Experimental and Theoretical Characterization of Metabolic Coordination

在这个项目中，PI将使用实验和理论相结合的方法来重新研究分子生物学中深入研究的系统之一-分解代谢抑制。 这是一种普遍的现象，其中微生物生长在“良好”（即，快速生长的）碳源如葡萄糖抑制消耗“贫”（缓慢生长的）碳所需的蛋白质的合成。尽管在分子水平上对细菌E.然而，对于大肠杆菌的“大图景”仍然缺乏：特别是，这种调节系统是什么，细胞如何感知碳源的质量？基于许多惊人的初步发现，PI假设分解代谢物抑制的生理功能的完全不同的图片，其在协调碳代谢与其他营养源（例如，氮和硫），而不是控制碳代谢的层次。PI将通过定量表征一系列关键突变体在各种碳限制和氮限制条件下参与碳和氮代谢的酶的表达来建立新的图像，特别注意不同生长条件下生长速率的变化。 结果将通过PI实验室最近开发的指数增长现象学理论进行分析。 这项研究计划将建立一种新的现象学方法来研究基因调控和代谢，这种方法涉及很少的参数，因此具有预测性。这种方法的简单性将使传统生物学训练的学生能够抓住定量物理推理的本质，并使物理学训练的学生能够在生理学的背景下学习生物系统。这项研究的结果将对代谢调节的主题以及更广泛的定量生物学领域产生强大的变革性影响。 由于分解代谢物阻遏在分子生物学发展中所起的历史作用，对这一经典主题的理解的重大修订也将在生物学界的其他部分得到广泛关注。它们将有助于定量现象学方法的使用，这种方法在阐明复杂的物理系统方面非常有效，但迄今为止在生物分子系统的研究中的应用非常有限。研究成果将被纳入PI的“定量生物学”年度课程和PI组织的夏季研讨会，以向物理科学家介绍定量生物学。该项目由物理学部的生命系统物理学计划和MCB的生物分子动力学，结构和功能共同支持。

In this project, the PI will use a combination of experimental and theoretical approaches to revisit one of the intensively studied systems in molecular biology-catabolic repression. This is a widespread phenomenon whereby microorganisms grown in "good" (i.e., fast-growing) carbon sources such as glucose inhibit the synthesis of proteins needed for the consumption of "poor" (slow-growing) carbons. Despite a tremendous amount of knowledge characterized for this phenomenon at the molecular level for the bacterium E. coli, the "big picture" is still missing: In particular, what is this regulatory system for and how does the cell sense the quality of a carbon source? Based on a number of striking preliminary findings, the PI hypothesizes a radically different picture for the physiological function of catabolite repression, with its predominant role in coordinating the metabolism of carbon with other nutrient sources (e.g., nitrogen and sulfur), rather than in controlling the hierarchy of carbon metabolism. The PI will establish the new picture by quantitatively characterizing the expression of enzymes involved in carbon and nitrogen metabolism for a series of key mutants, under a variety of carbon-limiting and nitrogen-limiting conditions, paying special attention to changes in growth rates in the different growth conditions. The results will be analyzed by a phenomenological theory of exponential growth developed recently by the PI's lab. This research program will establish a new phenomenological approach to studying gene regulation and metabolism, an approach that involves very few parameters and is hence predictive. The simplicity of the approach will allow students with traditional biology training to grab the essence of quantitative physical reasoning, and allow students with physics training to learn a biological system in the context of physiology. The results of this research will exert a strong, transformative impact on the subject of metabolic regulation and more broadly on the field of quantitative biology. Due to the historical role catabolite repression played in the development of molecular biology, major revision in the understanding of this classic subject will also be noted broadly in other parts of the biology community. They will lend weight to the use of quantitative phenomenological approaches, which are very effective in elucidating complex physical systems but have so far seen very limited use in the study of biomolecular systems. Research output will be integrated into the PI's annual course on "quantitative biology", and the summer workshops the PI organizes for introducing physical scientists to quantitative biology.This project is being supported jointly by the Physics of Living Systems Program in the Physics Division and by Biomolecular Dynamics, Structure and Function in MCB.