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

心脏重塑和心力衰竭中组织驻留和募集巨噬细胞的规格和功能

• 批准号: 10352659
• 负责人: Kory J. Lavine
• 金额: $ 78.75万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2028-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10352659
• 关键词: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Biological; Cardiac; Cardiovascular Diseases; Clinical Research; Congestive Heart Failure; Discipline; Disease; Etiology; Goals; Graft Rejection; Heart; Heart Diseases; Heart Transplantation; Heart failure; Immune; Immune Targeting; Immune system; Immunology; Individual; Inflammation; Inflammation Mediators; Inflammatory; Laboratories; Left Ventricular Remodeling; Medical; Myocardial Infarction; Pathogenesis; Patient-Focused Outcomes; Patients; Recovery; Recovery of Function; Reporting; Research; Role; Serum; Signal Transduction; TNF gene; Time; Tissues; Translating; cell type; cytokine; drug development; experience; improved outcome; interest; macrophage; mechanotransduction; monocyte; novel diagnostics; novel therapeutic intervention; prevent; programs; recruit; tissue repair

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.

项目摘要/摘要 导致“免疫革命”的开创性发现确定了重要性 跨医学学科的免疫学。炎症长期以来一直被认为是一种重要机制 有助于心力衰竭的缺血性和非缺血性形式的进展。无数研究 报道了许多血清细胞因子，不良左心室重塑和患者之间的关联 在慢性心力衰竭和心肌梗塞的环境中的结果。这些观察突出了 抑制心脏感染的潜在效用，早期临床研究研究了抗 - 经历心肌梗死（皮质类固醇）或患有心肌梗死的患者的炎症疗法或 慢性心力衰竭（皮质类固醇，TNF封锁）表现出令人失望的结果和该死的热情 围绕进一步的药物开发。当时，有关精确免疫细胞的信息有限 促进疾病的类型以及执行其作用的信号传导机制。 近年来，已经出现了对针对心血管疾病的免疫系统的新兴趣。 这种复苏是由于发现心脏和心脏炎症的细胞介体提供了动力 识别协调其激活和破坏效应子功能的机制。这些 发现示例了令人兴奋但未满足的机会，可以有效地针对免疫系统并改善 心脏病患者的结果。 拟议的研究计划将基于我们实验室的先前成就，这些成就已发现 巨噬细胞在健康，失败和 移植的心。我们将将3个活跃项目集成到一个统一的研究计划中，该计划的目的是1）剖析 掌管心脏巨噬细胞多样性和功能的新生物学机制，以及2）翻译我们的发现 进入新的诊断和治疗方法，以消除心力衰竭发病机理，潜在的功能 恢复失败的心脏，并防止心脏移植拒绝。关键主题将包括 心力衰竭发病机理中的机械感应，炎症信号传导和单核细胞命运规范 跨越疾病的病因，心脏组织修复和恢复以及心脏移植排斥。