Specificity and Spatial Dynamics of Cell Signaling: The*

描述（由申请人提供）：在许多生物信号转导途径中，多个输入信号汇聚在一组共享的信号组件上，这些组件将每个输入路由到适当的输出。如何维持信号的特异性，使一个信号不破坏另一个信号的反应？例如，在酵母中，交配、侵入性生长和渗透胁迫的信号都是通过相同的MAPK（丝裂原激活蛋白激酶）级联传递的，尽管每个信号都会引起不同的反应。在这里，我们建议通过数学和实验方法的综合方案来研究信号级联的动力学和调控。我们将开发最先进的数学理论和计算工具来分析和模拟信号转导途径，重点是脚手架，空间动力学，特异性以及它们如何相互关联。我们的最终目标是建立一个理论框架，以理解在高度互联的生化网络中如何进行适当的信号处理，并通过对酵母MAPK系统的详细建模和实验来验证它们。

DESCRIPTION (provided by applicant): In many biological signal transduction pathways, multiple input signals converge on a shared set of signaling components, which route each input to the appropriate output. How is signaling specificity maintained so that am signal does not corrupt the response of another? For example in yeast, the signals for mating, invasive growth, and osmotic stress are all funneled through the same MAPK (Mitogen Activating Protein Kinase) cascade although each elicits a different response. Here we propose to investigate the dynamics and regulation of signaling cascades through an integrated program of mathematical and experimental approaches. We will develop state-of-the-art mathematical theory and computational tools to analyze and simulate signal transduction pathways, with an emphasis on scaffolding, spatial dynamics, specificity, and how they relate to one another. Our ultimate goal is to develop a theoretical framework for understanding how proper signal processing occurs in highly interconnected biochemical networks and to validate them by detailed modeling and experimentation focusing on the yeast MAPK system. As steps toward this goal, we will first develop generic representations of signaling pathways with shared components and test them in the yeast MAPK system. In this setting, we will rigorously address how scaffolds and feedback regulation can give rise to specificity and what are the limits and tradeoffs. Then, we will include spatial dynamics and explore the implementation of specificity-promoting mechanisms. A hierarchy of models from microscopic levels involving spatial interplay between the scaffold and the resident kinases to a full-scale network level for the yeast MAPK system will be explored. We plan to test our conclusions and predictions from such mathematical and computational analysis by performing selected experiments. The quantitative analysis will involve control theory and large systems of nonlinear ordinary and partial differential equations on networks. New mathematical theories and numerical algorithms will have to be developed for the analysis and simulations.