Multi-Cellular Metabolic Modeling

描述(申请人提供)：在Genomatica，我们开发了一个新的技术平台，称为SimPheny，它能够有效地开发基因组规模的新陈代谢模型，并使用基于约束的建模方法进行模拟。在该SBIR计划的第一阶段，我们展示了将我们的建模方法从单细胞微生物网络扩展到多细胞人体新陈代谢的科学和技术可行性，该模型使用了人类脂肪细胞(脂肪细胞)和肌肉细胞(肌肉细胞)的集成双细胞模型。使用重建的多细胞模型，我们计算了SimPheny中两种细胞类型的整合功能，并提出了可以通过实验验证的假设，增加了我们对人类代谢和生理的理解。基于我们在SimPheny中对多细胞人体新陈代谢建模的初步成功以及市场对电子建模和数据集成平台日益增长的需求，我们启动了一个3-5年计划，以开发一个用于对高等真核生物进行建模的计算平台，并构建针对细胞、组织和疾病的针对人类新陈代谢的模型。作为这一长期计划的一部分，我们寻求开发一个计算基础设施和生物学内容，用于在这个第二阶段SBIR计划中重建和建模集成的多细胞人类网络。这一第二阶段提案的总体目标是开发一个数据集成和计算软件平台，以及一个全面的人体新陈代谢数据库，其中包括注释的人类基因、蛋白质和代谢途径。成功完成这一二期计划后，我们将拥有在SimPheny软件平台内进行内容管理、数据分析和高通量数据可视化的完整基础设施，以及用于人类代谢的全面网络信息概要，以及用于脂肪细胞-心肌细胞代谢的基于扩展基因组的集成多细胞模型。该提案中开发的基础设施和内容将使我们能够在未来与学术、生物技术和制药研究小组合作开发特定于组织和疾病的模型。

DESCRIPTION (provided by applicant): At Genomatica, we have developed a novel technology platform, called SimPheny that enables the efficient development of genome-scale models of metabolism and their simulation using a constraint-based modeling approach. In the Phase I of this SBIR program, we demonstrated the scientific and technical feasibility of extending our modeling approach from single-cell microbial networks to multi-cellular human metabolism using an integrated two-cell model of human adipocyte (fatty cell) and myocyte (muscle cell). Using the reconstructed multi-cellular model, we computed the integrated function of the two cell types in SimPheny and formulated hypotheses that may be verified experimentally and increase our understanding of human metabolism and physiology. Based on our initial success with modeling multi-cellular human metabolism in SimPheny and the growing market demand for in silico modeling and data integration platform, we have initiated a 3-5 year plan to develop a computational platform for modeling higher eukaryotes and to construct cell-, tissue-, and disease-specific models for human metabolism. As a part of this long-term plan, we seek to develop a computational infrastructure and biological content for reconstructing and modeling integrated multi-cellular human networks in this Phase II SBIR program. The overall goal of this Phase II proposal is to develop a data-integration and computational software platform and a comprehensive database for human metabolism that accounts for the annotated human genes, proteins, and metabolic pathways. Upon the successful completion of this Phase II proposal, we will have a complete infrastructure for content management, data analysis, and visualization of high throughput data within SimPheny software platform and a comprehensive compendium of network information for human metabolism, as well as an expanded genome based integrated multi-cellular model for adipocyte-myocyte metabolism. The infrastructure and content developed in this proposal will enable us to develop tissue- and disease-specific models in collaboration with academic, biotechnology, and pharmaceutical research groups in the future.