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

• 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
• 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

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.

项目摘要 心力衰竭（HF）是全球一个主要的公共卫生问题，尤其是心肌梗死引起的HF 减少了占所有HF病例的50％的射血分数（HFREF）。恶性心律失常 在HF患者中占死亡率的近50-60％。心脏交感过度激活，主要特征 HF，​​可能会引发性心室心律不齐和心脏猝死。我的研究实验室是 不断关注周围神经系统在周围组织中的调节作用（例如 心肌）在包括HF在内的病理生理状况下。我们最近的研究项目发现心脏 交感神经功能障碍有助于心脏交感神经过度激活和恶性心室 高级HF中的心律不齐。为了扩展我们当前的工作，此R01应用程序的总体愿景是测试 卫星神经胶质调节的巨噬细胞是否可以推动心脏交感神经功能和结构性 重塑并成为改善心脏交感神经功能并降低恶性肿瘤的治疗靶点 晚期HF中心心律失常。为了实现这一愿景，该提案仍将使用心肌 梗塞引起的晚期HF和假手术动物作为先驱的主要实验工具 在3个特定目标中发现。我们还将在该项目中使用多方面的方法，从有意识和 麻醉动物到细胞分子遗传学水平，以及一些特别尖端的技术 （例如，光学遗传卫星胶质沉默，带有组织制造商软件的3D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 确定卫星神经胶质和巨噬细胞的激活以及卫星胶质和 高级HF中心脏交感神经节中的巨噬细胞，因为有关 晚期HF中卫星神经胶质，巨噬细胞和交感神经神经元之间的关系。具体目标 2将确定卫星神经胶质和巨噬细胞参与心脏交感神经重塑 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HF触发心脏交感神经重塑的信息。特定目标3将与 其他特定目的是建立光遗传学卫星的神经胶质沉默和水凝胶包裹（也是 与巨噬细胞相关的）治疗方法，以防止交感神经过度活化，心室 晚期HF中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 心脏交感神经过度活化和恶性心室心律失常发生的相关治疗靶标 高级HF。