Development of the Predictive NeuroCardiovascular Simulator

1628年，威廉·哈维（William Harvey）写道：“心灵的每一种情感，无论是伴随着痛苦还是痛苦， 快乐，希望或恐惧，是一种激动的原因，其影响延伸到心脏。 尽管几个世纪以来人们都认识到大脑和心脏之间的基本联系， 对于自主神经控制在正常心脏控制中的作用， 以及危及生命的心脏事件的阵发性。来预测 神经系统放电和由此产生的突发事件之间的相互作用的基础 心脏和血管事件将最终允许个体识别和特定靶向 心律失常的诱因条件下的药物，甚至是直接电刺激。我们提出 开发神经心血管模拟器套件来解决这个问题。拟议 模拟器是无与伦比的，因为它将整合解剖和功能数据，从 原子水平的离子通道和关键信号蛋白，以亚细胞到细胞，器官， 系统数据和模拟。重要的是，我们的模拟器采用了多尺度可变性， 反映了个体受试者的差异，允许使用独特的预测工具。实验- 模拟器的预测结果将被用来进一步指导正在进行中的、在美国宇航局进行的试验。 项目和解释患者数据，允许多个项目之间的紧密集成和协同作用， 的武器。模拟器有8个任务。在任务1中，我们对神经回路进行建模。在 任务2，我们在模拟器中加入了固有的解剖特征， 自主调节心血管功能。在任务3中，我们模拟突触控制， 血管和心肌细胞。任务4涉及对亚细胞的自主效应进行建模， 信号和电生理学，而任务5涉及 肾上腺素能信号级联中分子相互作用的原子尺度细节。任务6 整合前5项任务的数据，预测自主神经对心血管的影响 系统在任务7中，我们开发了用于模型传播和其他人使用的工具（工作流）。 最后，在任务8中，我们将不确定性量化、灵敏度 分析和鲁棒性测试。拟议的研究有可能改变我们的 了解心脏和血管功能如何由自主神经调节 系统，并提供如何在临床上调整这种神经-心血管轴的见解 用分子精确度来改善病人的治疗效果

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.