Innate-like CD8+ T-cells facilitate in cardiac remodeling post-MI

先天性 CD8 T 细胞促进 MI 后心脏重塑

• 批准号: 10703797
• 负责人: Kristine Y DeLeon-Pennell
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703797
• 关键词: 3-Dimensional; Anterior Descending Coronary Artery; Binding; Biomechanics; CD8-Positive T-Lymphocytes; CD8B1 gene; Cardiac; Cell Separation; Cell secretion; Cells; Characteristics; Cicatrix; Clinical Treatment; Coculture Techniques; Collagen; Compensation; Data; Deposition; Echocardiography; Engraftment; Extracellular Matrix; Extracellular Matrix Degradation; Fibroblasts; Fibrosis; Flow Cytometry; Goals; Granzyme; Health; Healthcare; Healthcare Systems; Heart; Hypertrophy; Immunohistochemistry; Impairment; Infarction; Inflammatory; Injury; Ischemia; Knowledge; Left; Left Ventricular Dysfunction; Left Ventricular Remodeling; Left ventricular structure; Ligation; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mechanics; Mediating; Methods; Mission; Molecular; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Necrosis; Necrosis Induction; PAR-1 Receptor; Paracrine Communication; Pathway interactions; Peptides; Perfusion; Personal Satisfaction; Phenotype; Physiological; Play; Population; Process; Production; Proliferating; Property; Proteomics; Research; Role; Signal Transduction; Stress; Stroke Volume; Structure; T-Lymphocyte; Targeted Research; Testing; Tissue Inhibitor of Metalloproteinases; Translations; Ventricular; Ventricular Function; Ventricular Remodeling; Veterans; clinical practice; cytokine; cytotoxic; experimental study; gain of function; healing; heart function; improved; improved outcome; inhibitor; loss of function; migration; mouse model; novel; overexpression; physical property; preservation; scaffold

Regional myocardial ischemia that leads to injury and myocyte necrosis results in focal scar formation and a reduction in ventricular systolic function. The constitutive properties of the infarcted myocardium are major determinants of left ventricular remodeling. The long-term goal of the proposal is to investigate the mechanisms of cardiac healing and scar composition after myocardial infarction (MI) to provide targets and novel pathways that drive adverse cardiac remodeling and left ventricular dysfunction. The specific objective is to characterize the physiological effects of a specialized CD8+ T-cell population termed the innate-like CD8+ T-cells (ILTs) and dissect how these cells regulate cardiac scar composition and biomechanics after MI. The central hypothesis is that ILTs decrease (ECM) deposition and alter fibroblast activity via granzyme K (GzmK)-mediated paracrine signaling through protease activated receptor-1 (PAR1) leading to a less stiff scar. Aim 1 will test the hypothesis that ILTs are a fundamental determinant of the constitutive properties of ischemia induced myocardial scar and resulting changes in ventricular structure and function. Aim 2 will test the hypothesis that one mechanism by which ILTs influence scar biomechanics and LV remodeling is GzmK induced alterations in ECM degradation. Aim 3 will test the hypothesis that one mechanism by which ILTs inhibit fibroblast activation is through GzmK induced PAR1 signaling. Our proposed research targets a novel cellular, molecular mechanism that alters scar properties. Understanding this mechanism behind ILT-mediated effects on constitutive properties of ischemia induced myocardial scar will provide targets and novel pathways that drive adverse cardiac remodeling and LV dysfunction. The proposed study aligns with the mission of the VA healthcare system by providing molecular knowledge to clinical practices so that we can continue to provide exceptional health care that improves veteran health and well-being.

局部心肌缺血导致损伤和心肌细胞坏死，导致局灶性瘢痕形成， 心室收缩功能降低。梗死心肌的组成特性是主要的 左心室重构的决定因素。该提案的长期目标是调查机制 心肌梗死（MI）后心脏愈合和瘢痕组成的研究，以提供靶点和新途径 导致不良心脏重塑和左心室功能障碍。具体目标是描述 被称为先天样CD 8 + T细胞（ILT）的特化CD 8 + T细胞群体的生理效应， 剖析这些细胞如何调节心肌梗死后的心脏瘢痕成分和生物力学。核心假设是 ILT通过颗粒酶K（GzmK）介导的旁分泌减少（ECM）沉积并改变成纤维细胞活性 通过蛋白酶激活受体-1（PAR 1）的信号传导导致较不僵硬的疤痕。目标1将测试 假设ILT是缺血诱导的组织结构特性的基本决定因素， 心肌瘢痕及由此引起的心室结构和功能的改变。目标2将检验以下假设： ILT影响瘢痕生物力学和LV重塑的一种机制是GzmK诱导的 ECM降解。目的3将检验ILT抑制成纤维细胞活化的一种机制 是通过GzmK诱导的PAR 1信号传导。我们提出的研究目标是一种新的细胞，分子 改变疤痕性质的机制。了解ILT介导的对以下疾病的影响背后的机制 缺血诱导的心肌瘢痕的组成特性将提供靶点和新的途径， 不良心脏重塑和LV功能障碍。拟议的研究与VA的使命一致 通过为临床实践提供分子知识，使我们能够继续提供 改善退伍军人健康和福祉的特殊医疗保健。