Effects of Sleep Deprivation on Infection Induced Organ Failure

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DESCRIPTION (provided by applicant): Recent studies indicate that critically ill patients experience poor sleep, frequent disruptions, loss of circadian rhythm and a marked reduction of the percentage of sleep time spent in restorative stages. Importantly, sleep deprivation in these patients may have adverse consequences. In keeping with this concept, two recent animal studies found that sleep deprivation markedly increases death in sepsis, but the mechanisms responsible for this phenomenon are completely unknown. We will test the specific hypotheses that sleep deprivation interacts with infection to activate endoplasmic reticulum (ER) stress pathways and that ER stress pathway activation, in turn, causes failure of multiple organs. Aim 1 will determine if infection and sleep deprivation synergistically induce ER stress in multiple tissues and if ER stress pathway activation produces organ failure. Studies will be performed using animal models of sepsis (cecal ligation and puncture, CLP) and sleep deprivation (SD). Experiment 1.1 will test the hypothesis that sepsis and sleep deprivation interact to induce ER stress, with ER stress pathways activated in parallel with development of organ failure. Experiment 1.2 will test the hypothesis that chemical activation of ER stress triggers pathological alterations (e.g. activation of downstream proteolytic pathways) that produce organ dysfunction. Aim 2 will elucidate the upstream mechanisms by which sepsis and sleep deprivation activate ER stress pathways. Experiment 2.1 will test the hypothesis that cytokine-induced production of reactive oxygen species (ROS) is the key upstream trigger that activates ER stress in sepsis. Experiment 2.2 will test the hypothesis that upstream alterations in peripheral tissue clock gene function activate ER stress pathways in response to sleep deprivation. Experiment 2.3 will test the hypothesis that disruption of peripheral tissue clock function increases ROS generation, and activates ER stress pathways. Aim 3 will determine if administration of pharmacological inhibitors of ER stress pathways improves organ function in sepsis and sleep deprivation. Experiments 3.1, 3.2, and 3.3 will test the hypothesis that either z- ATAD-fmk (a caspase 12 inhibitor), salubrinal (a selective inhibitor of eIF2¿ dephosphorylation), or melatonin (an endogenous hormone that inhibits the IRE1¿ pathway) will block ER stress pathway dependent cell damage and improve organ function in CLP+SD. Experiment 3.4 will test the hypothesis that delayed administration of the pharmacologic agent to found to produce the best therapeutic effect will block ER stress pathway dependent cell damage and improve organ function in CLP+SD.