Cardiac Macrophage Plasticity in Sepsis-induced Cardiomyopathy

项目摘要 脓毒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 了解脓毒症引起的多器官衰竭的机制，并确定 潜在的新的治疗机会，这种毁灭性的临床条件。研究 本申请中提出的这些新的病理学功能被设计用于阐明神经元的新的病理学功能。 免疫代谢调节剂，生长激素促分泌素受体（GHS-R）， 败血症诱发的心肌病的临床前模型。 最近的研究表明，位于心脏的巨噬细胞来源于 不同的来源具有从修复到炎症的多种功能， 改变这些巨噬细胞亚群的动力学形成了一个心脏 巨噬细胞可塑性我们正在进行的调查获得了令人振奋的初步结果 有证据表明GHS-R是重编程巨噬细胞的关键细胞开关 极化到炎症状态。此外，在一个新产生的遗传小鼠中， 模型，我们的数据表明，髓系巨噬细胞特异性GHS-R的消融 减轻全身炎症和改善心脏功能， 内毒素血症挑战，其益处与 代谢、线粒体和心脏中的自噬。在这个探索性的项目中，我们将 使用体外和体内方法来测试巨噬细胞GHS-R 脓毒症期间重新编程心脏巨噬细胞可塑性并刺激炎症 (aim 1）。我们将进一步研究巨噬细胞GHS-R是否刺激线粒体 缺乏，代谢紊乱和适应不良的自噬在心脏中， 败血症（目的2）。总而言之，这项调查预计不仅会推进 对脓毒症病理学的基本理解，同时也评估是否靶向 GHS-R信号改善脓毒症的心脏结局，为以下研究奠定了科学基础 新疗法的未来发展。

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.