Specificity and Spatial Dynamics of Cell Signaling: The*

描述(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发送到适当的输出。如何保持信号的专一性，使AM信号不破坏另一个信号的反应？例如，在酵母中，交配、侵袭生长和渗透胁迫的信号都通过相同的MAPK(有丝分裂原激活蛋白激酶)级联传递，尽管每种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节。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路径，重点是脚手架、空间动力学、专一性以及它们之间的关系。我们的最终目标是开发一个理论框架，用于理解在高度互联的生化网络中如何进行适当的信号处理，并通过以酵母MAPK系统为重点的详细建模和实验来验证它们。 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系统中测试它们。在这种情况下，我们将严格解决脚手架和反馈监管如何产生特殊性，以及限制和权衡是什么。然后，我们将包括空间动力学，并探索专用性促进机制的实施。我们将探索从微观层次到酵母MAPK系统的完整网络层次的模型，这些模型涉及支架和驻留的激酶之间的空间相互作用。我们计划通过进行精选的实验来检验我们从这样的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组和偏微分方程组。必须开发新的数学理论和数值算法来进行分析和模拟。

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.