Model-based design for synthetic (micro)biology

基于模型的合成（微）生物学设计

• 批准号: RGPIN-2018-03826
• 负责人: Ingalls, Brian
• 金额: $ 4.97万
• 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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=654266
• 关键词: Model; based; design; synthetic; micro

My research program involves the development and analysis of computer models of cellular biology, to aid in investigations of cellular behaviours and for prediction of the effects of interventions. The proposed research involves applying this modelling approach to the biology of microbes. These unseen organisms have impact on major aspects of human activity, from food production to health, from the environment to manufacturing. We will use computer models to improve our understanding of the behaviour of individual microbial cells and of microbial populations, with the goal of enabling manipulation of microbes to benefit humanity. We propose research activities targeted toward three short-term aims:******Our first aim is to investigate strategies for manipulation of microbial populations in the environment by delivery of genetic elements that alter their behaviour. We are motivated by the possibility of suppressing populations of antibiotic resistant bacteria, either by rendering them antibiotic-susceptible, or by killing them outright. We will investigate the performance of a number of such manipulation strategies in laboratory populations, and will build computer models to consolidate our understanding of their behaviour and to provide predictions of performance in potential applications.******Our second aim is to develop computer models of interacting microbial populations. In most natural environments, microbes occur in ecologies consisting of large numbers of interacting species. The research community has only recently begun to understand the complexities of these assemblies. We have acquired video microscopy of simple two-species communities in the lab. By developing computer models of these interacting populations, we will be taking an important first step toward generating mechanistic descriptions of natural microbial ecologies. These descriptions will allow us to predict the effect of intervention in these systems toward improvements in health, agriculture, and the environment.******Our third aim takes advantage of light-sensing systems from photosynthetic microbes. These can be ‘re-wired' to allow control by light of a range of cellular activities. This ‘optogenetic' system allows unprecedented control of cellular activity by time-varying light inputs. We have built a computer-controlled light excitation system with which we can explore this system. Using a computer model, we will identify light inputs that provide maximum informativeness for probing cellular behaviours. We will then investigate the use of this system for temporal control in metabolic engineering, with the goal of improving efficiency in biomanufacturing of drugs and other useful chemicals. ******This work will result in improvements in our ability to manipulate microbes to our advantage, contributing to solving a range of pressing problems in health, agriculture, manufacturing, and the environment.

我的研究计划涉及细胞生物学计算机模型的开发和分析，以帮助细胞行为的调查和干预措施的影响的预测。拟议的研究涉及将这种建模方法应用于微生物生物学。这些看不见的生物对人类活动的主要方面产生影响，从食品生产到健康，从环境到制造业。我们将使用计算机模型来提高我们对单个微生物细胞和微生物种群行为的理解，目标是使微生物的操纵造福人类。我们提出了针对三个短期目标的研究活动：* 我们的第一个目标是研究通过传递改变其行为的遗传元素来操纵环境中微生物种群的策略。我们的动机是抑制抗生素耐药细菌种群的可能性，要么使它们对抗生素敏感，要么直接杀死它们。我们将研究一些这样的操作策略在实验室人群中的表现，并将建立计算机模型，以巩固我们对它们行为的理解，并提供对潜在应用中性能的预测。我们的第二个目标是开发相互作用的微生物种群的计算机模型。在大多数自然环境中，微生物存在于由大量相互作用的物种组成的生态系统中。研究界直到最近才开始了解这些组件的复杂性。我们已经在实验室获得了简单的两种群落的视频显微镜。通过开发这些相互作用的种群的计算机模型，我们将朝着生成自然微生物生态的机械描述迈出重要的第一步。这些描述将使我们能够预测干预这些系统对改善健康，农业和环境的影响。我们的第三个目标是利用光合微生物的感光系统。这些可以“重新布线”，以允许通过光控制一系列细胞活动。这种“光遗传学”系统允许通过时变光输入对细胞活性进行前所未有的控制。我们已经建立了一个计算机控制的光激发系统，我们可以探索这个系统。使用计算机模型，我们将识别光输入，为探测细胞行为提供最大的信息量。然后，我们将研究使用这个系统的时间控制代谢工程，以提高药物和其他有用的化学品的生物制造的效率的目标。** 这项工作将提高我们操纵微生物的能力，为解决健康，农业，制造业和环境中的一系列紧迫问题做出贡献。