Recent data indicate that after a variety of acute CNS injuries, there is a massive proliferation of stem/progenitor cells. Identification of the origin and fate of these cells is an area of intensive investigation. Whether these proliferative cells are stem cells that are capable of differentiation to neurons, glia, or other cell types that may repopulate damaged brain regions and enhance recovery remains to be determined. The provision of new cells from exogenous sources is an alternative approach to enhance recovery of function and may be necessary when neuronal loss and axonal injury are severe. Stem cell-like transplants from various sources have been shown to improve function in several models of brain and spinal cord injury. This project will utilize established animal models and histopathological and immunocytochemical techniques to characterize the temporal and regional cellular response to traumatic brain injury (TBI) and determine the consequences of stem cell transplantation in the post-injured brain. Indicators of cellular proliferation, mitotic divisions, cellular phenotypes, and apoptotic cell death will be specifically assessed. Preliminary data presented in this proposal indicative a massive proliferation of cells in the first several days after TBI, with many of these cells becoming astrocytes. Proposed studies in Specific Aim 1 will first characterize the temporal and regional cellular response to moderate TBI.
In Specific Aim 2, the effects of growth factor treatment on cellular proliferation and differentiation and differentiation and/or cell death will be assessed. Quantitative sensorimotor and cognitive endpoints will be used to document behavioral deficits and treatment strategies after TBI. Prior to stem cell transplantation, Specific Aim 3 will determine effectors that may control embryonic rat neutral in vitro. Finally, in Specific Aim 4, the assessment of whether growth factor treatment can alter the cellular response to injury or induce neuronal and/or oligodendrocyte stem cell graft differentiation and result in improved functional outcome will be tested. Together, these studies emphasize endogenous as well as exogenous reparative processes and should provide novel information concerning strategies to enhance recovery of function following TBI.
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