Comprehensive Structural and Functional Mapping of the Mammalian Cardiac Nervous System

摘要 心力衰竭、心律失常和高血压等心血管疾病是发病率的主要原因。 美国和世界范围内的死亡率。自主神经系统在脑血管疾病中起着关键作用 这些疾病的病理生理学和神经轴调节为治疗提供了重要途径 干预。我们研究团队的主要目标是精确定义心脏神经层级和 开发从宏观到细胞和分子级别的电路图，并在 与科学界正在进行的合作。这项工作还将提供经过验证的方法和工具 评估神经调节。研究小组将向科学界免费提供这些数据。一个 与人类疾病高度相关的跨不同物种的多尺度、多学科方法将用于 高清定义心脏神经支配的解剖学。神经结构将与心脏功能联系起来。 心脏神经控制的复杂性需要一种综合的方法，它将是一种强有力的手段。 在这个领域。最新的解剖学、生理学和药理学方法从细胞到人 必须结合起来才能实现上述目标。这种方法将在每个级别的 神经轴(心脏、心外胸内神经结构和胸外神经结构)。这个 提出的技术将第一次允许对解剖和分子的详细描述 心脏和心外神经节突触和细胞体水平的相互作用。使用的技术和 这些通路的整合代表了理解心脏神经控制的最具创新性的尝试。 从未承担过的。了解这些途径有可能加速治疗方法的发展 将能够精确地定位神经结构，并指导已有的方法重新使用 用于治疗目的的疗法(如神经刺激剂)。归根结底，需要这些方法来 开发新的、有效的和负担得起的心脏病管理和预防干预措施 心源性猝死。

ABSTRACT Cardiovascular diseases such as heart failure, arrhythmias, and hypertension are leading causes of morbidity and mortality in the United States and world-wide. The autonomic nervous system plays a critical role in the pathophysiology of these diseases and neuraxial modulation provides an important avenue for therapeutic intervention. The major goal of our research team is to precisely define the cardiac neural hierarchy and develop circuit diagrams from the macroscopic to cellular and molecular levels and share these data on an ongoing basis with the scientific community. This effort will also provide verified methods and tools for assessing neuromodulation. The research team will make them freely available to the scientific community. A multiscale, multidisciplinary approach across various species, highly relevant to human disease, will be used to define the anatomy of cardiac innervation in high definition. Neural structure will be linked to cardiac function. The complexity of cardiac neural control necessitates an integrative approach that will represent a tour de force in this field. State-of-the-art anatomical, physiological, and pharmacological approaches from `cells to man' must be combined in order to achieve the above goals. This approach will be utilized at each level of the neuraxis (heart, extracardiac intrathoracic neural structures and extrathoracic neural structures). The techniques proposed will allow, for the first time, a detailed description of the anatomical and molecular interactions at the synaptic and cell body levels in cardiac and extracardiac ganglia. The techniques used and the integration of these pathways represents the most innovative attempt to understand cardiac neural control ever undertaken. Understanding these pathways has the potential to accelerate development of therapies that will be able to precisely target neural structures and also guide methods to re-purpose already available therapies (e.g. nerve stimulators) for therapeutic purposes. Ultimately, these approaches are required to develop novel, effective, and affordable interventions for the management and prevention of heart disease and sudden cardiac death.