Schultz - Proj 5

舒尔茨 - 项目 5

• 批准号: 10434076
• 负责人: Daniel Schultz
• 金额: $ 35.14万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434076
• 关键词: Address; Antibiotic Resistance; Antibiotics; Architecture; Bacteria; Behavior; Bioinformatics; Biological Assay; Biology; Cell physiology; Cells; Cellular Structures; Clinical; Complex; Costs and Benefits; DNA; Development; Disease; Ecosystem; Environment; Escherichia coli; Evolution; Exposure to; Gene Expression; Gene Expression Regulation; Genes; Goals; Growth; Homologous Gene; Knowledge; Laboratories; Libraries; Link; Liquid substance; Malignant Neoplasms; Microfluidic Microchips; Mobile Genetic Elements; Modeling; Mutation; Nature; Operon; Organism; Outcome; Pharmaceutical Preparations; Pharmacotherapy; Phylogeny; Population; Process; Ramp; Recording of previous events; Regulation; Research; Resistance; Soil; System; Techniques; Testing; Tetanus Helper Peptide; Tetracycline Resistance; Tetracyclines; Time; Variant; Work; antimicrobial; base; cost; design; efflux pump; environmental change; experimental study; fitness; genome database; genome sequencing; human disease; imprint; mathematical model; microbial; pressure; resistance gene; resistance mechanism; response; sample fixation; synthetic biology; whole genome

PROJECT SUMMARY Our conventional understanding of antibiotic resistance is based almost entirely on the notion of a bacterial population’s ability to maintain growth under steady-state drug conditions. Yet, it is becoming increasingly apparent that the outcome of drug treatment depends on highly-dynamic responses that require complex regulation. Despite a growing body of knowledge on the regulatory circuits governing the behavior of different classes of antibiotic-resistance mechanisms, a quantitative understanding of how these architectures evolved and diversified to optimize expression in different environments is still lacking. A comprehensive understanding of the design principles of gene regulation is essential to explain how control mechanisms can mitigate the costs of antibiotic resistance and allow fixation throughout bacterial populations. Recent findings from this research group show that the tetracycline resistance, tet, operon in E. coli, when suddenly exposed to tetracycline, optimizes gene expression by rapidly expressing the repressor (TetR) of the efflux pump (TetA). Moreover, variations in the dynamics of gene expression reveal a diversity of cell fates at the single-cell level. Recognizing that the time-dependent component of cell responses makes an important contribution to the fitness of an organism, the goal of this study is to investigate the process by which evolution optimizes antibiotic responses when addressing environmental pressures that require fast action (“dynamical efficacy”). Focusing on the tet operon, this project will test the concept that gene regulation of a resistance mechanism is optimized for the dynamics of gene expression. Through the following specific aims, this study will combine bioinformatics, mathematical modeling, and experimental approaches to determine what kinds of optimized regulatory architectures emerge in response to given environmental constrains, and to explain how gene regulation can be diversified in response to ecological challenges. The proposed aims are: Aim 1. Explore the dynamics of antibiotic response in natural circuits: design, optimality, and variability. This aim will analyze whole-genome databases to investigate the idea that natural variation will identify key regulatory strategies for effective resistance. Aim 2. Develop synthetic circuits optimized for specific dynamical regimes. Work in this aim will develop quantitative models of antibiotic resistance to design and implement optimal regulatory architectures and investigate the hypothesis that gene regulation found in nature is optimized to specific environments. Aim 3. Perform experimental evolution of resistance mechanisms in different drug regimes. This aim will experimentally evolve a resistance mechanism under different dynamical settings to explore how gene regulation changes in response to new environmental challenges. The understanding of how changes in gene regulation define the dynamics of cellular processes will directly inform the development of new antimicrobial therapies and explain how misregulation may be the cause of human disease, such as cancer. !

项目摘要 我们对抗生素耐药性的常规理解几乎完全基于细菌的概念 人口在稳态药物条件下维持生长的能力。但是，它变得越来越 显然，药物治疗的结果取决于需要复杂的高度动态反应 规定。尽管越来越多地了解管理电路的行为 抗生素耐药机制的类别，对这些体系结构如何发展的定量理解 并且仍然缺乏多元化以优化不同环境中的表达。全面的理解 基因调节的设计原理对于解释控制机制如何减轻控制机制至关重要 抗生素耐药性的成本，并允许在细菌种群中固定。最新发现 研究小组表明，大肠杆菌中的四环素抗性Tet，Operaon，突然暴露于 四环素，通过快速表达外排泵（TETA）的副本（TER）来优化基因表达。 此外，基因表达动力学的变化揭示了单细胞水平的细胞命运多样性。 认识到细胞反应的时间依赖性成分对 生物体的适应性，这项研究的目的是研究进化优化的过程 应对需要快速动作的环境压力时（“动力效率”）时会产生抗生素反应。 该项目专注于TET操纵子，将测试抗药性基因调节的概念 为基因表达的动力学优化了机制。通过以下特定目标， 研究将结合生物信息学，数学建模和实验方法，以确定什么 响应给定的环境约束而出现了多种优化的调节架构，并 解释如何应对生态挑战的响应如何多元化基因调节。拟议的目的是： 目标1。探索自然电路中抗生素反应的动态：设计，最佳性和 可变性。该目标将分析全基因组数据库，以调查自然变化将会 确定有效抵抗的关键监管策略。 AIM 2。开发针对特定动态制度优化的合成电路。在这个目标中工作 开发抗生素抗性的定量模型，以设计和实施最佳的调节架构 并研究了在自然界中发现的基因调控的假设已被优化为特定环境。 AIM 3。在不同药物方案中执行抗性机制的实验演变。这 AIM将在不同的动态设置下实验发展一种电阻机制，以探索基因 法规响应新的环境挑战。 对基因调控的变化如何定义细胞过程的动力学的理解将 直接告知新的抗菌疗法的发展，并解释 人类疾病的原因，例如癌症。 呢