DESCRIPTION (provided by applicant): Dr. Zielinski's research is focused on understanding mechanisms of how inflammation regulates sleep and is activated by sleep loss and disease. Currently, Dr. Zielinski is a postdoctoral fellow under the mentorship of Dr. Radhika Basheer at the Veteran Affairs Boston Healthcare System. Compared to the general population, veterans have an increased prevalence of sleep disorders and sleep disturbances including those that induce sleep loss. Sleep loss causes lost productivity, sleepiness, fatigue, and increased health and memory problems. Sleep loss increases inflammatory substances in the brain. Enhancements in these inflammatory molecules in the brain are associated with sleepiness, impaired cognition, and sleep disorders including insomnia. However, the exact mechanisms governing these inflammatory processes in relation to sleep loss remain poorly understood. My current research has provided strong preliminary evidence that the nucleotide leucine-rich protein-3 inflammasome protein complex, which forms in response to increased extracellular adenosine tri-phosphate levels to activate caspase-1 and cleave the pro-form of interleukin-1 beta into its mature active form is activated by sleep loss and enhances sleep and electroencephalogram delta power (0.5- 4 Hz range; an indicator of sleep need). Interestingly, cerebral blood flow is associated with changes in sleep state and electroencephalogram delta power and interleukin-1 beta is a potent vasodilative substance enhancing cerebral blood flow suggesting a common mechanistic link. The neurovascular unit is comprised of different cell types including microglia, brain macrophages, astrocytes, and neurons that sense neuronal activity and function to alter cerebral blood flow to maintain homeostasis from pathogenic and normal physiologic activities. The neurovascular unit does this, in part, through releasing inflammatory substances including interleukin-1 beta-a molecule that enhances cerebral blood flow and sleep. The goal of this proposal is to determine how energy-related mechanisms induced by sleep loss activate a mechanism of inflammation, the inflammasome, to alter sleep and cerebral blood flow. Aim 1 tests the hypothesis that sleep loss enhances energy substrates to activate the inflammasome to enhance sleep. Aim 2 investigates the hypothesis that sleep loss activates the inflammasome in cells of the neurovascular unit. Aim 3 examines the hypothesis that sleep loss enhances interleukin-1 beta to alter cerebral blood flow during sleep states. Findings from this proposal will allow for an understanding of inflammatory mechanism induced by sleep loss so that novel pharmaceutical and treatments can be identified for veterans who experience debilitating disturbed sleep including those with insomnia, post-traumatic stress disorder, traumatic brain injury and schizophrenia. The team of mentors and collaborators assembled for this proposal at the Veteran...