Core (Grandi)

核心（格兰迪）

• 批准号: 10006339
• 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/10006339
• 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; Pharmacology; Phenotype; Phosphotransferases; Physiological; Predisposition; Property; Protein Kinase; Proteins; Research; Sarcoplasmic Reticulum; Signal Transduction; Solid; Statistical Data Interpretation; Structure; Subcellular structure; Subgroup; System; Testing; Tissue Model; Tissues; Translations; United States; Variant; Ventricular; Ventricular Arrhythmia; Ventricular Fibrillation; Ventricular Tachycardia; beta-adrenergic receptor; calmodulin-dependent protein kinase II; 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; induced pluripotent stem cell; interpatient variability; kinetic model; models and simulation; novel; 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.

核心B：计算机建模总监：Eleonora Grandi博士(加州大学戴维斯分校) 项目摘要：计算核心将开发和应用多尺度力学模型， 模拟和统计方法作为提供信息、解释和扩展实验的预测性工具 项目1、2和3中的观测。我们的定量模型将跨越物理尺度和 需要不同的生物功能来机械地将HF诱导的重塑电生理与患者- 特定的临床表型。也就是说，我们将开发出生理上详细的电气、化学和机械 模型从单通道到全脏器尺度。定量计算方法将增强我们的 从机制上理解复杂和非线性反馈系统参与心律失常的发生和发展 维修。这些工具还将用于电子筛查和预测药物对不同基因的影响 背景以预测患者的药理学反应。以计算人口为基础的方法将是 用于确定影响特定心力衰竭患者或亚组药物疗效或失败的因素 患者和遗传性扩张型心肌病患者。核心B还将提供对人类多能干细胞研究结果的翻译 细胞源性心肌细胞(IPSC-CMS)和兔心肌细胞向成人心肌细胞的分化 硅胶建模和仿真中的通孔。