Traumatic brain injury represents a considerable public health problem which exerts both a large financial burden on society, and post-traumatic reductions in quality of life through a constellation of cognitive impairments on individuals. The identification of pharmacological approaches to reduce brain injury-induced neuroinflammation currently exists as an unmet need despite advances in diagnostic techniques. Secondary mechanisms of neurodegeneration such as neuroinflammation are thought to contribute to post-traumatic cognitive impairments. Prostaglandins (PGs) and other eicosanoids have been found to play an important role in neuroinflammation, the production of which occurs via the conversion of arachidonic acid (AA) by biosynthetic enzymes. Recent discoveries yield new insight into a novel pathway which supports the production of AA from within the endocannabinoid system. In vitro work shows that inhibiting diacylglycerol lipase-? (DAGL-?) reduces the biosynthesis of 2-arachadonoyl glycerol, an endogenous cannabinoid ligand but also a precursor for the production of AA. This reduction in the production of free AA in turn results in decreases in PG formation and pro-inflammatory cytokine production. Therefore, we hypothesize that inhibiting DAGL-? will provide cognitive protection following brain injury in a murine learning and memory assay by reducing the pool of available AA that contributes to the production of PGE2 and other pro-inflammatory eicosanoids and cytokines in the hippocampus. Accordingly, the objectives of this training plan are to determine the distinct contribution of DAGL-? blockade on the reversal of TBI-induced memory impairments in mice, as well as the dampening of downstream production of prostanoids, and pro-inflammatory cytokines produced by microglial cells in the hippocampus. The proposed aims to examine these objectives are: 1) Evaluate the consequences of DAGL- inhibition on TBI-induced cognitive impairments in mice, 2) Evaluate the impact of DAGL-? inhibition on TBI-induced production of eCBs, AA, and PGs, and 3) Evaluate the impact of DAGL-? inhibition on TBI-induced production of a pro-inflammatory cytokine on CNS cell types. The completion of the research outlined in this training plan will contribute to the understanding of the role that DAGL-? plays in injury-induced production of pro-inflammatory eicosanoids separate from its action at cannabinoid receptors, as well as provide Ms. O'Brien with the necessary technical skills and theoretical foundation toward becoming an independent investigator.
Traumatic brain injury, despite being a global health problem, currently has no efficacious pharmacological treatments for the various functional deficits that impact survivors' quality of life. Specifically, cognitive impairments following brain injury are driven by secondary mechanisms of neurodegeneration, such as neuroinflammation. This research proposes a novel and strategic target to reverse traumatic brain injury- induced cognitive impairments through protection against neuroinflammation using Diacylglycerol Lipase- inhibition.
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