Development of the Predictive NeuroCardiovascular Simulator

1628 年威廉·哈维 (William Harvey) 写道：“心灵的每一种情感，如果伴随着痛苦或痛苦， 快乐、希望或恐惧，都是激动的原因，其影响延伸到心灵。” 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， 对于自主控制在正常心脏控制中的作用仍然知之甚少 以及危及生命的心脏事件的阵发性。预测机制 神经系统放电与由此产生的突发事件之间相互作用的基础 心脏和血管事件最终将允许个体识别和特定目标 药物甚至直接电刺激引起心律失常的情况。我们建议 开发神经心血管模拟器套件来解决这个问题。拟议的 模拟器是无与伦比的，因为它将集成从解剖学和功能数据到 原子水平的离子通道和关键信号蛋白从亚细胞到细胞、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，从而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 中正在进行的实验 项目并解释患者数据，从而实现多个项目之间的紧密集成和协同 SPARC 倡议的武器。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，我们将内在功能所需的解剖特征纳入模拟器中 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 涉及模拟自主神经对亚细胞的影响 血管和心肌细胞的信号传导和电生理学，而任务 5 涉及 肾上腺素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 项任务的数据来预测自主神经对心血管的影响 系统。在任务 7 中，我们开发用于模型传播和供他人使用的工具（工作流程）。 最后，在任务 8 中，我们将不确定性量化、灵敏度纳入模拟器中 分析和稳健性测试。拟议的研究有可能改变我们的 了解自主神经如何调节心脏和血管功能 系统并提供有关如何在临床上调整该神经心血管轴的见解 具有分子精度，可改善患者的治疗效果。

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.