The overall goal of the UCLA Brain Injury Research Program is to understand the neurobiology of human traumatic brain injury (TBI). Our basic science efforts have described much of the neurochemical and metabolic cascade that is initiated by TBI. Out of these efforts, we have described how TBI increases the extracellular concentration of potassium. This injury-induced ionic flux increased the demand for energy to drive sodium/potassium pumps. The demand for this energy is primarily satisfied from the selective activation of glycolysis. Utilizing [/14C]deoxy-D- glucose autoradiography in experimental animals, we have been able to detect the extent of this injury-induced hyperglycolysis thereby obtaining an """"""""image of the insult."""""""" Incorporation both conventional and state-of-the-art metabolic imaging studies, we have been successful in documenting that the injury-induced hyperglycolysis occurs following human TBI. From our preliminary findings, the mechanisms behind the increase in glucose metabolism and its effect on neurophysiology are identical to what we have described in our animal models of TBI. The current proposal takes advantage of this observation by designing two clinical and one basic science projects, each addressing different, but interrelated, aspects of this unprecedented finding. A Project will determine the incident rate of global hyperglycolysis following TBI utilizing arterial-venous differences. A Project will determine the regional distribution of hyperglycolysis following human TBI utilizing positron emission tomography. Both projects will address the ideology and consequences of hyperglycolysis following TBI with specific emphasis on the changes in neurochemistry, cerebral blood flow and lactate production. A Project will determine the implication of hyperglycolysis in terms of cellular vulnerability to secondary insults. The experimental design of this project will address the degree and extent of cerebral blood flow-metabolic uncoupling following TBI and how this relates to cell survival. Our general hypothesis is that hyperglycolysis, defined in terms of the metabolic ratio between glucose and oxidative metabolism, is a immutable consequence of TBI. Hyperglycolysis is a result of cellular energy demands in direct response to ionic fluxes. This increase in fuel demand results in a metabolic crisis during which cerebral blood flow may not be sufficient and reflects an inefficient production of energy, resulting in the accumulation of lactate. This metabolic crisis define the degree and extent of injury and provides important insight into explaining why the brain in so vulnerable following TBI.
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