Problem Solving Environment for Modeling the Cell Cycle

在建立从细胞基因组到蛋白质组再到生理学的联系的过程中，科学家们遇到了许多具有挑战性的计算问题，其中最不为人所知的是“最后一步”，从相互作用的蛋白质的复杂网络到完整细胞的调节行为。这项提议的目的是改进从细胞内部分子机制得出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，使国际实验和计算生物学家能够接触到这些环境，并培训新一代科学家谈判分子细胞生物学的最后一步。我们的战略是与多个小组合作，为特定的应用(真核细胞中细胞分裂周期的调节)开发一个解决问题的环境，这些小组正在为“最后一步”的查询开发更通用的计算平台。我们打算创建第一个功能齐全的细胞周期建模环境，将先进的计算工具整合到数据挖掘、模型开发、模拟、动力系统理论、数据分析和参数估计中。我们的软件将可以在网上访问，在那里它将成为世界范围内研究哺乳动物细胞增殖调控的强大工具。然后，细胞周期问题解决环境可以作为特定于活细胞的信号、发育、运动和其他基本属性的其他环境的模板。该提案汇集了这一领域的一些主要参与者：细胞周期建模师(Tyson、Novak和Chen)，一个在高性能计算、解决问题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和Ramakrishnan)，Gepasi(弗吉尼亚生物信息研究所的Mendes)的作者，“虚拟细胞”团队(由康涅狄格州大学的勒夫领导)，以及一些杰出的合作者(Sible和Cross，实验细胞周期研究；Kitano和Bolouri，分子细胞生物学软件开发；Kohn，哺乳动物细胞周期控制生物信息学)。

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).