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Development of the Predictive NeuroCardiovascular Simulator

预测性神经心血管模拟器的开发

基本信息

批准号：
10092300
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
项目类别：
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/10092300
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

项目摘要

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.

项目总结