Comprehensive Structural and Functional Mapping of the Mammalian Cardiac Nervous System

哺乳动物心脏神经系统的全面结构和功能图谱

• 批准号: 9299950
• 负责人: Charless Fowlkes
• 金额: $ 263.13万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-24 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9299950
• 关键词: Ablation; Adverse effects; Anatomy; Animal Model; Animals; Area; Arrhythmia; Autonomic nervous system; Behavior; Binding; Botulinum Toxins; Brain Stem; Cardiac; Cardiac Electrophysiologic Techniques; Cardiovascular Diseases; Carotid Body; Cells; Cervical; Cessation of life; Chest; Clinical; Communities; Data; Decentralization; Destinations; Disease; Efferent Neurons; Electrophysiology (science); Epidural Anesthesia; Functional disorder; Ganglia; Goals; Heart; Heart Diseases; Heart failure; Hospitalization; Human; Hypertension; In Vitro; Injection of therapeutic agent; Intervention; Knowledge; Life; Link; Maps; Marshal; Mechanics; Mediastinal; Methods; Molecular; Morbidity - disease rate; Muscle Cells; Myocardial; Nerve; Nerve Fibers; Nervous system structure; Neuraxis; Neurons; Neurostimulation procedures of spinal cord tissue; Neurotransmitters; Nodose Ganglion; Organ; Pathway interactions; Patients; Physiological; Physiology; Play; Precision therapeutics; Proteomics; Public Health; Quality of life; Research; Role; Sensory; Sensory Ganglia; Spinal Cord; Spinal Ganglia; Structure; Sympathectomy; Sympathetic Ganglia; Synapses; Techniques; Therapeutic; Therapeutic Intervention; Time; Tissues; United States; Veins; Viral; Work; afferent nerve; base; data sharing; heart disease prevention; heart innervation; heart rhythm; human disease; improved; in vivo; indexing; innovation; interdisciplinary approach; man; mortality; neurochemistry; neuroregulation; novel; prevent; relating to nervous system; research study; sudden cardiac death; targeted treatment; therapeutic target; therapy development; tool; transcriptome sequencing; vagus nerve stimulation

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.

抽象的 心力衰竭、心律失常和高血压等心血管疾病是发病的主要原因 以及美国和世界各地的死亡率。自主神经系统在 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 干涉。我们研究团队的主要目标是精确定义心脏神经层次结构和 开发从宏观到细胞和分子水平的电路图，并在网络上共享这些数据 与科学界的持续基础。这项工作还将提供经过验证的方法和工具 评估神经调节。研究小组将把它们免费提供给科学界。一个 跨不同物种的多尺度、多学科方法，与人类疾病高度相关，将用于 以高分辨率定义心脏神经支配的解剖结构。神经结构将与心脏功能相关。 心脏神经控制的复杂性需要一种综合方法，这将是一项杰作 在这个领域。从“细胞到人”的最先进的解剖学、生理学和药理学方法 必须结合起来才能实现上述目标。该方法将在各个级别使用 神经轴（心脏、心外胸内神经结构和胸外神经结构）。这 所提出的技术将首次允许对解剖学和分子学的详细描述 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 这些途径的整合代表了理解心脏神经控制的最具创新性的尝试 曾经进行过。了解这些途径有可能加速治疗方法的开发 将能够精确地瞄准神经结构，并指导重新利用现有可用的方法 用于治疗目的的疗法（例如神经刺激器）。最终，这些方法需要 开发新颖、有效且负担得起的干预措施来管理和预防心脏病和 心源性猝死。