Chemokines in Healing Myocardial Infarction

描述(申请人提供)：趋化因子驱动的炎症在心肌梗死后的修复反应中发挥重要作用，并在不利重构的发病机制中起关键作用。单核细胞和淋巴细胞亚群的趋化因子受体的不同表达控制了它们在梗死心肌中的运输，导致了具有不同功能特性的亚群的渗透。我们认为，除了参与启动和激活梗死后炎症反应外，趋化因子介导的相互作用也通过招募具有抑制特性的白细胞亚群在抑制炎症中发挥重要作用。我们的研究表明，通过CC趋化因子受体5(CCR5)的信号介导抑制性单核细胞亚群和调节性T细胞(Tregs)的募集，Tregs是一种在免疫反应调节中起重要作用的CD4+T淋巴细胞亚群。因此，本研究的目的是研究Tregs和抑制性单核细胞亚群在调节梗死后炎症反应中的作用，研究它们的保护作用的分子信号，并探讨趋化因子信号在它们在梗死心肌中的募集中的作用。这些概念将在三个特定目标中进行检验：特定目标1：研究具有抗炎特性的单核细胞亚群在控制梗死后炎症反应中的作用。具体目的2：研究Tregs在抑制炎症损伤、防止过度基质降解和保护心肌梗死后不良重塑发展中的作用。具体目的3：研究趋化因子/趋化因子受体相互作用对Tregs和效应性T细胞在梗死心肌中的募集作用。趋化因子通过募集调节性单个核细胞亚群抑制炎症似乎在心脏修复和保护不良重构的发展中发挥重要作用。了解抑制单核细胞和Tregs的作用可能为心肌梗死患者的药物干预和细胞治疗确定新的治疗靶点。

DESCRIPTION (provided by applicant): Chemokine-driven inflammation plays an important role in the reparative response following myocardial infarction and is critically involved in the pathogenesis of adverse remodeling. Differential expression of chemokine receptors by monocyte and lymphocyte subsets governs their trafficking in the infarcted myocardium resulting in infiltration with subpopulations that exhibit distinct functional properties. We propose that beyond their involvement in initiation and activation of the post-infarction inflammatory reaction, chemokine-mediated interactions also play an important role in suppression of inflammation through recruitment of leukocyte subsets with inhibitory properties. Our studies suggest that signaling through the CC chemokine receptor 5 (CCR5) mediates recruitment of suppressive monocyte subsets and regulatory T cells (Tregs), a CD4+ T lymphocyte subpopulation with an essential role in regulation of immune responses. Accordingly, the objective of the current proposal is to investigate the role of Tregs and inhibitory monocyte subpopulations in regulation of post-infarction inflammation, to study the molecular signals responsible for their protective effects, and to explore the role of chemokine signaling in their recruitment in the infarcted myocardium. These concepts will be examined in three specific aims: Specific aim 1: to investigate the role of monocyte subsets with anti-inflammatory properties in controlling the post-infarction inflammatory response. Specific aim 2: to study the involvement of Tregs in inhibition of inflammatory injury, in prevention of excessive matrix degradation and in protection from the development of adverse remodeling following myocardial infarction. Specific aim 3: to investigate chemokine/chemokine receptor interactions responsible for recruitment of Tregs and effector T cells in the infarcted myocardium. Chemokine-mediated suppression of inflammation through recruitment of regulatory mononuclear cell subpopulations appears to play an essential role in cardiac repair and protects from the development of adverse remodeling. Understanding the effects of inhibitory monocytes and Tregs may identify novel therapeutic targets for pharmacologic interventions and cell therapy in patients with myocardial infarction.