Cardiac Neuromodulation: Mechanisms and Therapeutics

心脏神经调节：机制和治疗

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要 - 总体我们的项目资助 (PPG) 重点关注慢性梗塞心脏之间复杂的相互作用和交感神经系统（SNS），目标是定义心室的精确机制 PPG 的首要目标是测试“时空”。神经递质释放假说的异质性假设疤痕改变神经的超微结构并导致心肌中神经递质释放不均匀，这是一个关键且直接的原因我们建议 1）了解慢性心律失常之间的适应不良相互作用。受伤的心脏和 SNS，以及 2) 使用该框架来研究慢性迷走神经神经刺激（VNS）作为一种典型的神经调节疗法发挥其有益作用和增益我们的 PPG 团队在心脏神经控制、心肌细胞方面取得了开创性的发现。电生理功能、心肌水平上室性心动过速回路的控制以及复杂的星状神经节内交感神经元功能障碍的多细胞范式是主要来源这些发现与受损心脏的节后交感神经驱动力增强有关。电生理不稳定是导致致命性室性心律失常的原因之一我们的 PPG 项目和核心领导者以及更广泛的研究团队之间的多方面合作。项目 1，Shivkumar 博士和他的同事将利用新颖的 3D 心脏电图测绘方法结合正常和慢性梗塞的实时体内神经递质/神经肽检测跳动的心脏来定义生理和病理生理神经-肌细胞相互作用的机制。项目 2，Harvey 博士和同事将在单个肌细胞水平上研究各种神经递质如何（在正常和患病心肌环境中单独或组合观察）影响心肌细胞在项目 3 中，Ajijola 博士和他的同事将研究正常心脏和疤痕边界区域的心脏。心脏交感神经传递过度和功能失调的根源，特别是炎症星状神经节项目 3 将研究神经元和其他细胞之间的适应不良相互作用。神经胶质细胞和免疫细胞等类型会导致慢性损伤的心脏控制功能失调。组成项目将得到由 Ardell 和 Ajijola 博士领导的两个科学核心的支持。由 Shivkumar 博士领导的行政核心科学核心将提供正常和患病的数据流。人类心脏和星状神经节用于项目 1-3 的研究，以及高通量组织透明化技术和高分辨率成像（核心 A）。猪体内神经肽/神经递质释放模型和监督技术（核心 B）。团队对其成功充满信心，因为我们正在现有的知识和深度协作的基础上继续发展团队之间的关系，并对正在测试的新假设充满热情创新工具和方法。