Collaborative Research: Mechanistic Models of Cooperative Biopolymerization Processes

合作研究：协同生物聚合过程的机理模型

基本信息

批准号：
1951510
负责人：
Tomas Gedeon
金额：
$ 37万
依托单位：
Montana State University
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1951510&HistoricalAwards=false
关键词：
Collaborative Research Mechanistic Models Cooperative

项目摘要

Synthetic biology is currently used to develop advanced medical treatments using engineered bacterial consortia. Bacteria are able to exquisitely fine-tune their growth rate to their environment, responding efficiently to sudden environmental changes. Abundance of ribosomes in a cell correlates tightly with the growth rate, and growth rate is controlled by the abundance of ribosomes that translate mRNA into protein. This biopolymerization process is influenced by an interconnected web of both direct and indirect feedbacks that depend on both transcription of genes and translation of ribosomal mRNA. Transcription and translation rates play a key role in response time of the microbe to changing conditions. This research seeks to develop a comprehensive mathematical model to describe ribosome assembly and abundance control in bacteria. The project emphasizes the integration of a broad knowledge of molecular biology, principles of physics, mathematical modeling and sensitivity analysis of a complex biological system. Both undergraduate and graduate students will be trained to use tools from mathematics and physics within the broad field of systems biology, thereby contributing mathematicians with interdisciplinary skills towards the national goal of STEM workforce development. A new continuum model will have the flexibility to describe three biopolymerization processes: transcription of ribosomal RNA, transcription of mRNA of ribosomal proteins and the translation of ribosomal proteins. The model for each process is referred to as an individual compartment within the full assembly model. The prototypical compartment is a generalization of vehicular motion models, and it provides a mechanism for including inflow and outflow phenomena as well as torque-assisted transcription when appropriate. The full ribosome assembly model is described by a system of ordinary differential equations whose variables are related to the outputs of the individual compartments. The full model also includes a set of feedbacks that regulate initiation and translocation rates governing the dynamics occurring within each compartment. Ribosome production rate is the key determinant of bacterial growth rate, and it depends on several fundamental quantities including the response time after a nutritional up-shift or down-shift, the combined time of transcription and translation, and the time to produce a ribosome. Several system parameters exhibit inherent uncertainties due to the stochastic nature of availability of various enzymes. The project includes a sensitivity analysis effort to quantify effects of the most crucial system parameters on each fundamental quantity. Examining these effects and their variability allows one to determine the average community response of bacteria to its environment. The variability in microbial community response to antibiotic application is often an important determinant of antibiotic effectiveness.This award is funded jointly by the MPS Division of Mathematical Sciences (DMS) through the Mathematical Biology Program and BIO/MCB through the Program of Genetic Mechanisms.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

合成生物学目前用于使用工程细菌联盟开发先进的医疗治疗。细菌能够将其生长速度精确地调整到环境中，从而有效地响应突然的环境变化。细胞中的核糖体丰度与生长速率密切相关，生长速率受到将mRNA转化为蛋白质的丰度。这种生物聚合过程受到直接反馈和间接反馈的相互联系的影响，这些反馈既取决于基因的转录和核糖体mRNA的翻译。转录和翻译率在微生物对变化条件的响应时间中起关键作用。这项研究旨在开发一个综合的数学模型，以描述细菌中的核糖体组装和丰度控制。该项目强调了对分子生物学的广泛知识，物理学原理，数学建模和复杂生物系统的灵敏度分析的整合。本科生和研究生都将接受培训，可以在系统生物学广泛领域中使用数学和物理学的工具，从而为数学家提供跨学科技能的贡献者，以实现STEM劳动力发展的国家目标。一个新的连续体模型将具有描述三个生物聚合过程的灵活性：核糖体RNA的转录，核糖体蛋白mRNA的转录和核糖体蛋白的翻译。每个过程的模型被称为完整组装模型中的单个隔室。原型室是对车辆运动模型的概括，它提供了一种机制，可以在适当时进行流入和流出现象以及扭矩辅助转录。完整的核糖体组装模型由一个普通微分方程的系统描述，其变量与单个隔室的输出有关。完整的模型还包括一组反馈，这些反馈调节启动和易位率，以控制每个隔室内发生的动态。核糖体的产量是细菌生长速率的关键决定因素，它取决于几个基本量，包括营养上移或下移后的响应时间，转录和翻译的合并时间以及产生核糖体的时间。由于各种酶的可用性的随机性，几个系统参数表现出固有的不确定性。该项目包括敏感性分析工作，以量化最关键的系统参数对每个基本数量的影响。检查这些效果及其可变性使人们能够确定细菌对环境的平均社区反应。微生物社区对抗生素应用的反应的可变性通常是抗生素有效性的重要决定因素。该奖项由国会议员分工数学科学（DMS）共同资助，通过数学生物学计划和生物/MCB通过遗传机制进行了遗传机制。标准。