权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Multi-scale modeling to predict and refine genotype-to-phenotype relationships in mammals

用于预测和完善哺乳动物基因型与表型关系的多尺度建模

基本信息

批准号：
9789879
负责人：
DANIEL A BEARD
金额：
$ 7.8万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2018-09-21 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789879
关键词：
5&apos -Nucleotidase Accounting Adenine Nucleotides Affect Angiotensins Biological Assay Blood Pressure CRISPR/Cas technology Cardiac Cardiovascular Physiology Cardiovascular system Catecholamines Cells Chest Computer Simulation Congestive Heart Failure Data Device or Instrument Development Devices Discipline Echocardiography Endocrine Energy Metabolism Enzymes Evaluation Event Gene Deletion Gene Targeting Genes Genotype Heart Diseases Heart Hypertrophy Heart failure Human Genome Individual Kidney Knock-out Mammals Maps Mechanics Medicine Metabolic Metabolic dysfunction Modeling Molecular Molecular Genetics Mutation Myocardial Organ Organism Pathway interactions Pharmacology Phase Phenotype Physiological Physiology Plasma Purines Rattus Renin Reporting System Systems Biology Techniques Technology Testing Transgenic Organisms Validation Whole Organism Work base body system cardiovascular disorder risk computer framework constriction drug development enzyme activity genetic predictors genome analysis genome-wide improved knock-down models and simulation multi-scale modeling physiologic model predictive modeling purine metabolism simulation success therapeutic target tool

项目摘要

Abstract Tools and technology for multi-scale modeling of physiological systems have matured to the point where systems simulations are finding applications in drug development and predictive medicine. Indeed, disciplines of model-based drug development and systems pharmacology are beginning to impact all phases of drug development. Similarly, modeling and simulation are crucial tools for device development, and increasingly computational modeling is finding applications in simulation of the integration of physiological systems and device function. In this proposed project we will test and refine the ability of multi-scale systems physiology modeling to make specific predictions about the genotype-to-phenotype map in vertebrate organisms. Specifically, we will use an existing modeling and simulation framework (accounting for myocardial energy metabolism, cardiac mechanics, and whole-body cardiovascular systems dynamics) to predict the effects of knockouts of specific genes involved in purine metabolism on whole-body phenotype. These predictions will be tested using targeted gene knockdown using CRISPR/Cas9 technology in rat models. By testing and refining our ability to predict whole-body impacts of molecular genetic perturbations we will develop a uniquely powerful understanding of genotype-to-phenotype relationships in higher organisms. Validation of specific targets in purine metabolism will potentially point to an entirely new set of therapeutic targets in heart disease. More broadly, demonstration of the ability to make successful genotype-to-phenotype predictions has the potential to find broad applications in the field of quantitative systems pharmacology, potentially leading to far reaching applications.

摘要