Unraveling the quantitative dynamics of cAMP-PKA signaling in yeast

项目总结 从细胞的蓝图开始，包括它的信号电缆的地图，我们现在面对 理解信号如何在这些电缆中流动和解密是一个巨大的挑战 蜂窝信息传输协议。 一个特别令人望而生畏的问题是，细胞经常使用共享路径(相同的电缆)来 传输不同的信号，但具有专门解释这些信号的精湛能力。 单元格如何对信息进行编码，然后高保真地解码，以优化共享 信号通道在很大程度上仍然是未知的。发现这些策略需要协同效应 在独一无二的多学科技术工具包、计算建模和高级 分辨率/高通量实验研究。使用蛋白激酶A(PKA)，以及 重要的生物信号中心，以及我们独特的多学科方法，我们将剖析 酿酒酵母中PKA通道编码不同输入的机制和 然后被下游转录因子和基因解码。我们将调查 这种信号编码和解码方案中的错误的影响，通过这样做，我们 将能够提取细胞用来绕过其信息的基本原则 传输瓶颈。从根本上说，这些调查将提供一个全面的 以及作为一个集成系统的PKA途径的动态运行的定量描绘， 并对其失效模式及其与细胞生理的关系进行了详细的概述。我们的 实验设计还将生成PKA与其余部分的连接性目录 蜂窝底盘。

PROJECT SUMMARY Starting from a blueprint of the cell, including a map of its signaling cables, we now face the monumental challenge of understanding how signals flow in these cables and deciphering cellular information transmission protocols. One particularly daunting problem is that cells often use shared pathways (the same cables) to transmit different signals, yet have an exquisite capacity to specifically interpret these signals. How cells encode information and then decode it with high fidelity to optimize the use of shared signaling channels remains largely unknown. Uncovering these strategies requires synergy between a unique multidisciplinary toolkit of technology, computational modeling, and high resolution/high throughput experimental investigations. Using Protein Kinase A (PKA), an important biological signaling hub, and our unique multidisciplinary approach, we will dissect the mechanisms by which different inputs are encoded by the PKA channel in S. cerevisiae and then decoded by downstream transcription factors and genes. We will investigate the repercussions of errors in such signal encoding and decoding schemes, and by doing so, we will be able to extract fundamental principles that cells use to circumvent their information transmission bottlenecks. Fundamentally, these investigations will provide a comprehensive and quantitative portrait of the dynamic operation of the PKA pathway as an integrated system, and a detailed synopsis of its failure modes and their connections to cellular physiology. Our experimental design will also generate a catalogue of the connectivity of PKA to the rest of the cellular chassis.