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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：
10416426
负责人：
Olujimi A Ajijola
金额：
$ 59.18万
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/10416426
关键词：
Ablation Animals Arrhythmia Attenuated Calcium Signaling Cardiac Cardiomyopathies Catecholamines Cause of Death Chronic Chronic Disease Communication Connexin 43 Data Dilated Cardiomyopathy Disease Electrophysiology (science)Fibrosis Functional disorder Future G-Protein-Coupled Receptors Gap Junctions 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 structure Neuroglia Neuronal Dysfunction Neurons Norepinephrine Patients Pharmaceutical Preparations Play Prevention Process Purines Reperfusion Injury 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 base beta-adrenergic receptor cardiogenesis cell type chronic pain cytokine glial activation human data human model inhibitor mortality mortality risk mouse model multidisciplinary neurochemistry neuronal excitability neuroregulation neurotransmission novel organ injury porcine model prevent relating to nervous system 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.

项目总结/文摘