kinetic Flux Balance Analysis (kFBA) Framework to Simulate Multi-Cell Metabolism

描述（由申请人提供）：摘要随着高通量技术的进步和越来越多的临床数据，通过公共倡议和生物制药公司内变得可用，有一个立即和迫切需要开发计算工具来分析和理解这些数据，并与最终目标预测全身对环境和遗传变化的反应。为了开发一个全面的人体代谢建模平台，需要一个集成的动态和稳态框架来建模全身和细胞内水平的代谢。为了理解和表征这种复杂的生物系统，已经开发了通常属于两类的计算模型，自上而下或自下而上模型。虽然这些方法，本身，不提供一个准确的表示复杂的动态生物系统，在这个建议中，我们试图整合自上而下和自下而上的方法来模拟动态人体生理条件的混合动态/稳态框架的发展。我们已经开发了一个集成的动力学FBA建模框架，允许将临床数据与细胞内代谢网络分析相结合。该方法利用动力学速率方程参数和输入营养物浓度来计算动态细胞内代谢物浓度。使用软件技术平台SimPhenyTM，我们已经重建了肝细胞、脂肪细胞和肌细胞的代谢网络。此外，肝细胞和脂肪细胞的集成模型的开发用于表征不同的生理条件，并导致生成可通过实验研究的可检验假设。对开发综合动力学FBA方法和应用于多细胞模型框架的科学和计算可行性的评估将是迈向人类疾病研究和药物开发综合代谢建模平台的重要一步。公共卫生相关性：随着高通量技术的进步和越来越多的临床数据通过公共倡议和生物制药公司变得可用，迫切需要开发计算工具来分析和理解这些数据，最终目标是预测全身对环境和遗传变化的反应。在这个建议中，我们试图通过开发一个混合动态/稳态框架来模拟动态人体生理条件。评估开发综合动力学通量平衡分析（FBA）方法和应用于多细胞模型框架的科学和计算可行性将是迈向人类疾病研究和药物开发综合代谢建模平台的重要一步。

DESCRIPTION (provided by applicant): Abstract With the advancements in high throughput technologies and a growing volume of clinical data that is becoming available through public initiatives and within biopharmaceutical companies, there is an immediate and imperative need for developing computational tools to analyze and understand this data and with the ultimate aim to predict the whole body response to environmental and genetic changes. To develop a comprehensive platform for modeling human metabolism, an integrated dynamic and steady state framework is required for modeling metabolism at the whole-body and intracellular level. To understand and characterize such complex biological systems, computational models have been developed that fall generally within two categories, top-down or bottom-up models. While these approaches, by themselves, do not provide an accurate representation of complex dynamic biological systems, in this proposal, we seek to integrate the top-down and bottom-up approach to simulate the dynamic human physiological conditions by development of a hybrid dynamic/steady state-framework. We have developed an integrated kinetic FBA modeling framework that allows for the integration of clinical data with intracellular metabolic network analysis. This approach utilizes kinetic rate equation parameters and input nutrient concentrations to calculate dynamic intracellular metabolite concentrations. Using the software technology platform SimPhenyTM, we have reconstructed metabolic networks for hepatocyte, adipocyte and myocyte. In addition, the development of an integrated model of hepatocyte and adipocyte was used to characterize in distinct physiological conditions and resulted in the generation of testable hypotheses that can be investigated experimentally. The assessment of the scientific and computational feasibility of developing an integrated kinetic FBA approach and application to a multi-cell model framework will be an important step towards a comprehensive metabolic modeling platform in human disease research and drug development. PUBLIC HEALTH RELEVANCE: With the advancements in high throughput technologies and a growing volume of clinical data that is becoming available through public initiatives and within biopharmaceutical companies, there is an immediate and imperative need for developing computational tools to analyze and understand this data and with the ultimate aim to predict the whole body response to environmental and genetic changes. In this proposal, we seek to simulate the dynamic human physiological conditions by development of a hybrid dynamic/steady state-framework. The assessment of the scientific and computational feasibility of developing an integrated kinetic Flux Balance Analysis (FBA) approach and application to a multi-cell model framework will be an important step towards a comprehensive metabolic modeling platform in human disease research and drug development.