PROJECT SUMMARY Low-grade or unresolved inflammation is involved in the pathogenesis of many human diseases. Common sleep patterns of restricting sleep during the work week and ‘catching up’ on sleep over the weekend lead to inflammatory upregulation that does not recover completely after the weekend. Goal of this proposal is to investigate, for the first time, inflammatory resolution pathways. Inflammatory resolution mediators, such as resolvins, are derived from omega-3 free fatty acids and actively ‘turn-off’ inflammation. Based on preliminary data from our lab, we hypothesize that common sleep restriction- recovery patterns disrupt inflammatory resolution pathways, making it difficult to return to inflammatory homeostasis. If true, pharmacologically increasing the body’s natural production of endogenous inflammatory resolution mediators may one day provide a way to reduce the detrimental inflammatory consequences of common sleep restriction-recovery patterns. The hypothesis will be tested using an experimental model that mimics common patterns of restricting sleep on week days and ‘catching up’ on sleep on the weekend. The proposal will further utilize the unique ability of low-dose aspirin, which – like no other non-steroidal anti-inflammatory drug – is able to activate inflammatory resolution pathways. Healthy women and men between the ages of 18 to 50 years will be tested under three 10-day long in-hospital stays, during which they will be exposed to control sleep or common patterns of sleep restriction-recovery. The two sleep restriction-recovery stays will be combined with preemptive administration of low-dose aspirin or placebo. Aim 1 will investigate whether exposure to commonly experienced sleep patterns of sleep restriction followed by recovery sleep will not only activate inflammatory (e.g., interleukin-6), but disrupt inflammatory resolution pathways (e.g., resolvins), as well. Aim 2 will test that activation of inflammatory resolution pathways by aspirin dampens the inflammatory response to sleep restriction. Aim 3 is target-unspecific and will profile a wide range of resolution lipid mediators using a liquid chromatography/tandem mass spectrometry (LC-MS/MS) platform, which may fuel the search of a biomarker to be used in the monitoring of sleep health. Targeting inflammatory resolution pathways could provide a novel, non-behavioral strategy to mitigate both inflammatory consequences and future disease risks in those undergoing periods of sleep restriction-recovery patterns – a behavior pattern that is unlikely to be eradicated in the near future, as changes in sleep are generally difficult to make and to maintain.