Problem Solving Environment for Modeling the Cell Cycle

在将细胞基因组、蛋白质组和生理学联系起来的过程中，科学家们遇到了许多具有挑战性的计算问题，其中最不容易理解的是“最后一步”，即从相互作用的蛋白质的复杂网络到完整细胞的受调节行为。本提案的目的是改进从内部分子机制中推导细胞生理学的计算工具，将这些工具整合到有效的“解决问题的环境”中，使这些环境可供国际实验和计算生物学家使用，并培训新一代科学家在分子细胞生物学的最后一步进行谈判。我们的策略是为特定的应用（真核生物细胞分裂周期的调节）开发一个解决问题的环境，与一些团队合作，他们正在研究更通用的计算平台，用于“最后一步”的查询。我们打算为细胞周期建模创建第一个功能齐全的环境，结合数据挖掘，模型开发，仿真，动力系统理论，数据分析和参数估计方面的复杂计算工具。我们的软件将可以在网上访问，在那里它将作为一个强大的工具，为全世界的研究团体研究哺乳动物细胞增殖的调节。然后，细胞周期问题解决环境可以作为其他环境的模板，这些环境与活细胞的信号、发育、运动和其他基本特性有关。该提案汇集了这个领域的一些主要参与者：细胞周期建模者（Tyson， Novak和Chen），一个在高性能计算，问题解决环境和数据挖掘方面经验丰富的计算机科学家团队（Watson, Shaffer, Kafura, Ramakrishnan）， Gepasi的作者（弗吉尼亚生物信息学研究所的Mendes），“虚拟细胞”团队（在康涅狄格州大学的勒夫领导下），以及一些杰出的合作者(Sible和Cross，实验细胞周期研究；Kitano和Bolouri，分子细胞生物学的软件开发；和Kohn，哺乳动物细胞周期控制的生物信息学)。

In making connections from cellular genome to proteome to physiology, scientists have run up against many challenging computational problems, of which the least well understood is the "last step," from complex networks of interacting proteins to the regulated behavior of intact cells. The purpose of this proposal is to improve the computational tools for deriving the physiology of a cell from its internal molecular machinery, to integrate these tools into effective "problem-solving environments," to make these environments accessible to the international community of experimental and computational biologists, and to train a new generation of scientists in negotiating the last step of molecular cell biology. Our strategy is to develop a problem-solving environment for a specific application (regulation of the cell division cycle in eukaryotes), in collaboration with a number of groups who are working on more general computational platforms for "last-step" inquiries. We intend to create the first, fully functional environment for cell cycle modeling, incorporating sophisticated computational tools in data mining, model development, simulation, dynamical systems theory, data analysis and parameter estimation. Our software will be web-accessible, where it will serve as a powerful tool for the worldwide research community studying the regulation of mammalian cell proliferation. The cell-cycle problem-solving environment can then serve as a template for other environments specific to signaling, development, movement, and other basic properties of living cells. The proposal brings together some of the principal players in this arena: cell cycle modelers (Tyson, Novak and Chen), a team of computer scientists experienced in high-performance computing, problem-solving environments, and data mining (Watson, Shaffer, Kafura, Ramakrishnan), the author of Gepasi (Mendes at the Virginia Bioinformatics Institute), the "Virtual Cell" team (under Loew at U. Conn.), and some outstanding collaborators (Sible and Cross, experimental cell cycle research; Kitano and Bolouri, software development for molecular cell biology; and Kohn, bioinformatics of mammalian cell cycle controls).