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传导组件上，这些组件将每个输入路由到适当的输出。如何保持信号的特异性，使一个信号不会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通过相同的MAPK（促分裂原活化蛋白激酶）级联传递，尽管每一种都引起不同的反应。在这里，我们建议调查的动态和调节信号级联通过一个综合方案的数学和实验方法。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，重点是支架，空间动力学，特异性以及它们如何相互关联。我们的最终目标是开发一个理论框架，以了解如何正确的信号处理发生在高度互连的生化网络，并验证他们的详细建模和实验，重点是酵母MAPK系统。 作为实现这一目标的步骤，我们将首先开发具有共享组件的信号通路的通用表示，并在酵母MAPK系统中对其进行测试。在这种情况下，我们将严格解决支架和反馈调节如何产生特异性，以及限制和权衡是什么。然后，我们将包括空间动力学，并探讨具体的促进机制的实施。将探索从微观层次的模型，涉及空间之间的相互作用的支架和居民激酶的酵母MAPK系统的全面网络水平。我们计划通过进行选定的实验来测试我们从这种数学和计算分析中得出的结论和预测。定量分析将涉及控制理论和网络上的非线性常微分方程和偏微分方程的大系统。必须为分析和模拟开发新的数学理论和数值算法。

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.