The goal of this study is to recruit endogenous neural progenitor cells (NPCs) within the neocortex and direct their cell fate so that they can contribute to brain repair. The brain and spinal cord are vulnerable to cell death or loss of neuronal function as a result of neurodegenerative disease, stroke, or injury. There is little spontaneous generation of replacement cells, resulting in limited neurological recovery and sustained impairment in those afflicted, while placing a burden on the public health system. The identification of neural stem cells that can produce new neurons has generated hope for their use as a therapy to treat such neurological conditions. Neurogenesis, the generation of new neurons from stem/progenitor cells, does persist in the adult brain, but is spatially restricted to two, small regions, leaving most of the brain, where therapeutic intervention is critically needed, without new neurons. However, NPCs have been isolated and cultured from widespread brain regions, despite their lack of differentiation in vivo. Furthermore, limited spontaneous migration of NPCs from germinal centers to sites of injury in some experimental models has been reported with limited and transient neuronal differentiation. The prevalent view is that most of the brain lacks a suitable environment, or niche, to support neurogenesis, suggesting the creation of a suitable niche may permit recruitment of local, endogenous quiescent NPCs. Thus one of the critical questions facing the field at this time is how neuronal differentiation can be directed and the resulting new neurons integrated to support brain repair outside of the small neurogenic centers. This study will investigate recruitment of local, quiescent endogenous NPCs in the entorhinal cortex by using gene delivery approaches to create a neurogenic niche where candidate cell autonomous factors can be expressed. The entorhinal cortex was chosen as a target, non- neurogenic region for its distance from migratory subventricular zone neuroblasts, its participation in the processing of spatial memory, and its relevance to the early development of Alzheimer's disease pathology. This study will address recruitment of endogenous NPCs with three specific aims.
Aim One will characterize in vivo the properties of endogenous NPCs in regard to cell cycle frequency, self renewal, and multipotentiality using an innovative birthdating approach in combination with selective killing of proliferating cells and lineage analysis. To assess the recruitment of expanded NPCs to the desired cell lineage, Aim Two will use in vivo gene delivery to express proneuronal environmental factors to create a stem cell niche, while Aim Three will express transcription factors for neuronal differentiation in proliferating NPCs to assess the role of cell autonomous fate determinants. Neurological disease and injury are increased with advancing age, yet recent reports indicate that changes in the aging brain may limit its ability to support neurogenesis. This study will include both young and aged animals to address this important, clinically relevant factor.
The goal of this study is to recruit endogenous neural progenitor cells (NPCs) within the neocortex and direct their cell fate so that they can contribute to brain repair.
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