能的因素。监管潜力 心血管疾病中的循环RNA（CIRCRNA）已开始引起人们在很大程度上没有探索的话题的兴趣。 圆形RNA是新发现的非编码RNA，从普遍于蛋白质编码基因产生 在哺乳动物组织中表达，物种之间高度保守，最近与可能的 巨噬细胞激活的调节。但是，目前尚无关于circrnas在 巨噬细胞生物学和心脏缺血期间的功能。我们的中心假设是Circrna可能调节 心脏损伤期间的单核细胞/巨噬细胞生物学对伤害后心脏 炎。在抗炎和抗炎中差异表达的CIRCRNA的初步数据 巨噬细胞，包括circrna cdr1as（Circ-Cdr1as）。该项目旨在确定循环的具体作用 CDR1A在促进单核细胞/巨噬细胞类切换以及Circ-CDR1AS调制的方式中 单核细胞后心脏损伤的功能。此外，我们计划测试Circ-CDR1AS心脏的功效 通过函数方法的损失/增益，使用鼠标MI模型在体内修复。最后，研究机制 循环循环CDR1A通过稳态和巨噬细胞的生理变化 受伤的心。总的来说，我们的目标是识别和确定Circ-Cdr1as作为潜在治疗的作用 为了解决心脏损伤后的炎症，以促进心脏修复和重塑。