MACROPHAGE HETEROGENEITY IN HEART FAILURE PROGRESSION AND CARDIAC RECOVERY

心力衰竭进展和心脏恢复中的巨噬细胞异质性

• 批准号: 10176173
• 负责人: Kory J. Lavine
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176173
• 关键词: Ablation; Acute; Adult; Aldosterone Antagonists; Angiotensin II; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Cells; Child; Childhood; Childhood Injury; Chronic; Clinical; Clinical Trials; Complex; Development; Devices; Dilated Cardiomyopathy; Disease Progression; Embryo; Gene Expression; Goals; Growth; Heart; Heart Injuries; Heart failure; Hematopoietic; Heterogeneity; Human; Immune; Inflammation; Inflammatory; Innate Immune System; Left Ventricular Function; Left Ventricular Remodeling; Mediating; Modeling; Mus; Myocardial; Neprilysin; Outcome; Pathogenesis; Pathologic; Patients; Pharmaceutical Preparations; Physiological; Population; Population Heterogeneity; Quality of life; Recovery; Recovery of Function; Signal Pathway; Specimen; System; Testing; Therapeutic; Tissues; Treatment Failure; Yolk Sac; angiogenesis; base; experience; experimental study; heart function; heart preservation; improved; inhibitor/antagonist; injured; innovation; ischemic cardiomyopathy; macrophage; monocyte; mortality; mouse model; neonatal injury; neonatal mice; new therapeutic target; novel; novel therapeutic intervention; progenitor; recruit; response; tissue injury; tissue repair

PROJECT SUMMARY/ABSTRACT Dilated and ischemic cardiomyopathies represent prevalent causes of heart failure and cardiovascular mortality worldwide. While landmark clinical trials have led to the establishment of effective heart failure therapies and improved clinical outcomes, mortality rates remain high and many patients ultimately experience disease progression, highlighting the clinically unmet need to identify novel treatments. Myocardial recovery is an increasingly recognized outcome for a small but significant number of patients with heart failure. Patients who experience myocardial recovery have improved quality of life and survival. Based on these observations, myocardial recovery represents an achievable outcome and a potential new therapeutic target. However, the mechanisms that dictate recovery and ultimately determine why some patients recover cardiac function while others experience disease progression are poorly defined. Remarkably, children with heart failure demonstrate a significantly greater capacity for myocardial recovery compared to adults. To dissect the mechanisms that mediate myocardial recovery in this context, we developed a mouse model of acute heart failure and successfully recapitulated the observation that the pediatric heart has a robust capacity for tissue repair and functional recovery. Mechanistically, we discovered that the injured pediatric and adult heart harbor distinct primitive and definitive macrophage subsets and that these cells govern why pediatric and adult mice display differing pathologic responses and capacities to recover following tissue injury. Collectively, these experiments uncovered a previously unrecognized complexity within the innate immune system and have challenged the paradigm that all macrophages are derived from monocyte progenitors. While these observations are thought provoking and provide proof of principle that distinct macrophage lineages have the capacity to differentially orchestrate cardiac tissue repair and heart failure progression, it is unclear how these concepts apply to the chronically failing heart. The overarching goal of this proposal is to test the hypothesis that the chronically failing mouse and human heart contains evolutionarily conserved macrophage subsets derived from distinct developmental origins that orchestrate cardiac tissue repair and adverse remodeling, respectively. Specifically, we hypothesize that primitive macrophages preserve cardiac function by stimulating tissue repair, whereas definitive monocyte-derived macrophages promote heart failure progression through inflammation, resultant collateral damage, and subsequent adverse remodeling. Clinically, the identification of reparative and inflammatory cardiac macrophage populations and elucidation of the signaling pathways by which these cells exert their effects is likely to provide the necessary information to develop novel therapeutic strategies to limit disease progression and promote recovery of the failing heart.

项目摘要/摘要 扩张和缺血性心肌病代表了心力衰竭和心血管的普遍原因 全球死亡率。虽然具有里程碑意义的临床试验导致建立有效的心力衰竭 疗法和改善的临床结果，死亡率保持较高，许多患者最终经历 疾病进展，强调诊断新治疗的临床上未满足的需求。心肌恢复是 对于少数但大量的心力衰竭患者来说，越来越认识的结果。患者 经历心肌康复的人可以改善生活质量和生存。基于这些观察， 心肌恢复代表了可实现的结果和潜在的新治疗靶点。但是， 决定恢复并最终确定为什么某些患者恢复心脏功能的机制 其他经历疾病进展的定义很差。 值得注意的是，心力衰竭的儿童表现出明显更大的心肌能力 与成年人相比恢复。为了剖析在这种情况下介导心肌恢复的机制，我们 开发了急性心力衰竭的小鼠模型，并成功概括了这样的观察 小儿心脏具有强大的组织修复和功能恢复能力。从机械上讲，我们发现了 受伤的儿科和成人心脏藏有明显的原始和确定的巨噬细胞子集，并且 这些细胞控制着为什么儿科和成年小鼠表现出不同的病理反应和能力 组织损伤后恢复。总的来说，这些实验发现了以前未被认可的 先天免疫系统内的复杂性，并挑战了所有巨噬细胞的范式 源自单核细胞祖细胞。虽然这些观察结果被认为令人发指并提供了证明 不同的巨噬细胞谱系具有差异性心脏组织修复的能力的原理 和心力衰竭进展，尚不清楚这些概念如何适用于长期失败的心脏。 该提案的总体目标是检验以下假设：长期失败的鼠标和 人心中包含从不同发育中得出的进化保守的巨噬细胞子集 分别编排心脏组织修复和不良重塑的起源。具体来说，我们 假设原始巨噬细胞通过刺激组织修复来保留心脏功能，而 确定的单核细胞衍生的巨噬细胞通过炎症促进心力衰竭进展 附带损坏，随后进行不良重塑。在临床上，识别修复和 炎症性心脏巨噬细胞种群和这些细胞的信号传导途径阐明 发挥其影响可能会提供必要的信息来制定新颖的治疗策略以限制 疾病进展并促进心脏恢复。

项目成果

Cardiac Lymphatic Vessels, Transport, and Healing of the Infarcted Heart.

• DOI: 10.1016/j.jacbts.2017.02.005
• 发表时间: 2017-08
• 期刊: JACC. Basic to translational science
• 作者: Huang LH;Lavine KJ;Randolph GJ
• 通讯作者: Randolph GJ

Skeletal muscle inflammation and atrophy in heart failure.

• DOI: 10.1007/s10741-016-9593-0
• 发表时间: 2017-03
• 期刊: Heart failure reviews
• 影响因子: 4.6
• 作者: Lavine KJ;Sierra OL
• 通讯作者: Sierra OL