Cardiac Neuromodulation: Mechanisms and Therapeutics

心脏神经调节：机制和治疗

• 批准号: 10627573
• 负责人: KALYANAM SHIVKUMAR
• 金额: $ 227.58万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627573
• 关键词: 3-Dimensional; Address; Adrenergic beta-Antagonists; Angiotensin Receptor; Arrhythmia; Autonomic nervous system; Biochemical; Cardiac; Cardiac Myocytes; Cardiac ablation; Cardiomyopathies; Cells; Cessation of life; Chronic; Cicatrix; Collaborations; Complex; Defibrillators; Detection; Disease; Doctor of Philosophy; Dose; EFRAC; Electrophysiology (science); Eligibility Determination; Ensure; Etiology; Functional disorder; Goals; Health; Heart; Heart Diseases; Heart Injuries; Heterogeneity; Immune; Implantable Defibrillators; In Vitro; Infarction; Inflammation; Ischemia; Knowledge; Lead; Left Ventricular Ejection Fraction; Left Ventricular Function; Maps; Measurement; Medical; Medicare; Molecular; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Nerve; Neuroglia; Neuronal Dysfunction; Neurons; Neuropeptides; Neurosecretory Systems; Neurostimulation procedures of spinal cord tissue; Neurotransmitters; Normal tissue morphology; Organism; Pathway interactions; Patient Care; Patients; Pattern; Peptides; Peptidyl-Dipeptidase A; Physiological; Predisposition; Process; Prognosis; Program Research Project Grants; Public Health; Quality of life; Recurrence; Reflex action; Reproducibility; Risk; Role; Seminal; Shock; Source; Stream; Structure; Structure of stellate ganglion; Sympathectomy; Sympathetic Nervous System; Tachyarrhythmias; Techniques; Technology; Testing; Therapeutic; Time; Tissues; United States; Ventricular; Ventricular Arrhythmia; Ventricular Tachycardia; beneficiary; cardiac implant; cell type; clinically relevant; experience; high resolution imaging; human disease; in vivo; inhibitor; injured; innovation; insight; mortality; nerve supply; neural; neuroregulation; neurotransmission; neurotransmitter release; novel; porcine model; prevent; programs; response; spatiotemporal; standard of care; success; sudden cardiac death; tool

PROJECT SUMMARY/ABSTRACT - Overall Our Program Project Grant (PPG) focuses on the complex interplay between the chronically infarcted heart and sympathetic nervous system (SNS), with the goal of defining precise mechanisms of ventricular arrhythmias and sudden cardiac death. The overarching objective of the PPG is to test ‘The Spatiotemporal Heterogeneity of Neurotransmitter Release Hypothesis’ that postulates scars alter the ultrastructure of nerves and result in non-uniform neurotransmitter release in the myocardium which is a crucial and proximate cause of lethal arrhythmias. We propose to 1) understand the maladaptive interactions between the chronically injured heart and the SNS, and 2) using this framework to investigate the mechanisms by which chronic vagal nerve stimulation (VNS) as a prototypical neuromodulation therapy exerts its beneficial effects and gain broader insights. Our PPG team has made seminal discoveries in cardiac neural control, cardiomyocyte electrophysiologic function, control of ventricular tachycardia circuits at the myocardial level, and the complex multicellular paradigms that underlie sympathetic neuronal dysfunction within stellate ganglia, the major source of enhanced postganglionic sympathetic drive to the injured heart. These discoveries are relevant to the electrophysiologic instabilities that underlie susceptibility to lethal ventricular arrhythmias and are a result of the multifaceted collaborations between our PPG project & core leaders, and the broader study team. In Project 1, Dr. Shivkumar and his colleagues will utilize novel 3D cardiac electrical mapping approaches combined with real time in vivo neurotransmitter/neuropeptide detection in normal and chronically infarcted beating hearts to define the mechanisms of physiologic and pathophysiologic nerve-myocyte interactions. In Project 2, Dr. Harvey and colleagues will study, at the single myocyte level, how various neurotransmitters (alone and in combinations seen in the normal and diseased myocardial milieu) impact cardiomyocytes from normal hearts and from the scar-border zone. In Project 3, Dr. Ajijola and his colleagues will investigate the source of excessive and dysfunctional sympathetic neurotransmission to the heart, specifically inflammation in the stellate ganglia. Project 3 will investigate how maladaptive interactions between neurons and other cell types such as glia and immune cells lead to dysfunctional control of the chronically injured heart. These three component projects will be supported by two scientific cores, led by Drs. Ardell and Ajijola and an administrative core led by Dr. Shivkumar. The scientific cores will provide a stream of normal and diseased human hearts and stellate ganglia for studies in Projects 1-3, as well as high throughput tissue clearing techniques and high-resolution imaging (Core A). The cores also aim to reproducibly generate experimental porcine models and oversee technologies for in vivo neuropeptide/neurotransmitter release (Core B). Our PPG team is confident in its success as we are building on pre-existing intellectual and deep collaborative relationships among the teams and are enthusiastic about the novel hypotheses being tested utilizing innovative tools and approaches.

项目摘要/摘要 - 总体 我们的计划项目赠款（PPG）着重于长期梗塞心脏之间的复杂相互作用 和交感神经系统（SNS），目的是定义心室的精确机制 心律不齐和心脏猝死。 PPG的总体目标是测试“时空” 神经递质释放假设的异质性假设疤痕改变了神经的超微结构 并导致心肌中的神经递质释放不均匀，这是一个至关重要的原因 致命性心律不齐。我们提出1）了解长期的适应不良相互作用 受伤的心脏和SNS，以及2）使用此框架研究慢性迷走神经的机制 神经刺激（VNS）作为一种典型的神经调节疗法会产生其有益作用并获得 更广泛的见解。我们的PPG团队在心脏神经控制，心肌细胞方面有第二次发现 电生理功能，心肌水平的心室心动过速电路的控制和复合物 在星状神经节内的交感神经功能障碍的基础的多细胞范例，主要来源 增强的后旋转后交感神经驱动器向受伤的心脏驱动。这些发现与 电生理的不稳定性是对致命性心律不齐的敏感性的基础 我们的PPG项目与核心领导者与更广泛的学习团队之间的多方面合作。在 项目1，Shivkumar博士及其同事将利用新颖的3D心脏电气映射方法 结合实时在正常和长期梗塞的体内神经递质/神经肽检测 跳动心脏来定义生理和病理生理神经神经神经细胞相互作用的机制。在 Harvey博士及其同事将在单个肌细胞级别学习各种神经递质 （单独和在正常和解散的心肌环境中看到的组合）撞击心肌细胞 正常的心脏和疤痕境区域。在项目3中，Ajijola博士及其同事将调查 过度和功能失调的交感神经传递对心脏的介绍，特别是在 星状神经节。项目3将研究神经元与其他细胞之间的适应不良的相互作用 胶质细胞和免疫细胞等类型会导致对慢性损伤心脏的功能失调。这三个 组件项目将由DRS领导的两个科学核心支持。 Ardell和Ajijola以及 由Shivkumar博士领导的行政核心。科学核心将提供一系列正常和剥落的流 人类的心脏和星形神经节在项目1-3中进行研究，以及高通量组织清除 技术和高分辨率成像（核心A）。核心还旨在可重复生成实验 用于体内神经肽/神经递质释放的猪模型和海外技术（Core B）。我们的PPG 团队对我们的成功充满信心，因为我们正在建立先前存在的智力和深入协作 团队之间的关系，并对使用的小说假设充满热情 创新的工具和方法。