Mechanisms of metabolic adaptation after traumatic brain injury

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PROJECT SUMMARY / ABSTRACT Traumatic brain injury (TBI) results in life-long cognitive and motor disabilities. TBI elicits acute and prolonged metabolic adaptations in an attempt to provide physiological fuel and to enable the survival of damaged nervous tissue. The overall objective of this proposal is to determine the mechanisms of metabolic adaptation to injury and the metabolic requirements that promote recovery following TBI. The pathophysiology of TBI is complex and characterized largely by dysregulated glucose metabolism. However, brain contains high concentration of fatty acids, which are liberated from plasma membrane following TBI and further propagate secondary injury by promoting inflammation and lipid peroxidation. We have shown that brain is capable of utilizing these fatty acids for energy and metabolism via β-oxidation. Specifically, this mechanism is present in neural progenitor cells and astrocytes. Thus, this mechanism allows to re-direct fatty acids to mitochondria for β-oxidation. Importantly, our preliminary data show that fatty acid oxidation is increased following traumatic brain injury. We hypothesize that the injured brain requires the up-regulation of fatty acid oxidation specifically in astrocytes in order to spare glucose for neurons as well as eliminating toxic fatty acid intermediates following damage to nervous tissue and blood brain barrier. Using tissue specific transgenic and knockout mouse models, we will test this hypothesis and detail these fundamental unanswered questions. To test these hypothesis we propose three specific aims: 1) Determine the spatial and temporal contribution of brain fatty acid metabolism following TBI; 2) Determine the requirement for brain fatty acid oxidation following TBI; 3) Determine the requirements for systemic metabolic adaptations following TBI. The long-term goal of this project is to determine the regulation and requirement for fatty acid oxidation pathway following TBI. Thus, these studies will elucidate how fatty acid metabolism is regulated following the injury and advance our understanding of metabolic adaptations. Furthermore, the fundamental knowledge how fatty acid metabolism is altered after TBI could lead to targeted therapies to improve brain energy and metabolism after neurological insult. !