CAREER: Exploring the windows of selection for insecticide resistance evolution

对除草剂、杀菌剂、杀虫剂、抗菌剂、抗病毒药物和抗癌药物的耐药性的演变是一项重大的全球挑战。要制定有效的抗药性管理策略，重要的是要了解不同的组合和浓度如何影响抗药性的演变。这一知识可以用来理解在不同的暴露下或随着浓度随着时间的推移，抗性进化是如何变化的。该项目的目的是通过将蚊子的抗药性进化作为一个模型系统来填补这一知识的空白。通过测量抗性和敏感蚊子在不同杀虫剂组合和浓度下的选择，将建立一个全面的抗药性进化框架。此外，由于像耐药性演变这样复杂的问题预计在可预见的未来将在全球范围内继续存在，迫切需要一支多元化的劳动力队伍。该项目将围绕杀虫剂抗性进化为本科生和K-12学生开发基于研究和探究的经验。重点将放在社会经济背景较低或代表性较低的学生身上，以加强学生对科学的参与，并使不同群体的学生接触到科学过程。抗药性进化是由抗药性生物在异生环境(含有杀虫剂、抗生素或其他“杀菌剂”的环境)中相对于敏感生物的生存增加而推动的。选择窗口是观察到不同死亡率的浓度范围，并被用作一个框架来确定发生选择的浓度，或确定该窗口在不可避免的浓度下降时打开的时间长度。在这一框架中常常忽略了种间竞争在两个菌株存活的浓度下的作用：在低浓度下。研究的目的是检验这样一种假设，即选择窗口包含一个或多个子竞争窗口，之后是一个负选择窗口。具体目标是：1)在选择窗口内建立不同剂量的抗药性等位基因的选择系数，2)确定与抗药性等位基因相关的适合度成本的大小，3)使用实验和数学方法确定遵循各种抗药性管理策略的选择。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The evolution of resistance against herbicides, fungicides, pesticides, antimicrobials, antivirals, and anticancer drugs is a major global challenge. To develop effective resistance management strategies, it is important to understand how the different combinations and concentrations affect the evolution of resistance. This knowledge could be used to understand how resistance evolution changes under varying exposures or as concentrations wane over time. The aim of this project is to fill the gap in this knowledge by focusing on insecticide resistance evolution in mosquitoes as a model system. A comprehensive evolutionary framework of insecticide resistance evolution will be developed by measuring the selection acting upon resistant and susceptible mosquitoes under different insecticide combinations and concentrations. Furthermore, with problems as complex as resistance evolution that is predicted to continue globally in the foreseeable future, a diverse workforce is urgently needed. This project will develop research and inquiry-based experiences for undergraduate and K-12 students around insecticide resistance evolution. The focus will be on students from lower socio-economic or underrepresented backgrounds to bolster student engagement in science and expose a diverse group of students to the process of science.Resistance evolution is driven by increased survival of resistant organisms in a xenobiotic environment (an environment with pesticides, antibiotics, or other "-cides") relative to susceptible organisms. The window of selection is the range of concentrations at which differential mortality is observed and is used as a framework to identify concentrations at which selection occurs, or identify the length of time this window is open at inevitably waning concentrations. Often missing from this framework is the role of interspecific competition at concentrations for which both strains survive: at low concentrations. The research goal is to test the hypothesis that the window of selection contains one or more sub-windows of competition, followed by a window of negative selection. The specific aims are to: 1) establish the selection coefficient of insecticide resistance alleles at different doses within the window of selection, 2) determine the magnitude of fitness costs associated with insecticide resistance alleles and 3) determine selection following various resistance management strategies using experimental and mathematical approaches.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.