Feedback regulation and transcirptional coupling in bacterial stress-response

描述（由申请人提供）：活细胞的一个关键特性是它们能够以特定的生化反应对内部或外部刺激作出反应。细菌已经进化到通过基因表达的变化来感知和快速适应环境刺激。调节这些反应的应激反应网络的分子细节已经被许多模式细菌发现。然而，我们仍然缺乏跨物种的这些反应的网络水平的知识，这是必要的，以获得更深入的了解细胞功能，并最好地应用与模型细菌获得的结果，致病性细菌物种，是不好的特点或不能在实验室培养。在这个应用程序中，我们专注于两个常见的基本构建块的细菌压力反应网络：两个组件系统和替代西格玛因子网络。结合理论，计算和实验方法，我们的多学科团队将探索网络组织的两个重要方面-由于转录自动调节和网络基因在同一操纵子中的共转录的反馈回路。具体目的是（SA 1）了解来自单个操纵子的细菌基因的共表达与相应网络的信息处理中的随机性之间的关系，以及（SA 2）评估反馈调节在交替西格玛因子和双组分系统网络中的作用。对于每一个具体目标，研究计划将包括三个基本组成部分：（1）制定和分析生物药理学上现实的，但分析易处理的模型的主调节模块的压力反应网络，（2）模拟和分析的详细模型的特定网络的模式生物分枝杆菌耻垢分枝杆菌，和（3）实验测试的预测在M。恶臭这将导致理论/模型和实验之间的迭代和协同反馈。所提出的工作的结果预计将揭示新的进化设计原则，其特征在于网络结构和细菌物种之间的动态性能之间的关系，这对于操纵自然发生的网络和设计合成基因电路至关重要。

DESCRIPTION (provided by applicant): A key property of living cells is their ability to react to internal or external stimuli with specific biochemical responses. Bacteria have evolved to sense and rapidly adapt to environmental stimuli by changes in gene expression. Molecular details of the stress response networks regulating these responses have been uncovered for many model bacteria. However, we still lack network-level knowledge of these responses across species, which is necessary to obtain a deeper understanding of cellular functions and to best apply results obtained with model bacteria to pathogenic bacterial species that are poorly characterized or cannot be cultured in a laboratory. In this application we focus on two of the common basic building blocks of bacterial stress-response networks: two-component systems and alternative sigma-factor networks. Combining theoretical, computational and experimental approaches, our multi-disciplinary team will explore two important aspects of network organization - feedback loops due to transcriptional autoregulation and co-transcription of network genes in the same operon. The Specific Aims are (SA1) To understand the relationship between co-expression of bacterial genes from a single operon and stochasticity in information processing of the corresponding networks and (SA2) To assess the role of feedback regulation in alternative sigma factor and two-component system networks. For each Specific Aim the research plan will involve three essential components: (1) formulation and analysis of biophysically realistic but analytically tractable models of master-regulation modules of stress-response networks, (2) simulations and analysis of detailed models of particular networks in the model organism Mycobacterium smegmatis, and (3) experimental tests of predictions in M. smegmatis. This will lead to iterative and synergistic feedback between theories/models and experiments. The results of the proposed work are expected to reveal novel evolutionary design principles characterizing relationships between network architecture and dynamical performance across bacterial species, which are essential for the manipulation of naturally occurring networks and for designing synthetic gene circuits.