Satellite Glial Cell Activation and Sympathetic Imbalance in Cardiomyopathy and Arrhythmias

心肌病和心律失常中的卫星胶质细胞激活和交感神经失衡

基本信息

批准号：
10599342
负责人：
Olujimi A Ajijola
金额：
$ 58.09万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599342
关键词：
Ablation Animals Arrhythmia Attenuated Calcium Signaling Cardiac Cardiomyopathies Catecholamines Cause of Death Chronic Chronic Disease Communication Connexin 43 Data Development Dilated Cardiomyopathy Disease Electrophysiology (science)Fibrosis Functional disorder Future G-Protein-Coupled Receptors Gap Junctions Genetic Glial Fibrillary Acidic Protein Goals Health Heart Heart Diseases Heart Injuries Heart failure Human Hyperactivity Inflammatory Inflammatory Bowel Diseases Injury Ischemia Left Ventricular Dysfunction Left Ventricular Remodeling Link Mediating Medical Modeling Morphology Mus Myocardial Infarction Myocardium Nervous System Neuroglia Neuronal Dysfunction Neurons Norepinephrine Patients Pharmaceutical Preparations Play Prevention Process Purines Reperfusion Therapy Research Personnel Role Signal Transduction Signaling Molecule Structure of stellate ganglion Supporting Cell Sympathetic Ganglia Synapses Techniques Testing Therapeutic Transgenic Mice Up-Regulation Ventricular Arrhythmia Ventricular Tachycardia Viral beta-adrenergic receptor cell type chronic pain cytokine glial activation human data human model inhibitor mortality mortality risk mouse model multidisciplinary neural neurochemistry neuronal excitability neuroregulation neurotransmission novel organ injury porcine model prevent release factor side effect targeted treatment therapeutic target tool

项目摘要

PROJECT SUMMARY/ABSTRACT Cardiac injury predisposes patients to heart failure (HF), and ventricular tachycardia/fibrillation (VT/VF). Development of HF and VT/VF after cardiac injury is tightly linked to sympathetic neural remodeling. Although several medications targeting cardiac sympathetic excess reduce mortality following cardiac injury, significant shortcomings of these drugs include off-target effects, limited efficacy, and focus on downstream consequences of neural remodeling such as excess catecholamine release, rather than preventing it upstream. In this proposal, we build on strong preliminary data from humans, porcine, and murine models demonstrating that satellite glial cell (SGC) activation is a central feature of chronic cardiac injury. Activated glia release inflammatory cytokines, ATP, and other factors that modulate neuronal function. Chemogenetic upregulation of glial calcium signaling (as observed in activated glia) increase cardiac sympathetic neuronal excitability, synaptic efficacy, and tonic firing. Based on these novel findings, the goal of this proposal is to test the hypothesis that satellite glial activation and enhanced glial-neuronal signaling is a primary driver of cardiac sympathetic neuronal dysfunction, heart failure and VT/VF after cardiac injury. We will test our hypotheses using novel tools from a multidisciplinary team of investigators in 3 specific aims in two murine models of cardiac injury (ischemia-reperfusion and dilated cardiomyopathy). We will test whether following cardiac injury, satellite glial cell activation within stellate ganglia exacerbates neuronal and cardiac remodeling (structural and functional) to promote LV dysfunction and VT/VF (Aim 1). We will investigate the mechanisms by which cardiac injury activates SGCs in stellate ganglia after injury (Aim 2). Finally, we will determine whether targeting glial Gq-GPCR Ca2+ signaling or Cx43-mediated glia-neuron/glial- glial communication mitigates adverse remodeling and arrhythmogenesis following cardiac injury (Aim 3). The results of this proposal will 1) indicate whether and how satellite glial cell activation contributes to sympathetic imbalance after cardiac injury; and 2) determine whether targeting satellite glial cell activation offers therapeutic potential in chronic cardiac injury.

项目摘要/摘要心脏损伤使患者患有心力衰竭（HF）和心室心动过速/金刚纤维（VT/VF）。心脏损伤后HF和VT/VF的发展与交感神经重塑紧密相关。虽然靶向心脏交感神经过剩的几种药物降低心脏损伤后死亡率，重大这些药物的缺点包括脱靶效应，有限的功效和专注于下游神经重塑的后果，例如过度的儿茶酚胺释放，而不是防止上游。在此提案中，我们以人类，猪和鼠模型的强大初步数据为基础，证明了该卫星神经胶质细胞（SGC）激活是慢性心脏损伤的核心特征。活化的神经胶质释放炎症细胞因子，ATP和其他调节神经元功能的因素。化学发生上调神经胶质钙信号传导（如在活化的神经胶质中观察到的）增加心脏交感神经兴奋性，突触功效和滋补功率。基于这些新颖的发现，该提案的目的是测试假设卫星神经胶质激活和增强的神经神经神经元信号是心脏的主要驱动力心脏损伤后交感神经功能障碍，心力衰竭和VT/VF。我们将使用来自3个特定研究人员的多学科团队的新工具来测试我们的假设目的是在两个心脏损伤的鼠模型中（缺血 - 灌注和扩张的心肌病）。我们将测试是否在心脏损伤后，星状神经节内的卫星神经胶质细胞活化加剧了神经元和心脏重塑（结构和功能）可促进LV功能障碍和VT/VF（AIM 1）。我们将研究心脏损伤在损伤后激活星状神经节中SGC的机制（AIM 2）。最后，我们将确定靶向Glial GQ-GPCR CA2+信号传导或CX43介导的神经胶质/神经胶质 - 神经胶质通信减轻心脏损伤后的不良重塑和心律失常（AIM 3）。这该提案的结果将1）指示卫星神经胶质细胞激活是否有助于同情心脏损伤后不平衡； 2）确定靶向卫星胶质细胞激活是否提供慢性心脏损伤的治疗潜力。