Mechanisms of interaction between sleep and the innate immune response in Drosophila

在免疫挑战期间，宿主将调整其行为，以增强其克服挑战的能力。在哺乳动物中，这种适应行为通常表现为睡眠增加。睡眠和免疫反应之间的复杂关系在功能和分子水平上都没有得到很好的理解。为了了解这种关系，这个项目利用了果蝇的遗传模型。果蝇是一个强大的模型系统，它展示了与睡眠相关的所有行为特征。该物种的先天免疫反应也有很好的特点，并具有许多与哺乳动物相同的特征。睡眠和免疫功能之间这种相互作用关系的核心是一组转录因子基因--核因子B。第一个目标将检验这样一种假设，即在没有感染的情况下，核因子B的活性在清醒状态下逐渐增加，并在达到阈值后促进睡眠。然后，睡眠会导致核因子&B水平下降。在活体苍蝇中，核因子和核因子B的实时每日活动水平将使用PI实验室开发的一种报告分析方法进行测量。缺乏一个或多个核因子B基因的果蝇预计也会严重减少睡眠。其次，在细菌感染后，核因子&B会大量爆发，在感染后6-12小时达到高峰，从而促进睡眠。使用机械或遗传方法控制睡眠将被用来扰乱这种核因子&B活性的爆发，并影响免疫功能。具体地说，在感染后增强峰值核因子B活性的手法以及随后的恢复睡眠将改善以存活率衡量的免疫功能。相反，通过阻止恢复睡眠来维持高水平的核因子&B会降低免疫功能。这项工作的结果将为了解睡眠作为一种适应行为如何影响免疫功能提供重要的机制见解。了解昆虫在免疫反应中适应行为的分子机制具有重要的农业意义和哺乳动物生物学意义。该项目将为博士后实习生、本科生和高中生提供教育机会。国际和平协会致力于参与教育项目，使传统上在科学界代表性不足的群体中的个人受益。

During an immune challenge, a host will adapt its behavior in a manner that enhances its ability to overcome that challenge. In mammals, this adaptive behavior is often manifested as increased sleep. The complex relationship between sleep and the immune response is not well understood at either the functional or the molecular level. In an effort to understand this relationship, this project exploits the Drosophila genetic model. The fruit fly Drosophila is a powerful model system that exhibits all of the behavioral features associated with sleep. The innate immune response in this species is also well characterized and has many features that are shared with that in mammals. Central to this reciprocal relationship between sleep and immune function is a family of transcription factor genes, NFκB. The first aim will test the hypothesis that, in the absence of infection, NFκB activity progressively increases during wakefulness and promotes sleep after reaching a threshold. Sleep then leads to decreased NFκB levels. Real time daily activity levels of NFκB in living flies will be measured using a reporter assay that was developed in the PI's laboratory. Flies that lack one or more NFκB genes are also expected to have severely reduced sleep. Second, following bacterial infection there is a large burst in NFκB that peaks 6-12 hours after the infection and promotes sleep. Manipulations of sleep using mechanical or genetic methods will be used to disrupt this burst of NFκB activity and to affect immune function. Specifically, manipulations that enhance peak NFκB activity after the infection as well as the ensuing recovery sleep will improve immune function as measured by rates of survival. Conversely, sustaining high levels of NFκB by blocking a recovery sleep will decrease immune function. Results of this work will provide important mechanistic insight into how sleep as an adaptive behavior influences immune function.Understanding molecular mechanisms of adaptive behavior during an immune response in insects has important agricultural implications as well as for mammalian biology. This project will provide educational opportunities for a post-doctoral trainee, undergraduate, and high school students. The PI is committed to participating in educational programs that benefit individuals from groups which are traditionally underrepresented in the sciences.