Collaborative Research: MODULUS: Copy Number Alterations and Xenobiotic adaptation

理解进化是理解地球上生命的基础。进化也给人类健康带来了一些最大的挑战。病毒、细菌、真菌和癌细胞都会进化出对外来生物的抗性。这些外来生物是在自然界中不存在的分子，但会影响自然界的进化。该项目旨在建立新的理论和实验来理解异种生物的进化。这个项目的成果将应用于许多不同的领域，如对抗生素有抗药性的细菌、对抗疟疾药物有抗药性的疟疾寄生虫、对抗癌药物有抗药性的肿瘤细胞、对除草剂有抗药性的植物以及对杀虫剂有抗药性的昆虫。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了研究机会，并开发了新的教育游戏，以异种生物进化为例，向K-12学生传授科学知识。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种适应的新方面。该项目检查复杂的，非线性的进化途径，导致异种适应的背景下，利福平诱导的抗生素耐药性进化大肠杆菌。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，该过程解释了进化细胞群体的隧道速率和空间结构。该项目利用了一个不连贯的前馈回路，在保持生化水平不变的同时，为细胞中质粒拷贝数的变化提供了合成控制。合成生物学实验的设计是为了使正在开发的模型参数化，并探索模型中已表明重要的特定参数的影响。该奖项反映了美国国家科学基金会的法定使命，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。

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.