Systems Biology of Cell Decision Processes

描述（由申请人提供）：生物系统的显著复杂性要求系统的分析方法。该提案的目标是建立一个麻省理工学院细胞决策过程卓越中心（CDP），围绕一个由细胞生物学家、计算机科学家和微系统工程师组成的跨学科团队，研究哺乳动物细胞中蛋白质网络和信号转导的系统生物学。CDP中心的基本假设是，理解细胞决策过程需要发展将定量严谨与分子细节相结合的网络模型。这些模型将是混合的，包含关键反应的高度具体表示和系统作为一个整体的抽象表示。有效的模型将以严格和可移植的形式持续并捕获知识的积累。CDP中心将遵循一种研究范式，在操作-测量-挖掘和建模的四步反馈循环中将系统实验和数值建模联系起来。该中心的生物学重点将是控制细胞凋亡的信号事件。我们将对凋亡网络中许多点的信号分子进行蛋白浓度、修饰状态和活性的测量。然后将使用从高度指定到高度抽象的几种建模方法对测量结果进行分析。为了收集足够的数据进行系统建模，CDP中心将自动化和标准化生化方法，开发紧凑的基于阵列的分析，并设计具有集成微流体和无标签传感器的新型微制造设备。为了组织和系统化数据，将开发支持严格推理方法的信息学方法。最后，物理-化学，结构-系统和贝叶斯模型将用于产生生物学假设进行实验验证。该中心的研究活动将由研究生和本科教育以及针对整个科学界，特别是为少数民族服务的机构的外联方案加以补充。

DESCRIPTION (provided by applicant): The remarkable complexity of biological systems demands a systematic approach to their analysis. The goal of this proposal is to establish an MIT Center of Excellence in Cell Decision Processes (CDP) around an interdisciplinary team of cell biologists, computer scientists and microsystems engineers tackling the systems biology of protein networks and signal transduction in mammalian cells. The basic hypothesis of the CDP Center is that understanding cell decision processes requires the development of network models that combine quantitative rigor with molecular detail. These models will be hybrids containing highly specific representations of critical reactions and abstract representations of the system as a whole. Effective models will endure and capture the accumulation of knowledge over time in a rigorous and portable format. The CDP Center will follow a research paradigm that links systematic experiments and numerical modeling in a four-step feedback loop of manipulation-measurement-mining and modeling. The biological focus of the Center will be the signaling events that control apoptosis. The measurement of protein concentrations, modification state and activity will be undertaken for signaling molecules at many points in the apoptotic network. The measurements will then be analyzed using several modeling approaches ranging from highly specified to highly abstract. To collect sufficient data for systematic modeling, the CDP Center will automate and standardize biochemical methods, develop compact array-based assays and design novel microfabricated devices with integrated microfluidics and label-free sensors. To organize and systematize the data, informatic methods will be developed that support rigorous approaches to inference. Finally, physico-chemical, structure-systems and Bayesian models will be used to generate biological hypotheses for experimental verification. The research activities of the CDP Center will be complemented by graduate and undergraduate education and by an outreach program targeted at the scientific community in general and minority-serving institutions in particular.