Neuronal cell survival is dependent upon many trophic influences, of which nerve growth factor (NGF) has been the most extensively studied and understood. The long term goal of this grant proposal is to understand the molecular mechanism of nerve cell survival. The NGF family includes brain derived neurotrophic factor and neurotrophins_3 and NT_4/5. Each of these proteins interacts with two different transmembrane receptors, members of the trk tyrosine kinase subfamily and the p75 neurotrophin receptor, a member of the TNF family of receptors. The actions of these receptors determine neuronal cell numbers during development. Co_expression of p75 with trk family members may play a number of crucial functions, including increasing the affinity of ligand binding when trophic factors are present only in limiting concentrations; regulation of tyrosine kinase activity; and greater discrimination between different neurotrophin factors. Additionally, novel signaling pathways utilizing sphingolipid turnover are used by neurotrophins and cytokines as another potential signal transduction mechanism to mediate apoptosis. Selectivity of neurotrophin action is likely to depend upon adual receptor system in which coexpression of trk family members with p75 result in distinctive downstream biological responses. This proposal will focus upon the receptor binding and signaling requirements for NGF. The investigation has implications for mechanisms of cell survival, differentiation and cell death of neuronal cell populations, which will ultimately bear upon our understanding of many neurodegenerative diseases, such as motor neuron and Alzheimer's dementia.
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