The complex relationship between sleep and the immune response is not well understood at either the functional or the molecular level. In humans, excess sleep and fatigue are commonly experienced with infectious illness. Sleep disturbance and inflammatory processes are also associated with a number of diseases, which include cancer, cardiovascular, metabolic and depressive disorders. However, the link between sleep and innate immunity and its role in clinical outcome are poorly understood. This project exploits the Drosophila genetic model to elucidate a neuronal and molecular mechanism by which the innate immune response promotes sleep. 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. Similar to mammals, fruit flies increase sleep during an immune response. This increase of sleep, defined as recovery sleep, requires expression of the NF?B transcription factor, Relish in the fat body, which is equivalent to visceral fat in mammals and is a major site of immune response signaling in flies. The overall objective of this project is to elucidate a molecular and cellular mechanism by which the immune response promotes recovery sleep. We propose that during an immune response, an increase in Relish activity in the fat body results in the secretion of a cytokine, unpaired (Upd). Upd targets the dome receptor within a distinct brain region and activates the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling cascade to promote sleep. To test this hypothesis, we will first use a genetic approach to manipulate expression of hopscotch and stat92E, Drosophila homologs of mammalian JAK and STAT, respectively, within restricted regions of the brain that are known to be involved in controlling sleep. Our hypothesis predicts that gain-of-function mutants will result in excess sleep, while loss-of-function mutants will have no effect on normal sleep in untreated flies, but will block recovery sleep in injured or infected flies. These manipulations are also expected to influence survival outcome during a bacterial infection. In the next aim, we will evaluate the effect of similar genetic manipulations of the Upd cytokine in distinct tissues on both normal sleep and recovery sleep during an immune response.
The third aim i s to analyze the activity of the STAT92E transcription factor within the brain, and determine its responses to injury and infection in the presence and absence of Relish in the fat body. Our hypothesis is that the activity of the transcription factor as measured by a GFP reporter will be dependent on the expression of Relish in the fat body. By evaluating a functional role of a novel signaling pathway in recovery sleep, results from this project are expected to lead to a better understanding of excess sleep and inflammatory processes that are associated with human disease and their impact on clinical outcome.

Public Health Relevance

Sleep disturbances and inflammation are associated with a number of human diseases, such as cancer, cardiovascular, metabolic, and depressive disorders. To understand how sleep and inflammation are involved in a recovery process, this project exploits the Drosophila genetic model to investigate a neuronal mechanism by which bacterial infection promotes sleep and influences survival outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS078582-01
Application #
8281785
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Gnadt, James W
Project Start
2012-02-15
Project End
2014-01-31
Budget Start
2012-02-15
Budget End
2013-01-31
Support Year
1
Fiscal Year
2012
Total Cost
$240,000
Indirect Cost
$90,000
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104