Many neurological deficits result from the loss of neurons through neurodegenerative disease, traumatic injury, or stroke. The adult central nervous system (CNS) demonstrates little endogenous capacity for repair and lost neurons are not replaced. However, the generation of new neurons persists in two specific brain regions. Recent progress in understanding the signals regulating the proliferation and differentiation of new neurons in these two neurogenic regions, opens the possibility to use these neural stem cells, as they are collectively called, to repopulate other non-neurogenic areas of the brain that have been injured. The major goal of this study is to repopulate the injured entorhinal cortex, a region with severe cell loss in Alzheimer's disease, with neural stem cells. To achieve this goal, post-injury changes in entorhinal cortex trophic factor expression will be evaluated and neural stem cells will be grafted into the intact or injured entorhinal cortex. To determine if trophic factor expression is a limiting component of successful stem cell neuronal differentiation, ex vivo and in vivo gene therapy will be used to augment expression. These objectives will be accomplished using a combination of molecular and protein analysis, gene therapy, quantitative stereology, and modern microscopic analysis to evaluate stem cell differentiation and connectivity. By increasing our understanding of the signals required for neuronal differentiation of stem cells, this study will provide a rationale for clinical cell replacement strategies for the treatment of various neurodegenerative diseases and traumatic injuries where neuron loss is experienced.
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