In addition to a role in growth, development and maintenance of normal brain structure and function, neurotrophic growth factors may also be involved in neurodegenerative disorders and in the normal response to injury in the nervous system. The investigator's research program has focused on identifying the mechanisms by which neurotrophic factors regulate both neuronal differentiation and the response of the adult nervous system to injury, using the PC12 pheochromocytoma cell line as a model. Upon addition of neurotrophic factors such as nerve growth factor (NGF), PC12 cells differentiate into neurite-bearing cells that share many properties with sympathetic neurons of the peripheral nervous system. Treatment of PC12 cells with non-neurotrophic factors such as epidermal growth factor (EGF) does not result in neuronal differentiation. The investigator employed subtractive hybridization techniques to clone cDNAs that were relatively rapidly and selectively induced by NGF in comparison to EGF, reasoning that these gene products might play a role in neuronal differentiation and further that study of the regulation of these genes might provide insight into the mechanism of neurotrophic factors action. The VGF clone is more robustly regulated by neurotrophic factors and is localized almost exclusively in neurons in the central and peripheral nervous systems. Recent studies demonstrate that VGF is rapidly regulated in vivo in response to seizure and injury and in addition, approximately 10 days following cortical injury VGF mRNA is upregulated in a region of the recovering brain in which compensatory regrowth of axons or sprouting occurs. Since VGF protein is stored in neurons and released from secretory vesicles, effects on surrounding cells may result from a rapid increases in vgf gene expression, suggesting that VGF may function n the formation of synapses during development and after injury.
The specific aims of this application are designed to (1) characterize the transcription factors that are activated by neurotrophin treatment, leading to neuronal differentiation and induction of vgf gene expression in vitro, and (2) determine the specific mechanisms that restrict vgf gene expression to particular subsets of neurons in the CNS and PNS. Finally, the investigator will (3) determine the function of VGF and/or peptides derived from it in the developing, adult and injured nervous system through analysis of vgf-/vgf-knockout mutant mice. The proposed studies will clarify how neurotrophic factors and gene products they regulate support neuronal development and regeneration in the aging and injured nervous system.
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