Core (Grandi)

核心（格兰迪）

基本信息

批准号：
10249145
负责人：
Eleonora Grandi
金额：
$ 38.66万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
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/10249145
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

项目摘要

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：计算机建模主任：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机械模型，模拟和统计方法作为预测工具来告知、解释和扩展实验项目 1、2 和 3 中的观测结果。我们的定量模型将跨越物理尺度和将高频诱导的重构电生理学与患者的机制联系起来所需的多种生物功能特定的临床表型。也就是说，我们将开发生理学详细的电气、化学和机械从单通道到全器官尺度的模型。定量计算方法将增强我们的对参与心律失常产生和发生的复杂和非线性反馈系统的机械理解维护。这些工具还将应用于计算机筛选和预测药物对不同遗传的影响背景来预测患者的药理反应。基于人口的计算方法将是旨在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 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源性心肌细胞 (iPSC-CM) 和兔心室肌细胞至成人心室肌细胞通过计算机建模和仿真。