Development of the Predictive NeuroCardiovascular Simulator

1628年，威廉·哈维写道：“头脑中的每一种情感，要么伴随着痛苦，要么伴随着 无论是快乐、希望还是恐惧，都是一种骚动的原因，其影响延伸到内心。 尽管几个世纪以来人们一直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，人们仍然知之甚少。 以及危及生命的心脏事件的突发性。来预测这些机制 神经系统放电和由此产生的突发事件之间的相互作用 心脏和血管事件最终将允许个人识别和特定目标 由药物或甚至通过直接电刺激引起的心律失常。我们建议 开发神经心血管模拟器套件来解决这一问题。建议数 模拟器是无与伦比的，因为它将整合从 离子通道和关键信号蛋白的原子水平从亚细胞到细胞、器官和 系统数据和模拟。重要的是，我们的模拟器结合了多尺度可变性 反映个体主题差异，提供独特的预测工具。实验- 知情的模拟器预测将用于进一步指导SPARC正在进行的实验 项目并解释患者数据，实现多个项目的紧密集成和协同 SPARC倡议的武器。该模拟器有8个任务。在任务1中，我们为神经电路建模。在……里面 任务2，我们将固有的所需的解剖特征合并到模拟器中 心血管功能的自主调节。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神经效应进行建模 血管和心肌细胞的信号和电生理学，而任务5处理 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项任务的数据以预测自主神经对心血管的影响 系统。在任务7中，我们开发了供其他人传播和使用模型的工具(工作流)。 最后，在任务8中，我们将不确定性量化、灵敏度 分析和稳健性测试。拟议的研究有可能改变我们的 了解自主神经是如何调节心脏和血管功能的 系统，并提供了对如何在临床上调整这个神经-心血管轴的见解 具有分子精确度，以改善患者的预后。

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.