The Principles of Regulatory, Conformational and Evolutionary Adaptation

项目摘要 活着的有机体的一个标志是它们适应周围世界的能力。是这样的 适应在空间和时间上发生在许多不同的尺度上。关于蜂窝 时间尺度，单个细胞中的分子使它们能够调节代谢基因和 尽管碳源不断变化，但仍能茁壮成长。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，我们将揭示以下原则 这种适应跨越了从分子到细胞再到种群的功能层次。至 为了实现这一目标，我们的实验室将利用我们集成精密 用生物物理理论对特定构建的生物系统进行测量。 我们的第一个研究重点是认识到，尽管取得了惊人的成就 在过去半个世纪的分子生物学和基因组科学中，我们仍然知道接下来 关于超过65%的基因是如何被调控的 共生肠道细菌大肠杆菌，可以说是生物学上最了解的 有机体。有了这个奖项，我们将为 整个大肠杆菌基因组-包括每个基因的结合能和身份 转录因子及其调控的基因或操纵子。第二次冲刺 重点关注生物对细胞内和环境做出反应的关键方式 信号：通过个别变构蛋白的构象变化 蛋白质的集合，如在负责染色体的纺锤体中发现的那些蛋白质 种族隔离。使用我们开发的系统来精细控制细胞骨架马达 利用光的相互作用，我们试图发现一种预测性的理论框架 指导和约束我们看待装配和适应的方式。我们的第三个推动力 适应研究将建立在前两条线索的基础上，通过提供严格的 研究基因组及其相互作用的蛋白质是如何进化的。这个 具体的案例研究将集中在转录调控的演变和特殊的 强调病原菌对抗生素药物的反应。该单元格是 生物有机体的基本组织单位和这里提出的工作将 为细胞如何适应提供了一个影响深远但详细的视图。我们采取的方法是 归根结底是生物物理学；我们坚持我们对细胞的分析既是定量的，也是 预测，尖锐我们的问题，加深我们的理解，以一种 最终可被用于改善人类健康的新战略。

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.