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