Specification and Function of Tissue Resident and Recruited Macrophages in Cardiac Remodeling and Heart Failure

项目总结/摘要 导致“免疫革命”的突破性发现已经确立了以下方面的重要性： 免疫学在医学学科中的应用炎症一直被认为是一种重要的机制 导致缺血性和非缺血性形式的心力衰竭的进展。无数的研究 据报道，许多血清细胞因子、不良左心室重塑和患者 慢性心力衰竭和心肌梗死患者的预后。虽然这些观察结果突出了 抑制心脏炎症的潜在效用，研究抗- 在发生心肌梗死（皮质类固醇）的患者或 慢性心力衰竭（皮质类固醇，TNF阻断）显示令人失望的结果，并挫伤了热情 进一步的药物开发。当时，关于精确的免疫细胞的信息有限， 促进疾病的类型和发挥其作用的信号机制。 近年来，针对心血管疾病的免疫系统的新兴趣已经出现。 这种复苏是由心脏炎症细胞介质的发现和心脏炎症细胞介质的发现所推动的。 识别协调其激活和破坏效应器功能的机制。这些 研究结果证实了令人兴奋的，但未满足的，有效靶向免疫系统和改善免疫系统的机会。 心脏病患者的预后。 拟议的研究计划将建立在我们实验室先前的成就之上， 在健康、衰竭和高血压患者中，巨噬细胞的组成和功能存在显著差异， 移植心脏我们将把3个活跃的项目整合成一个统一的研究计划，目的是：1）剖析 控制心脏巨噬细胞多样性和功能的新生物学机制，2）转化我们的发现 新的诊断和治疗方法，以消除心力衰竭的发病机制，增强功能， 恢复衰竭的心脏，并防止心脏移植排斥反应。关键主题将包括以下方面的作用： 心力衰竭发病机制中的机械感受、炎症信号和单核细胞命运特化 横跨疾病病因学、心脏组织修复和恢复以及心脏移植排斥。

PROJECT SUMMARY/ABSTRACT Groundbreaking discoveries resulting in the “immuno-revolution” have established the importance of immunology across medical disciplines. Inflammation has long been considered as an important mechanism contributing to the progression of ischemic and nonischemic forms of heart failure. Countless studies have reported associations between numerous serum cytokines, adverse left ventricular remodeling, and patient outcomes in the settings of chronic heart failure and myocardial infarction. While these observations highlight the potential utility of suppressing inflammation in the heart, early clinical studies investigating anti- inflammatory therapies in patients who experienced a myocardial infarction (corticosteroids) or those with chronic heart failure (corticosteroids, TNF blockade) revealed disappointing results and dampened enthusiasm around further drug development. At that time, limited information existed regarding the precise immune cell types that promote disease and the signaling mechanisms that exert their effects. In recent years, a renewed interest in targeting the immune system in cardiovascular disease has emerged. This resurgence is powered by the discovery of the cellular mediators of inflammation in the heart and the identification of the mechanisms that orchestrate their activation and damaging effector functions. These findings exemplify the exciting, but unmet, opportunity to effectively target the immune system and improve outcomes for individuals with cardiac diseases. The proposed research program will built upon our laboratory’s prior accomplishments that have uncovered remarkable diversity amongst the composition and function of macrophages in the healthy, failing, and transplanted heart. We will integrate 3 active projects into a unified research program that aims to 1) dissect new biological mechanisms governing cardiac macrophage diversity and function, and 2) translate our findings into new diagnostic and therapeutic approaches to abrogate heart failure pathogenesis, potentiate functional recovery of the failing heart, and prevent heart transplant rejection. Key themes will include the roles of mechanosensing, inflammatory signaling, and monocyte fate specification in the pathogenesis of heart failure across disease etiologies, cardiac tissue repair and recovery, and heart transplant rejection.