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.

导致损伤和心肌坏死的区域心肌缺血导致局灶性疤痕形成和A 心室收缩功能的降低。梗塞心肌的本构特性是主要的 左心室重塑的决定因素。该提案的长期目标是调查机制 心肌梗塞（MI）后心脏愈合和疤痕组成的靶标和新途径 驱动不良心脏重塑和左心室功能障碍。具体目标是表征 专门的CD8+ T细胞种群的生理效应称为先天的CD8+ T细胞（ILTS）和 剖析这些细胞在MI后如何调节心脏疤痕组成和生物力学。中心假设是 ILTS减少（ECM）沉积并通过谷物酶K（GZMK）介导的旁分泌改变成纤维细胞活性 通过蛋白酶激活的受体1（PAR1）发出信号导致疤痕较少。 AIM 1将测试 假设ILT是缺血诱导的本构特性的基本决定因素 心肌疤痕以及心室结构和功能的变化。 AIM 2将检验以下假设 ILTS影响疤痕生物力学和LV重塑的一种机制是GZMK引起的改变 ECM退化。 AIM 3将检验以下假设：ILT抑制成纤维细胞激活的一种机制 通过GZMK诱导的PAR1信号传导。我们提出的研究针对新型细胞分子 改变疤痕特性的机制。了解ILT介导的影响的这种机制 缺血诱导的心肌疤痕的本构特性将提供驱动目标和新型途径 不良心脏重塑和LV功能障碍。拟议的研究与VA的任务保持一致 医疗保健系统通过为临床实践提供分子知识，以便我们继续提供 卓越的医疗保健可以改善退伍军人的健康和福祉。