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

摘要 用于生理系统的多尺度建模的工具和技术已经成熟到 系统模拟在药物开发和预测医学中得到了应用。的确，纪律 基于模型的药物开发和系统药理学正在开始影响药物的所有阶段 发展。同样，建模和仿真是设备开发的关键工具，而且越来越多 计算建模在生理系统和生物系统集成的模拟中得到了应用 设备功能。在这个拟议的项目中，我们将测试和提炼多尺度系统生理学的能力 对脊椎动物的基因-表型图谱进行特定预测的建模。 具体地说，我们将使用现有的建模和仿真框架(考虑心肌能量 新陈代谢、心脏力学和全身心血管系统动力学)来预测 参与嘌呤代谢的特定基因敲除对全身表型的影响。这些预测将是 在大鼠模型上使用CRISPR/Cas9技术进行靶向基因敲除测试。通过测试和提炼 我们能够预测全身分子遗传扰动的影响，我们将开发出一种独一无二的强大 了解高等生物体中的基因型与表型的关系。验证中的特定目标 嘌呤代谢可能会指向心脏病的一套全新的治疗靶点。更多 从广义上讲，成功进行基因到表型预测的能力的证明有可能 在定量系统药理学领域找到广泛的应用，潜在地导致深远的影响 申请。

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.