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

• 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
• 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

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/摘要 心脏损伤使患者易于发生心力衰竭（HF）和室性心动过速/纤维性颤动（VT/VF）。 心脏损伤后HF和VT/VF的发展与交感神经重塑密切相关。虽然 几种针对心脏交感神经过度的药物可显著降低心脏损伤后的死亡率， 这些药物的缺点包括脱靶效应、有限的疗效和对下游的关注。 神经重塑的后果，如过量的儿茶酚胺释放，而不是阻止它上游。 在这个提议中，我们建立在来自人类、猪和小鼠模型的强有力的初步数据基础上， 卫星神经胶质细胞（SGC）活化是慢性心脏损伤的中心特征。活化胶质释放 炎性细胞因子、ATP和其他调节神经元功能的因子。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）增加心脏交感神经元兴奋性， 突触功效和紧张性放电。基于这些新的发现，本提案的目标是测试 假设卫星神经胶质激活和增强的神经胶质-神经元信号传导是心脏运动的主要驱动力， 心脏损伤后交感神经功能障碍、心力衰竭和VT/VF。 我们将使用来自多学科研究团队的新工具在3个特定领域测试我们的假设。 目的是在两个小鼠模型的心脏损伤（缺血再灌注和扩张型心肌病）。我们将测试 无论是在心脏损伤后，星状神经节内的卫星胶质细胞激活加剧了神经元和 心脏重塑（结构和功能），以促进LV功能障碍和VT/VF（目的1）。我们将 研究心脏损伤激活损伤后星状神经节中SGCs的机制（目的2）。 最后，我们将确定是否靶向胶质细胞Gq-GPCR Ca 2+信号传导或Cx43介导的胶质神经元/胶质细胞， 神经胶质通讯减轻心脏损伤后的不良重塑和血管生成（Aim 3）。的 该提议的结果将1）指示卫星神经胶质细胞激活是否以及如何有助于交感神经系统的神经传导。 心脏损伤后失衡; 2）确定靶向卫星胶质细胞活化是否提供 慢性心脏损伤的治疗潜力。