Cardiac Neuromodulation: Mechanisms and Therapeutics

项目摘要/摘要--总体 我们的计划项目赠款(PPG)专注于慢性心肌梗死患者之间复杂的相互作用 和交感神经系统(SNS)，目的是定义心室的精确机制。 心律失常和心源性猝死。PPG的首要目标是测试时空 假设瘢痕改变神经超微结构的神经递质释放假说的异质性 并导致心肌中神经递质的不均匀释放，这是一个关键和直接的原因 致命的心律失常。我们建议1)理解长期不适应的相互作用 2)利用该框架研究慢性迷走神经损伤的机制。 神经刺激(VNS)作为一种典型的神经调节疗法，发挥了其有益的作用和收获 更广泛的洞察力。我们的PPG团队在心脏神经控制、心肌细胞 电生理功能，在心肌水平的室性心动过速回路的控制，以及复合体 星状神经节交感神经元功能障碍的多细胞范式 增强了对受伤心脏的神经节后交感神经冲动。这些发现与 电生理不稳定是致死性室性心律失常易感性的基础，是 我们的PPG项目和核心领导与更广泛的研究团队之间的多方面合作。在……里面 项目1，Shivkumar博士和他的同事将利用新的3D心脏电标测方法 结合在体神经递质/神经肽的实时检测在正常和慢性脑梗塞中的应用 心脏跳动以确定生理学和病理生理学神经-肌细胞相互作用的机制。在……里面 项目2，哈维博士和他的同事们将在单个心肌细胞水平上研究各种神经递质如何 (单独和在正常和病变心肌环境中看到的组合)影响心肌细胞 正常的心脏和疤痕边缘的区域。在项目3中，阿吉约拉博士和他的同事们将研究 交感神经传递到心脏的过度和功能障碍的来源，特别是心脏炎症 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心脏的控制功能障碍。这三个人 组成部分项目将得到两个科学核心的支持，由Ardell博士和Ajijola博士领导，以及 由希夫库马尔博士领导的行政核心。科学核心将提供一系列正常的和患病的 人类心脏和星状神经节，用于项目1-3的研究，以及高通量组织清除 技术和高分辨率成像(核心A)。这些核心还旨在可重现地产生实验数据 猪模型和体内神经肽/神经递质释放技术的监督(核心B)。我们的PPG 团队对其成功充满信心，因为我们正在建立在预先存在的智力和深度协作的基础上 团队之间的关系，并热衷于利用测试的新假设 创新工具和方法。

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.