Collaborative Research: MODULUS: Copy Number Alterations and Xenobiotic adaptation

合作研究：MODULUS：拷贝数改变和异生素适应

• 批准号: 2141650
• 负责人: Justin Pritchard
• 金额: $ 41.04万
• 依托单位: Pennsylvania State Univ University Park
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2141650&HistoricalAwards=false
• 关键词: Collaborative; Research; MODULUS; Copy; Number

Understanding evolution is fundamental to understanding life on earth. Evolution also creates some of the greatest challenges to human health. Viruses, bacteria, fungi, and cancer cells all evolve resistance to xenobiotics. These xenobiotics are molecules that are not found naturally but that influence evolution in the natural world. This project aims to create new theory and experiments to understand xenobiotic evolution. The results of this project would have applications across many different fields such as bacteria resistant to antibiotics, malaria parasites resistant to antimalarial drugs, tumor cells resistant to cancer drugs, plants resistant to herbicides, and insects resistant to insecticides. The award provides support to train STEM graduate students that will eventually become part of the workforce. The project also provides research opportunities for undergraduates and develops new educational games that teach K-12 students about science, using xenobiotic evolution as an example.The main goal of this project is to discover novel aspects of xenobiotic adaptation that result from the interactions between mutations and gene amplifications. The project examines the complex, nonlinear evolutionary pathways that lead to xenobiotic adaptation in the context of antibiotic resistance evolution induced by Rifampin in E. coli. Mathematically, the project would model resistance evolution as a function of plasmid copy number with the use of a stochastic process that accounts for tunneling rates and spatial structures of the community of evolving cells. The project makes use of an incoherent feed forward loop that gives synthetic control for providing variation in plasmid copy numbers in cells while keeping biochemical levels constant. Synthetic biology experiments are designed with a view to parametrizing the models under development and exploring the effects of specific parameters that have been indicated as important by the model.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.

理解进化是理解地球生命的基础。进化也给人类健康带来了一些最大的挑战。病毒、细菌、真菌和癌细胞都进化出对外源性物质的抵抗力。这些外源性物质是自然界中没有发现的分子，但它们会影响自然界的进化。该项目旨在创造新的理论和实验来理解异生物进化。该项目的结果将在许多不同领域得到应用，例如对抗生素具有抗性的细菌，对抗疟疾药物具有抗性的疟疾寄生虫，对癌症药物具有抗性的肿瘤细胞，对除草剂具有抗性的植物以及对杀虫剂具有抗性的昆虫。该奖项为培养STEM研究生提供支持，这些研究生最终将成为劳动力的一部分。该项目还为本科生提供研究机会，并开发新的教育游戏，以异生物进化为例向K-12学生教授科学知识。该项目的主要目标是发现突变和基因扩增之间相互作用导致的异生物适应的新方面。该项目研究了复杂的，非线性的进化途径，导致异生适应的背景下，抗生素耐药性演变诱导利福平在大肠杆菌。杆菌在数学上，该项目将利用随机过程将抗性进化建模为质粒拷贝数的函数，该随机过程考虑了隧道速率和进化细胞群落的空间结构。该项目利用了一个不连贯的前馈回路，该回路提供了合成控制，以提供细胞中质粒拷贝数的变化，同时保持生化水平恒定。合成生物学实验的目的是对正在开发的模型进行参数化，并探索模型中已表明重要的特定参数的影响。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。