Neurotrophins are secreted proteins which influence the proliferation, differentiation, survival and death of neuronal and non-neuronal cells during vertebrate development. It is likely that the information concerning the mechanism of action of neurotrophin receptors will lead to a greater understanding of how the multiple actions and specificity are encoded in these trophic factors. NGF, BDNF, NT-3 and NT-4 exert their actions through two types of receptors, the trk family of tyrosine kinase receptors and a unique receptor termed p75. While the effects of NGF upon neuronal cell survival and differentiation are well documented, recent evidence indicates that NGF may be involved in promoting programmed cell death in the nervous system. The purpose of this subproject is to elucidate the mechanism by which neurotrophins act through the p75 and trk receptors in regulating apoptosis. Downstream signaling pathways involving activation and time course of the stress-activated kinase (c-jun kinase) activity and Nfkappab transcription activity will be assessed. This investigation will yield new insights which may lead to the development of strategies to counter several neurodegenerative diseases, such as amyotrophic lateral sclerosis, Alzheimer's disease and multiple sclerosis.
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