Mechanisms of cardiac sympathetic hyperactivity in chronic heart failure

项目摘要 心力衰竭（HF）是世界范围内的主要公共卫生问题，尤其是心肌梗死诱导的HF， 射血分数降低（HFrEF）占所有HF病例的50%。恶性室性心律失常 占HF患者死亡率的近50-60%。心脏交感神经过度激活， HF可引发恶性室性心律失常和心源性猝死。我的研究实验室是 持续关注外周神经系统在外周组织（如 心肌）在包括HF的病理生理条件下。我们最近的研究项目发现， 交感神经元功能障碍导致心脏交感神经过度激活和恶性心室 晚期HF的心律失常。为了扩展我们当前的工作，这个R 01应用程序的总体设想是测试 卫星胶质细胞调节的巨噬细胞是否可以驱动心脏交感神经功能和结构 心脏交感神经功能的改善和恶性肿瘤的治疗靶点 晚期心力衰竭的心室重构。为了实现这一愿景，该提案仍将使用心肌 梗死诱导的晚期HF和假手术（假手术）动物作为主要实验工具， 三个具体目标的发现。我们还将在这个项目中使用多方面的方法，从有意识的， 沿着一些特别尖端的技术， (e.g.,光遗传学卫星胶质细胞沉默，组织制造软件三维重建，心脏切片 电化学记录和基于透明质酸的水凝胶递送系统）。具体目标1将 确定卫星胶质细胞和巨噬细胞的活化以及卫星胶质细胞和巨噬细胞之间的关系， 在晚期HF中，心脏交感神经节中的巨噬细胞，因为关于 晚期心力衰竭中卫星胶质细胞、巨噬细胞和交感神经节神经元之间的关系具体目标 2将确定卫星胶质细胞和巨噬细胞参与心脏交感神经重塑， 星状神经节内心交感神经元结构和功能变化 晚期HF中的终末，因为大多数已发表的研究（包括我们的工作）报告了分散的 关于HF触发的心脏交感神经重塑的信息。具体目标3将提供一个紧密的联系， 建立光遗传学卫星神经胶质沉默和水凝胶包封的（也 巨噬细胞相关的）治疗方法对抗交感神经过度激活，心室 晚期心力衰竭患者的心肌发生和心脏收缩功能障碍。实现这些目标将提供 主要的概念，技术和翻译的进步，我们的理解的病理生理学和 心交感神经过度激活和恶性心室肌纤维化相关治疗靶点 晚期HF

Project Summary Heart failure (HF) is a major public health problem worldwide, especially myocardial infarction-induced HF with reduced ejection fraction (HFrEF) accounting for 50% of all HF cases. Malignant ventricular arrhythmia accounts for nearly 50-60% of mortality in HF patients. Cardiac sympathetic overactivation, a major feature of HF, could trigger malignant ventricular arrhythmias and sudden cardiac death. My research laboratory is continually focusing on the regulatory role of the peripheral nervous system in peripheral tissues (such as myocardium) in pathophysiological conditions including HF. Our recent research project found that cardiac sympathetic neuronal dysfunction contributes to cardiac sympathetic overactivation and malignant ventricular arrhythmias in advanced HF. To extend our current work, the overall vision of this R01 application is to test whether satellite glia-modulated macrophages can drive cardiac sympathetic functional and structural remodeling and be the therapeutic target for improving cardiac sympathetic function and reducing malignant ventricular arrhythmogenesis in advanced HF. To accomplish this vision, the proposal will still use myocardial infarction-induced advanced HF and sham (sham surgery) animals as the primary experimental tool to pioneer discovery in 3 Specific Aims. We will also use multifaceted approaches in this project, from conscious and anesthetized animals to cellular-molecular-genetic levels, along with some especially cutting-edge techniques (e.g., optogenetic satellite glial silencing, 3D reconstruction with tissue-maker software, cardiac slice electrochemistry recording, and a hyaluronic acid-based hydrogel delivery system). Specific Aim 1 will determine activation of satellite glia and macrophages as well as relations between satellite glia and macrophages in cardiac sympathetic ganglia in advanced HF, because there is limited information about relations among satellite glia, macrophages, and sympathetic ganglionic neurons in advanced HF. Specific Aim 2 will determine the involvement of satellite glia and macrophages in cardiac sympathetic remodeling including structural and functional alterations in cardiac sympathetic neurons located in stellate ganglia and their nerve terminals in advanced HF, because most published studies (including our work) reported the scattered information about HF-triggered cardiac sympathetic remodeling. Specific Aim 3 will provide a tight link with other Specific Aims to establish optogenetic satellite glial silencing and hydrogel-encapsulated (also macrophage-related) therapeutic approaches against sympathetic overactivation, ventricular arrhythmogenesis, and cardiac contractile dysfunction in advanced HF. Accomplishing these goals will provide major conceptual, technical, and translational advances for our understanding of the pathophysiology and related therapeutic targets of cardiac sympathetic overactivation and malignant ventricular arrhythmogenesis in advanced HF.