Development of the Predictive NeuroCardiovascular Simulator

预测性神经心血管模拟器的开发

• 批准号: 10001997
• 负责人: COLLEEN E CLANCY
• 金额: $ 69.19万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001997
• 关键词: Adrenergic Agents; Agitation; Anatomy; Arrhythmia; Autonomic nervous system; Binding; Blood Vessels; Blood flow; Brain; Cardiac; Cardiac Myocytes; Cardiac Output; Cardiovascular Physiology; Cardiovascular system; Catecholamines; Cell model; Cells; Clinical; Collaborations; Collection; Crystallization; Data; Development; Doctor of Philosophy; Electric Stimulation; Electrophysiology (science); Ensure; Event; Fright; Goals; Heart; Heart Diseases; Heart failure; Hypertension; Individual; Ion Channel; Life; Link; Mind; Modeling; Molecular; Myocardium; Nature; Nerve; Nervous system structure; Organ; Output; Pain; Patient-Focused Outcomes; Patients; Peripheral Nerves; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Physiology; Problem Solving; Proteins; Protocols documentation; Recording of previous events; Regulation; Research Personnel; Role; Signal Transduction; Signaling Protein; Smooth Muscle; Stroke; Synapses; Synaptic Receptors; Testing; Therapeutic Intervention; Time; Tissues; Uncertainty; Vascular Diseases; Vascular Smooth Muscle; Yin; affection; arm; base; body system; computational suite; computerized tools; design; experimental study; flexibility; heart rhythm; hemodynamics; improved; individual response; insight; neural circuit; neural model; neuronal circuitry; neuroregulation; novel; pleasure; population based; predictive tools; prevent; response; sex; simulation; synergism; tool; verification and validation

Project Summary In 1628 William Harvey wrote, “Every affection of the mind that is attended with either pain or pleasure, hope or fear, is the cause of an agitation whose influence extends to the heart.” Despite centuries of recognition of the fundamental connection between the brain and heart, there is still very poor understanding of the role of autonomic control in normal cardiac control and in the paroxysmal nature of life threatening cardiac events. To predict the mechanisms underlying the interaction between nervous system discharge and the resultant emergent cardiac and vascular events would finally allow for individual identification and specific targeting of arrhythmia provoking conditions by drugs or even by direct electrical stimulation. We propose to develop the Neurocardiovascular Simulator suite to solve this problem. The proposed simulator is unparalleled, as it will integrate anatomical and functional data ranging from the atomic level for ion channels and key signaling proteins to subcellular to cellular, organ, and systems data and simulations. Importantly, our simulator incorporates multiscale variability that reflects individual subject differences, allowing for a uniquely predictive tool. Experiment- informed simulator predictions will be used to further guide ongoing experiments in SPARC projects and to interpret patient data, allowing for tight integration and synergy across multiple arms of the SPARC initiative. The simulator has 8 tasks. In Task 1, we model neural circuitry. In Task 2, we incorporate into the simulator the anatomical features required for intrinsic autonomic regulation of cardiovascular function. In Task 3, we simulate synaptic control of vascular and cardiac myocytes. Task 4 involves modeling autonomic effects on subcellular signaling and electrophysiology in vascular and cardiac myocytes, while Task 5 deals with atomic-scale details of the molecular interactions in the adrenergic signaling cascade. Task 6 integrates data from the previous 5 tasks to predict autonomic effects on the cardiovascular system. In Task 7, we develop tools (workflows) for model dissemination and use by others. Finally, in Task 8 we incorporate into the simulator uncertainty quantification, sensitivity analysis, and robustness tests. The proposed studies have the potential of transforming our understanding of how cardiac and vascular function is regulated by the autonomic nervous system and provide insights into how this neuro-cardiovascular axis could be clinically tuned with molecular precision to improve patient outcomes.

项目摘要 威廉·哈维（William Harvey）在1628年写道：“心灵的每一个感情都充满痛苦或 愉悦，希望或恐惧是激动的原因，其影响力延伸到心脏。” 尽管认识到大脑与心脏之间基本联系的几个世纪，但 人们对自主控制在正常心脏控制中的作用仍然很糟糕 以及威胁性心脏事件的阵发性性质。预测机制 神经系统排放与结果紧急的基础 心脏和血管事件最终将允许个人识别和特定靶向 通过药物甚至直接电刺激引起心律不齐的条件。我们建议 开发神经心血管模拟器套件以解决此问题。提议 模拟器是无与伦比的，因为它将集成从范围内的解剖和功能数据 离子通道和关键信号蛋白的原子水平至细胞，到细胞，器官和器官和 系统数据和仿真。重要的是，我们的模拟器结合了多尺度的可变性 反映个人主题差异，从而允许独特的预测工具。实验- 知情模拟器预测将用于进一步指导SPARC中的正在进行的实验 项目并解释患者数据，允许多个跨多个集成和协同作用 SPARC计划的武器。模拟器有8个任务。在任务1中，我们对神经电路进行建模。在 任务2，我们将固有所需的解剖特征纳入模拟器中 心血管功能的自主性调节。在任务3中，我们模拟了 血管和心肌细胞。任务4涉及建模对亚细胞的自主效应 血管和心肌细胞中的信号传导和电生理学，而任务5涉及 肾上腺信号级联中分子相互作用的原子尺度细节。任务6 从前5个任务中的集成数据，以预测对心血管的自主影响 系统。在任务7中，我们开发了用于模型传播和使用他人使用的工具（工作流）。 最后，在任务8中，我们将其纳入模拟器不确定性定量，灵敏度 分析和鲁棒性测试。提出的研究有可能改变我们的 了解心脏和血管功能如何受到自主神经系统的调节 系统并提供有关如何在临床上调整该神经性心脏血管轴的见解 具有分子精度以改善患者预后。