Mechanisms of cardiac sympathetic hyperactivity in chronic heart failure

慢性心力衰竭心脏交感神经亢进的机制

基本信息

批准号：
10585029
负责人：
Yu-Long Li
金额：
$ 65.84万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585029
关键词：
3-Dimensional Accounting Adult American Anesthesia procedures Animals Arrhythmia Astrocytes Biological Biological Products Brain Cardiac Cell membrane Cells Central Nervous System Colony-Stimulating Factor Receptors Computer software Congestive Heart Failure Connexin 43 Conscious Coronary artery Data EFRAC Electrochemistry Electrophysiology (science)Encapsulated Enteral Enzymes Functional disorder Glial Fibrillary Acidic Protein Goals Heart Heart Abnormalities Heart failure Hyaluronic Acid Hydrogels Hyperactivity Inflammatory Injectable Laboratory Research Ligation Light Link Macrophage Macrophage Activation Macrophage Colony-Stimulating Factor Receptor Malignant - descriptor Mediating Membrane Modeling Molecular Genetics Multiple Sclerosis Myocardial Infarction Myocardium Nerve Neuroglia Neuronal Dysfunction Neurons Neurotransmitters Norepinephrine Opsin Patients Peripheral Peripheral Nervous System Production Prognosis Proliferating Protein Kinase C Proton Pump Public Health Publishing Rattus Regulation Reporting Research Research Project Grants Role Signal Pathway Slice Structure of stellate ganglion Sympathetic Ganglia System TNF gene TNF-alpha converting enzyme Techniques Testing Therapeutic Therapeutic Effect Tissues Transfection Ventricular Ventricular Arrhythmia Vision Work cytokine design heart function heart imaging immunoregulation improved inhibitor light effects mortality novel optogenetics programs promoter receptor reconstruction sham surgery sudden cardiac death therapeutic evaluation therapeutic target therapeutically effective tool

项目摘要

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.

项目概要心力衰竭（HF）是世界范围内的一个重大公共卫生问题，特别是心肌梗死引起的心力衰竭射血分数降低 (HFrEF) 占所有 HF 病例的 50%。恶性室性心律失常占心衰患者死亡率的近 50-60%。心脏交感神经过度激活是心脏交感神经过度活跃的一个主要特征心力衰竭，可能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周围神经系统对周围组织（如心肌）在包括心力衰竭在内的病理生理条件下。我们最近的研究项目发现，心脏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心力衰竭的心律失常。为了扩展我们当前的工作，这个 R01 应用程序的总体愿景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重构并成为改善心脏交感功能、减少恶性病变的治疗靶点晚期心力衰竭的室性心律失常发生。为了实现这一愿景，该提案仍将使用心肌梗死诱发的晚期心力衰竭和假手术（假手术）动物作为主要实验工具开拓 3 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，从有意识的和将动物麻醉至细胞分子遗传水平，以及一些特别尖端的技术（例如，光遗传学卫星神经胶质沉默、使用组织制作软件进行 3D 重建、心脏切片电化学记录和基于透明质酸的水凝胶输送系统）。具体目标 1 将确定卫星胶质细胞和巨噬细胞的激活以及卫星胶质细胞和巨噬细胞之间的关系晚期心衰患者心脏交感神经节中的巨噬细胞，因为有关的信息有限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，包括位于星状神经节及其神经的心脏交感神经元的结构和功能改变高级 HF 中的终端，因为大多数已发表的研究（包括我们的工作）报告了分散的有关高频触发的心脏交感神经重塑的信息。具体目标 3 将提供与其他具体目标是建立光遗传学卫星神经胶质沉默和水凝胶封装（也巨噬细胞相关）针对交感神经过度激活、心室晚期心力衰竭中的心律失常和心脏收缩功能障碍。实现这些目标将提供我们对病理生理学和病理生理学的理解取得了重大的概念、技术和转化进展心脏交感神经过度激活和恶性室性心律失常发生的相关治疗靶点先进的高频。