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

在免疫挑战期间，宿主将以增强其克服该挑战的能力的方式调整其行为。在哺乳动物中，这种适应性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或分子水平上都没有得到很好的理解。为了理解这种关系，这个项目利用了果蝇的遗传模型。果蝇（Drosophila）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得到了很好的表征，并且具有许多与哺乳动物共有的特征。睡眠和免疫功能之间的这种相互关系的核心是转录因子基因家族，NF #954;B。第一个目标是检验假设，即在没有感染的情况下，NF #954;B活性在清醒期间逐渐增加，并在达到阈值后促进睡眠。睡眠导致NF #954;B水平降低。将使用PI实验室开发的报告基因测定法测量活蝇中NF #954;B的真实的实时每日活性水平。缺乏一个或多个NF #954;B基因的果蝇也会严重减少睡眠。其次，在细菌感染后，NF #954;B大量爆发，在感染后6-12小时达到峰值，并促进睡眠。使用机械或遗传方法操纵睡眠将被用于破坏NF #954;B活性的这种爆发并影响免疫功能。具体地说，增强感染后峰值NF#954;B活性的操作以及随后的恢复睡眠将改善免疫功能，如通过存活率所测量的。相反，通过阻断恢复性睡眠来维持高水平的NF#954;B会降低免疫功能。这项工作的结果将提供重要的机理洞察睡眠作为一种适应性行为如何影响免疫功能。了解昆虫免疫应答过程中适应性行为的分子机制具有重要的农业意义，以及对哺乳动物生物学。该项目将为博士后实习生、本科生和高中生提供教育机会。PI致力于参与教育计划，使传统上在科学领域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.