This is a request for continued support to study the mechanism underlying brain trauma-associated behavioral deficits. The long-term objective of this research project is to develop effective mechanism-based therapies to treat brain trauma victims. Traumatic brain injury (TBI) causes impairments of neurological and cognitive functions such as motor skills, attention, memory and motivation. Although brain trauma affects approximately one million people each year in the United States, no effective therapy is currently available to treat these patients. Using experimental models of brain injury, it has been demonstrated that neurotrophic factors, such as nerve growth factor (NGF), can enhance the survival and growth of subtypes of neurons after TBI. Evidence suggests that many of these neurotrophic factors exert their effects via extracellular signal-activated kinase (Erk), Akt (also called protein kinase B, PKB) and/or calcium/cAMP response element binding protein (CREB) cascades. We propose to examine the involvement of these cascades in brain trauma pathophysiology and to assess their therapeutic potential. The overall hypothesis to be evaluated is that activation of the Erk, Akt and CREB cascades can attenuate brain trauma-associated behavioral deficits through enhanced neuronal survival and process outgrowth. A multidisciplinary effort using biochemical, molecular, genetic knockout, pharmacological and behavioral approaches will be used to evaluate the contribution of these signaling pathways to trauma-associated behavioral deficits. In addition, the potential for the beneficial effects of activation of these cascades, in conjunction with infusion of neuronal progenitor cells, will be assessed. We propose to examine the following three specific aims: (1) to determine if intervention of Erk, Akt or CREB cascades can attenuate TBI-associated behavioral deficits, (2) to determine if Erk, Akt or CREB cascades alter synaptic function, neuronal survival and process outgrowth following TBI, and (3) to evaluate the combined effect of modulation of Erk, Akt and CREB cascades and transplantation of neuronal progenitor cells on attenuation of behavioral deficits following TBI. These studies will provide insight into mechanisms important to behavioral deficits, survival and growth of neurons following traumatic brain injury and yield valuable information for the development of new strategies for therapeutic intervention. Furthermore, this project will broaden our understanding of the pathogenesis of neurodegenerative diseases such as stroke and Alzheimer's disease.
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