Exploiting bacterial growth laws to characterize indirect mechanisms for generating phenotypic heterogeneity from isogenic populations

利用细菌生长规律来表征从同基因群体产生表型异质性的间接机制

• 批准号: 372011-2011
• 负责人: Scott, Matthew
• 金额: $ 2.49万
• 依托单位: University of Waterloo
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=572853
• 关键词: Exploiting; bacterial; growth; laws; characterize

From the time of Jacob and Monod, a dominant theme running through microbiology and bacterial physiology is the idea that the information encoded in DNA can be connected to the physiological state of the organism through a multi-scale assembly of simple elements: the gene within an operon, the operon within a network and the network within the cell. This bottom-up approach to the understanding (and, more recently, the synthesis) of genetic networks is analogous to the engineering principles of electrical circuit design - a fruitful analogy that has lead to significant conceptual advances particularly in the burgeoning field of systems biology. But the limitation of this analogy is, of course, that electrical circuits do not grow and divide. There is an increasing appreciation that genetic networks must be understood within the context of the growing organism; that core metabolic processes leading to rapid cell proliferation impose constraints on gene expression involved in auxiliary tasks. Recently, I have uncovered empirical relationships (called 'growth laws') that allow the interdependence between growth-rate and gene expression to be understood quantitatively. In the present proposal, I examine the consequences of these growth laws, specifically as a mechanism for generating distinct sub-populations in a culture that shares identical DNA. With focus on a simple synthetic inducible protein-expression system in Escherichia coli, I propose to determine the extent to which growth-mediated feedback effects are responsible for establishing observed phenotypic heterogeneity. The results of the investigation have immediate implications for the industrial optimization of protein expression systems to synthesize expensive therapeutics in bacteria, and for the treatment of virulent bacterial infections. In a broader context, the study highlights the importance of a holistic view of the regulation of gene expression in bacteria, where cell growth and protein synthesis are intimately interconnected, and provides insight into a new class of gene regulation through indirect feedback.

从雅各布和莫诺的时代开始，贯穿微生物学和细菌生理学的一个主导主题是，DNA中编码的信息可以通过简单元素的多尺度组装与生物体的生理状态联系起来：操纵子中的基因，网络中的操纵子和细胞内的网络。这种自下而上的理解（以及最近的合成）遗传网络的方法类似于电路设计的工程原理--这是一个富有成效的类比，导致了重大的概念进步，特别是在新兴的系统生物学领域。但这个类比的局限性在于，电路不会生长和分裂。 人们越来越认识到，必须在生长的有机体的背景下理解遗传网络;导致细胞快速增殖的核心代谢过程对参与辅助任务的基因表达施加了限制。最近，我发现了经验关系（称为“增长定律”），允许增长率和基因表达之间的相互依赖关系被定量理解。在本提案中，我将研究这些生长定律的后果，特别是作为一种在共享相同DNA的文化中产生不同亚群的机制。 专注于一个简单的合成诱导蛋白表达系统在大肠杆菌中，我建议确定在何种程度上生长介导的反馈效应负责建立观察到的表型异质性。研究结果对蛋白质表达系统的工业优化具有直接影响，以在细菌中合成昂贵的治疗剂，并用于治疗毒性细菌感染。在更广泛的背景下，该研究强调了细菌基因表达调控的整体观点的重要性，其中细胞生长和蛋白质合成密切相关，并通过间接反馈提供了对一类新的基因调控的见解。