Core (Grandi)

核心（格兰迪）

基本信息

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
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/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

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：在计算机建模总监中：Eleonora Grandi Ph.D. （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，仿真和统计方法是用于告知，解释和扩展实验的预测工具项目1、2和3中的观察结果。我们的定量模型将跨越物理量表的范围和机械机械地将HF诱导的重塑电生理学与患者联系起来所需的多种生物学功能特定的临床表型。也就是说，我们将开发生理上详细的电气，化学和机械从单个通道到全器量表的模型。定量计算方法将增强我们的对心律失常产生涉及的复杂和非线性反馈系统的机械理解和维护。这些工具还将用于用于硅氧筛查和对不同遗传的药物影响的预测预测患者药理反应的背景。基于计算人群的方法将是构建以确定影响HF的特定患者或亚组的药物功效或失败的因素患者并继承DCM患者。核心B还将提供人类多能茎中发现的翻译细胞衍生的心肌细胞（IPSC-CMS）和兔心室心肌细胞至成年人类心室心肌细胞通过计算机建模和仿真。