Core (Grandi)

核心（格兰迪）

• 批准号: 10677709
• 负责人: Eleonora Grandi
• 金额: $ 38.66万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10677709
• 关键词: Accounting; Adult; Affect; Arrhythmia; Behavior; Biochemical; Biological Models; Biological Process; Ca(2+)-Calmodulin Dependent Protein Kinase; Cardiac; Cardiac Myocytes; Cause of Death; Cell model; Cells; Cessation of life; Chemicals; Clinical Data; Cloud Computing; Complement; Complex; Computational Technique; Computer Models; Coupled; Cyclic AMP-Dependent Protein Kinases; Developed Countries; Development; Dilated Cardiomyopathy; Doctor of Philosophy; Drug Interactions; Electrophysiology (science); Event; Failure; Feedback; Functional disorder; Generations; Genetic; Heart Diseases; Heart failure; Human; Individual; Inherited; Ion Channel; Ion Transport; Kinetics; Link; Maintenance; Mathematical Model Simulation; Measures; Mechanics; Methods; Modeling; Muscle Cells; Organ; Oryctolagus cuniculus; Outcome; Pathologic; Patients; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Physiological; Predisposition; Property; Protein Kinase; Proteins; Research; Sarcoplasmic Reticulum; Signal Transduction; Solid; Statistical Data Interpretation; Subcellular structure; Subgroup; System; Testing; Tissue Model; Tissues; Translations; United States; Variant; Ventricular; Ventricular Arrhythmia; Ventricular Fibrillation; Ventricular Tachycardia; beta-adrenergic receptor; clinical phenotype; computational platform; computer framework; computing resources; drug efficacy; experimental study; familial dilated cardiomyopathy; heart function; human model; human pluripotent stem cell; human stem cells; improved; in silico; indium arsenide; interpatient variability; kinetic model; models and simulation; multi-scale modeling; novel; pharmacologic; population based; predictive tools; response; screening; simulation; stem cell model; three-dimensional modeling; tool

CORE B: IN SILICO MODELING Director: Eleonora Grandi Ph.D. (UC Davis) PROJECT SUMMARY: The computational core will develop and apply multi-scale mechanistic models, simulation and statistical approaches as predictive tools to inform, interpret, and extend experimental observations in Projects 1, 2 and 3. Our quantitative models will span the range of physical scales and the diverse biological functions needed to mechanistically link HF-induced remodeled electrophysiology to patient- specific clinical phenotype. Namely, we will develop physiologically detailed electrical, chemical, and mechanical models from single channel to whole-organ scales. Quantitative computational approaches will enhance our mechanistic understanding of complex and non-linear feedback systems involved in arrhythmia generation and maintenance. The tools will also be applied for in silico screening and prediction of drug effects on varied genetic backgrounds to predict patient pharmacological responses. Computational population-based approaches will be constructed to determine the factors influencing drug efficacy or failure in a specific patient or subgroup of HF patients and inherited DCM patients. CORE B will also provide translation of findings in human pluripotent stem cell derived cardiomyocytes (iPSC-CMs) and rabbit ventricular myocytes to adult human ventricular myocytes via in silico modeling and simulation.

CORE B：IN SILICO MODELING总监：Eleonora Grandi博士(UC戴维斯） 项目概述：计算核心将开发和应用多尺度机械模型， 模拟和统计方法作为预测工具，以告知，解释和扩展实验 项目1、2和3中的观察结果。我们的定量模型将跨越物理尺度的范围， 将HF诱导的重塑电生理学与患者机械联系起来所需的多种生物学功能- 特异性临床表型。也就是说，我们将开发生理详细的电气，化学和机械 从单通道到全器官规模的模型。定量计算方法将提高我们的 对心律失常产生中涉及的复杂和非线性反馈系统的机械理解， 上维护这些工具还将应用于计算机筛选和预测药物对不同遗传物质的影响。 以预测患者的药理学反应。基于人口的计算方法将是 旨在确定影响特定HF患者或亚组药物疗效或失败的因素 遗传性DCM患者。CORE B还将提供人类多能干细胞研究结果的翻译 细胞衍生的心肌细胞（iPSC-CM）和兔心室肌细胞到成人心室肌细胞 通过计算机建模和仿真。