The Principles of Regulatory, Conformational and Evolutionary Adaptation

项目摘要 生物体的一个标志是它们适应周围世界的能力。等 适应发生在空间和时间的许多不同尺度上。对细胞 在时间尺度上，单个细胞中的分子使它们能够调节代谢基因， 尽管碳源不断变化，经过几代人，细胞进化并适应 压力，如抗生素。在这里提出的工作中，我们将揭示 从分子到细胞再到群体的功能层次的适应。到 为了实现这一目标，我们的实验室将利用我们的传统， 测量与生物物理学理论对专门构建的生物系统。 我们的第一个研究重点是建立在这样一种认识上，即尽管取得了惊人的成功， 分子生物学和基因组科学在过去的半个世纪，我们仍然知道下一个 对基因是如何调控的一无所知，在基因组中超过65%的基因是如何调控的。 大肠杆菌E.大肠杆菌，这可以说是生物学上最好的理解， 有机体有了这个奖项，我们将创建第一个草案的调控基因组的 全E.大肠杆菌基因组-包括结合能和身份的每一个 转录因子及其调控的基因或操纵子。第二推力 重点是生物体对细胞内和环境的反应的关键方式 信号：通过个体变构蛋白和 蛋白质的组装，如在纺锤体中发现的负责染色体的蛋白质组装， 种族隔离使用我们开发的一个系统来精细地控制细胞运动 我们试图发现一个预测性的理论框架， 指导和约束我们如何看待装配和调整。我们的第三个推力 适应研究将建立在前两个线程，提供一个严格的 研究基因组和与之相互作用的蛋白质如何进化。的 具体的案例研究将集中在转录调控的演变与特殊的 强调病原菌对抗生素药物的反应。小区是 生物有机体的基本组织单位和这里提出的工作将 提供了一个关于细胞如何适应的深远而详细的观点。我们采用的方法是 最终生物物理;我们坚持我们的细胞分析是一次定量， 预测，尖锐我们的问题，加深我们的理解， 可以最终转化为改善人类健康的新策略。

Project Summary A hallmark of living organisms is their ability to adapt to the world around them. Such adaptation takes place across many different scales in both space and time. On cellular time scales, molecules in individual cells enable them to regulate metabolic genes and thrive despite changing carbon sources. Over generations, cells evolve and adapt to stresses such as antibiotics. In the work proposed here, we will uncover principles of such adaptation over the functional hierarchy from molecules to cells to populations. To achieve this goal, our laboratory will use our tradition of integrating precise measurements with biophysical theory on specifically constructed biological systems. Our first research thrust is built on the recognition that despite the amazing successes of molecular biology and genome science over the last half century, we still know next to nothing about how genes are regulated for more than 65% of the genes in the commensal gut bacterium E. coli, which is arguably biology's best-understood organism. With this award we will create a first draft of the regulatory genome for the entire E. coli genome - including the binding energies and identities of every transcription factor and the genes or operons that they regulate. A second thrust focuses on a key way that living organisms respond to intracellular and environmental signals: through conformational changes in individual allosteric proteins and in assemblies of proteins, such as those found in the spindle responsible for chromosome segregation. Using a system we developed to finely control cytoskeleton-motor interactions using light, we seek to discover a predictive theoretical framework that guides and constrains how we view assembly and adaptation. The third thrust in our study of adaptation will build upon the previous two threads by providing a rigorous examination of how genomes and the proteins that interact with them evolve. The specific case studies will focus on the evolution of transcriptional regulation with special emphasis on the response of pathogenic bacteria to antibiotic drugs. The cell is the fundamental organizational unit of living organisms and the work proposed here will provide a far-reaching but detailed view of how cells adapt. The approach we adopt is ultimately biophysical; we insist that our analysis of the cell be at once quantitative and predictive, sharpening our questions and deepening our understanding in a way that can ultimately be parlayed into new strategies for improving human health.