Multiscale Model of the Vagal Outflow to the Heart

迷走神经流出心脏的多尺度模型

• 批准号: 9152617
• 负责人: JAMES SCHWABER
• 金额: $ 57.96万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-10 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9152617
• 关键词: Address; Adult; Affect; Anatomy; Arrhythmia; Automobile Driving; Behavior; Biological Assay; Biological Neural Networks; Brain Stem; Cardiac; Cardiac Output; Cardiac health; Cereals; Clinical Data; Color; Computer Simulation; Coronary artery; Data; Disease; Early Diagnosis; Electrophysiology (science); Experimental Models; Female; Functional disorder; Fuzzy Logic; Ganglia; Generations; Genes; Genetic Transcription; Goals; Health; Heart; Heart Diseases; Heart Rate; Heart failure; Individual; Ischemia; Knowledge; Label; Left ventricular structure; Ligation; Link; Maintenance; Measures; Modality; Modeling; Molecular; Myocardial Ischemia; Neuronal Plasticity; Neurons; Nitric Oxide; Palliative Care; Pathogenesis; Pathology; Phenotype; Physiological; Prevention; Rattus; Regulator Genes; Rosa; Sinoatrial Node; Source; Study models; Sudden Death; System; Testing; Tropism; Vagus nerve structure; Ventricular; Viral Vector; anatomical tracing; base; chronotropic; dorsal motor nucleus; experimental study; heart function; hemodynamics; improved; insight; interest; laser capture microdissection; male; model development; multi-scale modeling; multimodality; network models; neuronal excitability; novel; novel therapeutics; nucleus ambiguus; protective effect; response; transcriptomics

PROJECT SUMMARY Vagal control of the heart has seen renewed interest due to the now well-recognized potential of manipulating cardiac vagal activity for novel therapeutic opportunities in treating heart disease. Recent anatomical and physiological evidence shows that vagal cardiac control is multimodal at both pre- and post-ganglionic neuronal levels. Coordination between multiple modes of control (e.g., of heart rate, ventricular contractility, etc) is essential for heart health. Disruption of such coordination is a hallmark of heart failure and arrhythmias, for example. Studies thus far have largely focused on the physiological effects of the vagus on heart rate without delving into the underlying neural networks, where insights are likely to yield targets for fine-grained manipulation of vagal activity to treat heart disease. Our project is aimed at addressing this unmet need by focusing on the central neuronal as well as cardiac ganglionic circuits driving chrono-, dromo- and iono- tropism. We will pursue an integrated multiscale modeling strategy that combines fine-grained anatomical tracing of control circuits and high-throughput transcriptional analysis of single neurons identified based on circuit connectivity, with computational modeling of the multiscale closed loop vagal cardiac control. These involve hemodynamics, brainstem neuronal networks, and cardiac ganglionic circuits involved in the coordinated inotropic and chronotropic control of the heart. We will develop detailed electrophysiological models of neuronal excitability in nucleus ambiguus (NA) and dorsal motor nucleus (DMV), as well as the targeted cardiac ganglia, and incorporate the transcriptional changes identified from coronary artery ligation experiments in these models. We hypothesize that coordination and integration of the control of rate and contractility occurring at the level of the NA/DMV and the level of the cardiac ganglia are the basis for cardioprotective vagal cardiac outflows. We will test this hypothesis in three Aims: (1) Develop a multiscale network model framework integrating the key modules controlling SA node and left ventricle. (2) Determine the molecular mechanisms affecting the coordination involved in cardiac functional control in heart disease by linking gene regulatory networks and neural network behavior. (3) Test model predictions in selective manipulation of function experiments. Our multiscale computational modeling framework will enable us to combine and interpret the anatomical, transcriptional, and physiological results from experiments. Our investigative team has previously collaborated in modeling the baroreflexes and comprises complementary expertise in all aspects of the proposal. Our approach is expected to identify the relative contribution of brainstem circuits and cardiac ganglionic circuits to the coordination of multimodal vagal control. Our expected results, by uncovering the molecular and physiological mechanisms underlying the source and maintenance of coordinated vagal outflows, have significant implications for identifying targets for early diagnosis, prevention, and even novel palliative therapy in treating heart disease.

项目概要 由于现在公认的操纵心脏的潜力，迷走神经对心脏的控制重新引起了人们的兴趣 心脏迷走神经活动为治疗心脏病提供了新的治疗机会。最近的解剖学和 生理学证据表明，迷走神经心脏控制在节前和节后都是多模式的 神经元水平。多种控制模式之间的协调（例如心率、心室收缩力、 等）对于心脏健康至关重要。这种协调性的破坏是心力衰竭和心律失常的标志， 例如。迄今为止的研究主要集中在迷走神经对心率的生理影响 无需深入研究底层神经网络，其中的见解可能会产生细粒度的目标 操纵迷走神经活动来治疗心脏病。我们的项目旨在解决这一未满足的需求 专注于驱动计时、驱动和离子的中枢神经元和心脏神经节回路 向性。我们将追求一种集成的多尺度建模策略，结合细粒度的解剖学 基于控制电路的追踪和基于识别的单个神经元的高通量转录分析 电路连接，以及多尺度闭环迷走神经心脏控制的计算建模。这些 涉及血流动力学、脑干神经元网络和心脏神经节回路 心脏的正性肌力和变时性协调控制。我们将制定详细的电生理学 疑核（NA）和背运动核（DMV）神经元兴奋性模型，以及 靶向心脏神经节，并纳入从冠状动脉结扎中识别出的转录变化 在这些模型中进行实验。我们假设速率和速率控制的协调和整合 发生在 NA/DMV 水平和心脏神经节水平的收缩力是 心脏保护性迷走神经心脏流出。我们将在三个目标中检验这一假设：（1）开发多尺度模型 网络模型框架集成了控制SA节点和左心室的关键模块。 (2) 确定 影响心脏病心脏功能控制协调的分子机制 将基因调控网络和神经网络行为联系起来。 (3) 选择性地测试模型预测 操作功能实验。我们的多尺度计算建模框架将使我们能够 结合并解释实验的解剖、转录和生理结果。我们的 研究小组之前曾合作对压力反射进行建模，并包括互补的 提案各方面的专业知识。我们的方法预计将确定以下方面的相对贡献： 脑干回路和心脏神经节回路协调多模态迷走神经控制。我们的预期 结果，通过揭示其来源和维持的分子和生理机制 协调迷走神经流出，对于确定早期诊断、预防、 甚至治疗心脏病的新型姑息疗法。