Adding an environment and motility in a Whole Cell Model of Escherichia Coli

在大肠杆菌的全细胞模型中添加环境和运动性

• 批准号: 10396393
• 负责人: Eran Agmon
• 金额: $ 7.05万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396393
• 关键词: Accounting; Automobile Driving; Bacteria; Behavior; Binding; Biological Models; Biological Process; Carrier Proteins; Cell Cycle; Cell model; Cell physiology; Cells; Chemoreceptors; Chemotaxis; Communities; Complex; Computer Models; Computer software; Energy Metabolism; Environment; Escherichia coli; Exhibits; Flagella; Foundations; Future; Gene Expression; Genetic; Glucose; Glucose Transporter; Goals; Growth; Individual; International; Mechanics; Metabolism; Methodology; Methylation; Modeling; Molecular; Motor; Motor Activity; Motor output; Nutrient; Phenotype; Population; Process; Production; Proteins; Proteomics; Reaction; Regulator Genes; Resources; Rotation; Running; Scientist; Secure; Sensory; Signal Transduction; Signaling Protein; Software Engineering; Techniques; Testing; Time; Training; Transmembrane Transport; Universities; Work; base; cell behavior; cell motility; cost; demethylation; in silico; information processing; kinetic model; large datasets; metabolomics; models and simulation; molecular modeling; monomer; protein expression; sensory input; simulation; symporter; transcriptomics; uptake

PROJECT SUMMARY This proposal focuses on extending a large-scale “whole-cell” model (WCM) of Escherichia coli (wcEcoli) to include a bacterial micro-environment and cell motility. wcEcoli is developed at the Covert lab at Stanford University, and was recently released to an international community of scientists. The specific aims of this application outline a plan to multi-scale the WCM, to introduce a simulated spatial environmentsthat can include other cells -- this will lead to the very first whole-colony simulations. A cell’s environment significantly impact its growth, division, and its overall phenotype throughout both a single cell cycle and evolutionary timescales. By accounting for these influences, the extensions proposed here will open up a new domain for whole-cell modeling that can examine cellular behavior in more natural environments. I worked with software engineers in the Covert lab to develop a preliminary multi-scale framework that integrates whole-cell modeling with agent-based modeling techniques -- the result is a simulation that can include multiple WCMs running in a spatial environment with molecular concentrations and physical forces. With the training plan proposed here, I will develop and test this framework using the same standards that went into the original WCM. This will lay a foundation for future extensions; the software will be built for scalable and incremental modeling of new cell-environment interactions. I will begin integrating cell-environment interactions by focusing on E. coli chemotaxis. First, a gene regulatory network will be implemented to control the expression of flagellar proteins; E. coli exhibit a “just-in-time” mechanism for flagella expression, with proteins synthesized roughly in the order they are needed. Monomers will be assembled into flagella complexes in the complexation module. A new flagella module will model the motor activity of individual flagella, this will track the energy expenditure and will generate motile forces that push the cell through its simulated environment. A sensory module will model the activity of chemoreceptors, and their adaptation to signals by methylation. A signaling module will connect sensory activity to the flagellar motor output with a protein network that controls the flagallas’ motor biases. Finally, a transport module will model the trans-membrane uptake of nutrients from the local environment. These transported nutrient fluxes will feed into the existing metabolism module and constrain its activity. The most exciting part of this project will be testing the wide-ranging consequences of E. coli’s chemotaxis behavior on cellular physiology. To survive in the wild, E. coli needs to process noisy information and make quick survival decisions. Information processing and motility require the necessary molecules and energy, and this cost needs to be offset by reliably securing key resources. Systematic analysis of wcEcoli will determine many of the trade-offs and how they are successfully navigated to a degree not previously possible.

项目摘要 该提案的重点是扩展大肠杆菌（wcEcoli）的大规模“全细胞”模型（WCM）， 包括细菌微环境和细胞运动性。wcEcoli是在斯坦福大学的Covert实验室开发的 大学，并于最近发布给国际科学家社区。具体目标是 应用程序概述了一个多尺度WCM的计划，介绍了一个模拟的空间环境，可以 包括其他细胞--这将导致第一个全菌落模拟。一个细胞的环境 影响其生长、分裂及其整个细胞周期和进化表型 时间尺度。通过考虑这些影响，这里提出的扩展将为 全细胞建模，可以在更自然的环境中检查细胞行为。 我与Covert实验室的软件工程师合作开发了一个初步的多尺度框架， 将全细胞建模与基于代理的建模技术相结合--结果是一个模拟， 包括在具有分子浓度和物理力的空间环境中运行的多个WCM。 有了这里提出的培训计划，我将使用相同的标准开发和测试这个框架， 原始的WCM。这将为未来的扩展奠定基础;该软件将构建为可扩展的， 新的细胞-环境相互作用的增量建模。 我将开始通过关注E.大肠杆菌趋化性。首先， 构建鞭毛蛋白表达调控网络;大肠杆菌展示A 鞭毛表达的“即时”机制，蛋白质大致按其顺序合成 needed.单体将在络合模块中组装成鞭毛复合物。一个新的鞭毛 模块将模拟单个鞭毛的运动活动，这将跟踪能量消耗，并将 产生推动细胞通过其模拟环境的能动力。一个感觉模块将模拟 化学感受器的活性，以及它们通过甲基化对信号的适应。一个信号模块将连接到 感觉活动与鞭毛运动输出的蛋白质网络，控制鞭毛的运动偏见。 最后，运输模块将模拟跨膜吸收当地环境中的营养物质。 这些被输送的养分通量将进入现有的代谢模块并限制其活动。 这个项目最令人兴奋的部分将是测试E。大肠杆菌 趋化行为对细胞生理学的影响。为了在野外生存，E。大肠杆菌需要处理噪音信息 快速做出生存决定信息处理和运动需要必要的分子， 能源，而这一成本需要通过可靠地保护关键资源来抵消。大肠杆菌的系统分析 确定许多权衡以及如何将它们成功导航到以前不可能的程度。