Cardiac Macrophage Plasticity in Sepsis-induced Cardiomyopathy

脓毒症引起的心肌病中心脏巨噬细胞的可塑性

• 批准号: 10728175
• 负责人: YUXIANG SUN
• 金额: $ 19.91万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-22 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728175
• 关键词: Ablation; Address; Age; American; Animal Model; Attenuated; Autophagocytosis; Bone Marrow; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cause of Death; Cells; Clinical; Coculture Techniques; Critical Care; Data; Development; Disease; Embryo; Endotoxemia; Foundations; Functional disorder; Future; Genetic; Goals; Heart; Homeostasis; Hormones; Hunger; Immune; Immune response; Immunity; In Vitro; Infection; Infiltration; Inflammation; Inflammatory; Injury; Investigation; Knock-out; Knockout Mice; Label; Laboratories; Life; Link; Macrophage; Mediating; Medical; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Molecular; Mouse Strains; Multiple Organ Failure; Mus; Myelogenous; Myocardial; Myocarditis; Myocardium; Organ; Outcome; Paracrine Communication; Pathologic; Pathology; Pathway interactions; Pattern; Performance; Phenotype; Physiological; Pneumonia; Pre-Clinical Model; Proliferating; Property; Receptor Signaling; Regulation; Research; Role; Sepsis; Signal Transduction; Source; Testing; Tissues; cell type; design; effective therapy; ghrelin; growth hormone secretagogue receptor; heart function; heart metabolism; improved; in vivo; loss of function; metabolomics; monocyte; mouse model; novel; novel therapeutics; programs; receptor; receptor expression; response; septic; systemic inflammatory response

Project Summary Sepsis is a leading cause of death in critical care units. Our long-term research goal is to understand the mechanisms of sepsis-induced multi-organ failure and to identify potential new therapeutic opportunities for this devastating clinical condition. Studies proposed in this application are designed to elucidate novel pathological functions of an immunometabolism regulator, growth hormone secretagogue receptor (GHS-R), in sepsis-induced cardiomyopathy using preclinical models. Recent studies revealed that macrophages localized in the heart are originated from different sources. With diversified functions ranging from reparative to inflammatory, the dynamics of changing these macrophage subsets forms a diagram of cardiac macrophage plasticity. Our ongoing investigation have obtained exciting preliminary evidence showing that GHS-R is a critical cellular switch that reprograms macrophage polarization to an inflammatory state. Furthermore, in a newly generated genetic mouse model, our data showed that ablation of myeloid linage macrophage-specific GHS-R attenuated systemic inflammation and improved heart function in response to endotoxemia challenge, which benefits were well associated with responses in metabolism, mitochondria, and autophagy in the heart. In this exploratory project, we will use in vitro and in vivo approaches to test the hypothesis that macrophage GHS-R reprograms cardiac macrophage plasticity and stimulates inflammation during sepsis (aim 1). We will further address whether macrophage GHS-R stimulates mitochondrial deficiencies, metabolic perturbations, and maladaptive autophagy in the heart during sepsis (aim 2). Together, this investigation is expected not only to advance the fundamental understanding of sepsis pathology but also to evaluate whether targeting GHS-R signal improves cardiac outcomes in sepsis, laying a scientific foundation for future development of novel therapies.

项目摘要 败血症是重症监护病房的主要死亡原因。我们的长期研究目标是 了解脓毒症所致多器官功能衰竭的机制 对于这种毁灭性的临床疾病，潜在的新的治疗机会。研究 在本申请中提出的是旨在阐明一个新的病理功能 免疫代谢调节剂生长激素促分泌素受体(GHS-R)，在 使用临床前模型研究脓毒症所致心肌病。 最近的研究表明，定位于心脏的巨噬细胞起源于 不同的来源。具有从修复到炎症的多种功能， 这些巨噬细胞亚群变化的动力学形成了一张心脏图 巨噬细胞可塑性。我们正在进行的调查取得了令人振奋的初步结果 证据表明GHS-R是重新编程巨噬细胞的关键细胞开关 两极分化到炎症状态。此外，在一种新产生的遗传小鼠中 模型中，我们的数据显示，消融髓系巨噬细胞特异性GHS-R 减轻全身炎症，改善心功能 内毒素血症挑战，哪些好处与应对措施密切相关 心脏中的新陈代谢、线粒体和自噬。在这个探索性项目中，我们将 使用体外和体内方法检验巨噬细胞GHS-R的假设 脓毒症时心脏巨噬细胞的可塑性和刺激炎症反应 (目标1)。我们将进一步探讨巨噬细胞GHS-R是否刺激线粒体 心脏的缺陷、代谢紊乱和不适应的自噬 脓毒症(目标2)。总而言之，这项调查预计不仅会推动 基本了解脓毒症的病理基础，也要评估是否有靶向 GHS-R信号改善脓毒症患者的心脏结局，为 新疗法的未来发展。