Traumatic brain injury (TBI) is a significant health concern, affecting 1.4 million people in the United States each year at a cost of $56 billion. The most common cognitive impairment among severely head-injured patients is memory loss. Although a number of therapeutic trials for TBI have been undertaken, there are no pharmacological therapies identified for TBI. Recently, attention has focused on potential therapeutic agents that enhance endogenous neuroplasticity including neurogenesis after brain injury, with a final goal of improving functional outcome. It is our objective to develop a restorative treatment for TBI by using recombinant human erythropoietin (rhEPO). Erythropoietin (EPO) is produced by the fetal liver and adult kidney and is the major cytokine that regulates erythropoiesis. In recent years, EPO has been demonstrated to have important nonhematopoietic functions in the nervous system. Our recent studies have shown that rhEPO enhances neurogenesis and improves cognitive function in TBI induced by controlled cortical impact (CCI). CCI causes selective neuronal death in the hippocampal CA3 region and the dentate gyrus (DG) both in rats and mice, leading to spatial learning and memory deficits. Although TBI evokes neurogenesis, a large proportion of the cells newly generated in the DG during the early phase after TBI die, during the late phase after TBI. The central hypothesis behind the proposed research is that the spatial learning impairment can be improved by manipulating the brain microenvironment (angiogenesis and molecular targets) by rhEPO. However, dose-response and therapeutic window studies using rhEPO have not been performed, nor have the mechanisms underlying therapeutic benefit for the treatment of TBI been established. In light of the potential of rhEPO to improve neurological outcome after TBI, three specific aims are proposed. Specific Aim 1: To measure the dose-response of rhEPO treatment on spatial learning function in rats after TBI. In addition, the therapeutic time window for rhEPO of TBI will be determined. Specific Aim 2: To study the effect of rhEPO treatment on the temporal and spatial profiles of neurogenesis and angiogenesis in the dentate gyrus after TBI. Specific Aim 3: To identify the molecular targets of rhEPO-induced neurogenesis and angiogenesis after TBI, the contribution of growth factors (vascular endothelial growth factor, brain-derived neurotrophic factor, and fibroblast growth factor) and the phosphoinositide 3-kinase/threonine protein kinase (PI3K/Akt) signal transduction pathway will be investigated. We expect to demonstrate that this therapy has promise for the improvement of spatial learning associated with TBI through upregulation of growth factors and PI3K/Akt signal pathway and the subsequent induction of angiogenesis and neurogenesis. The long-term goal of this application is to translate our finding of therapeutic benefit after treatment of TBI with rhEPO to the patient. PUBLIC HEALTH RELEVANCE: Although a number of therapeutic trials for traumatic brain injury (TBI) have been undertaken, there are no pharmacological therapies identified for TBI. Given the enormity of the clinical problem of TBI, affecting 1.4 million people in the United States each year at a cost of $56 billion, it is imperative that therapeutic approaches designed to improve functional recovery after TBI be developed. In this proposal, based on the newly discovered neuroprotective/neurorestorative properties of recombinant human erythropoietin (rhEPO), we seek to investigate its effect on neurogenesis and functional outcome in the rat after TBI and the mechanisms underlying therapeutic benefit of rhEPO for treatment of TBI.