Infrastructure for Multi-cellular Human Metabolic Models

描述（由申请人提供）：随着人类基因组计划的完成和高通量技术的最新进展，目前正在进行的大部分工作是寻找序列上的所有功能元件，并创建计算工具来分析和解释大量可用数据。这种压倒性的信息量以及生物系统的复杂性创造了对计算机建模和模型驱动系统生物学发展的需求。这些组分形成的反应网络的重建允许计算机模型的制定。投资于我们使用基于约束的方法建模微生物细胞的成功，我们打算评估建立第一个人类细胞基因组规模代谢模型的科学和计算可行性。我们将建立两个细胞特异性代谢模型，测试和表征它们，并定义与建立多细胞代谢模型相关的问题。鉴于代谢参与人类疾病的普遍性，这一努力既及时又具有重要意义。整合的序列注释，剪接变异体的关联关系，数据表示和计算的问题将在这个项目完成后解决。这一提议的成功将为开发人类代谢的综合模型奠定基础，这对药物发现和开发工作非常有价值，并有可能推动治疗研究的进程。

DESCRIPTION (provided by applicant): With the completion of the human genome project and recent advances in high throughput technologies, much of the ongoing effort is now to find all the functional elements on the sequence and to create computational tools to analyze and interpret the large volume of data available. This overwhelming amount of information together with the complexity of biological systems has created a need for in silico modeling and the development of model-driven systems biology. The reconstruction of the reaction networks that these components form allows for the formulation of in silico models. Investing on our success in modeling microbial cells using constraints-based approach, we intend to assess the scientific and computational feasibility of building the first genome-scale metabolic model for human cells. We will build two cell-specific metabolic models, test and characterize them, and define the issues associated with building multi-cellular metabolic models. Given the prevalence of metabolic involvement in human disease, this effort is both timely and of great significance. The integration of the sequence annotation, the association relationships for splice variants, data representation and computational issues will be addressed at the completion of this project. Success of this proposal would build the foundation for the development of a comprehensive model of human metabolism that would be extremely valuable for drug discovery and development efforts and has the potential to drive the process of therapeutic research.