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: 9908155
• 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/9908155
• 关键词: Address; Adult; Affect; Anatomy; Arrhythmia; Automobile Driving; Behavior; Biological Assay; Brain Stem; Cardiac; Cardiac Output; Cardiac health; Clinical Data; Color; Computer Models; Coronary artery; Data; Disease; Early Diagnosis; Electrophysiology (science); Experimental Models; Female; Functional disorder; Fuzzy Logic; Ganglia; Generations; Genes; Genetic Transcription; Goals; Grain; Health; Heart; Heart Diseases; Heart Rate; Heart failure; Individual; Ischemia; Knowledge; Label; Left ventricular structure; Ligation; Link; Maintenance; Measures; Modeling; Molecular; Myocardial Ischemia; Neuronal Plasticity; Neurons; Nitric Oxide; Palliative Care; Pathogenesis; Pathology; Phenotype; Physiological; Prevention; Rattus; Regulator Genes; Sinoatrial Node; Source; Study models; Sudden Death; System; Testing; Tropism; Vagus nerve structure; Ventricular; Viral Vector; anatomical tracing; base; cardioprotection; chronotropic; dorsal motor nucleus; experimental study; heart function; hemodynamics; improved; insight; interest; laser capture microdissection; male; model development; multi-scale modeling; multimodality; network models; neural network; neuronal excitability; novel; novel therapeutics; nucleus ambiguus; predictive modeling; protective effect; protective factors; 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.

项目摘要 迷走神经对心脏的控制已经重新引起人们的兴趣，这是由于现在公认的操纵心脏的潜力。 心脏迷走神经活动，为治疗心脏病提供新的治疗机会。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）对心脏健康至关重要。这种协调的破坏是心力衰竭和心律失常的标志， 比如迄今为止的研究主要集中在迷走神经对心率的生理作用上 如果不深入研究底层的神经网络，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， 集中于中枢神经元以及驱动时-，dromo-和iono-的心脏神经节回路， 向性我们将追求一个综合的多尺度建模策略，结合细粒度的解剖， 跟踪控制电路和高通量转录分析的基础上确定的单个神经元 电路连接，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， 协调心脏的变力性和变时性控制。我们会详细的电生理检查 在疑核（NA）和背侧运动核（DMV）的神经元兴奋性模型，以及 靶向心脏神经节，并纳入冠状动脉结扎鉴定的转录变化 这些模型中的实验。我们假设，协调和整合的控制率和 在NA/DMV水平和心脏神经节水平发生的收缩是 心脏保护迷走神经心脏流出。我们将测试这个假设在三个目标：（1）开发一个多尺度 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)选择性测试模型预测 操纵功能实验。我们的多尺度计算建模框架将使我们能够 联合收割机并解释来自实验的解剖、转录和生理结果。我们 调查小组以前曾合作建立压力感受器反射模型， 在提案的各个方面都有专业知识。我们的方法预计将确定的相对贡献 脑干回路和心脏神经节回路对多模式迷走神经控制的协调作用。我们预期的 结果，通过揭示潜在的来源和维持的分子和生理机制， 协调的迷走神经流出，对于确定早期诊断，预防， 甚至是治疗心脏病的新型姑息疗法。