The Virtual Physiological Rat Project

描述（由申请人提供）：许多疾病（包括心脏病、糖尿病、癌症和帕金森病等神经系统疾病）不能用单因/单效关系来理解。这是因为，尽管我们对基础生理学有了深入的了解，并且从疾病的动物模型中获得了大量的生理和基因组数据，但我们对多种基因和环境因素如何相互作用来决定表型缺乏了解。我们建议基于大鼠生理功能的系统多尺度测量、模拟和分析，彻底改变我们对复杂表型和疾病的理解。具体来说，我们建议启动虚拟生理大鼠项目，开发计算工具来捕获潜在的系统生理学以及与疾病相关的病理生理扰动。这些工具将根据大鼠多种器官系统生理功能的实验特征进行开发和验证，以显示相关的疾病表型。计算机模拟将用于整合不同的数据（基因组、解剖学、生理学等）来解释和预测功能，并将动物模型的发现转化为人类特定相关复杂疾病的新信息，包括高血压、肾病、心力衰竭和代谢综合征。建立的多尺度生理模型将与基因型-表型参数图相结合，构建虚拟生理大鼠资源，用于预测遗传变异和环境因素对表型的影响，并预测实验衍生和表征的新菌株的表型。通过系统和迭代地使用多尺度计算模型来分析数据，产生假设，设计实验，并预测新的大鼠菌株的表型，我们将获得预测和理解复杂性状出现的能力。除了拟议的科学研究的直接影响外，VPR中心还将通过为心血管系统研究提供独特的软件和相关数据，为更广泛的社区提供资源。此外，我们将开发课程、研讨会和相关的教育材料，培训和招募来自服务不足社区的科学家，并为附属和非附属调查人员举行年度科学会议。

DESCRIPTION (provided by applicant): Many diseases (including heart disease, diabetes, cancer, and neurological disorders such as Parkinson's disease) cannot be understood in terms of single-cause/single-effect relationships. This is because although there exist both a depth of knowledge of basic physiology and a host of physiological and genomic data from animal models of disease, we lack an understanding of how multiple genes and environmental factors interact to determine phenotype. We propose to revolutionize our understanding of complex phenotypes and diseases based on systematic multi-scale measurement, simulation, and analysis of physiological function in the rat. Specifically, we propose to initiate The Virtual Physiological Rat Project to develop computational tools to capture the underlying systems physiology as well as the pathophysiological perturbations associated with disease. These tools will be developed and validated based on experimental characterization of physiological function across a number of organ systems in rat strains engineered to show relevant disease phenotypes. Computer simulation will be used to integrate disparate data (genomic, anatomic, physiological, etc.) to explain and predict function, and to translate the findings from animal models to yield new information on specific interrelated complex diseases in humans, including hypertension, kidney disease, heart failure, and metabolic syndrome. The developed multi-scale physiological models will be linked to genotype- phenotype parametric maps to construct a Virtual Physiological Rat resource, which will be used to predict the influence of genetic variability and environmental factors on phenotypes and to predict phenotypes of new strains that will be experimentally derived and characterized. By systematically and iteratively using multi-scale computational models to analyze data, generate hypotheses, design experiments, and predict phenotypes in novel strains of rat, we will attain the capability to predict and understand the emergence of complex traits. In addition to the direct impact of the proposed scientific studies, the VPR Center will be a resource to the broader community by delivering unique software and associated data for cardiovascular systems research. In addition, we will develop courses, workshops, and related educational material, train and recruit scientists from underserved communities, and hold annual scientific meetings for affiliated and nonaffiliated investigators. RELEVANCE: Despite a depth of knowledge of basic cardiovascular physiology, we lack even a rudimentary understanding of how multiple genes and environmental factors interact to determine cardiovascular phenotype. This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship.