The overall goal of this project is to understand the signaling mechanisms underlying cell death and survival, using NGF as a model. As a member of the neurotrophin family, NGF regulates the balance between cell survival and death in the nervous system both during development and in adulthood. An imbalance in this regulation can cause a variety of neurodegenerative diseases such as Alzheimer's and Parkinson's. NGF exerts its effects by binding to the cell surface via two distinct types of receptors, TrkA and p75, each capable of eliciting its own signaling response. NGF can either promote neuronal survival or death and this dichotomous action depends on the outcome of the interplay between TrkA and P75. Specifically when JNK, a kinase, is activated by p75, cell die and when suppressed by TrkA, cells live. The primary objective of this application is to investigate the mechanism of TrkA/p75 crosstalk in oligodendrocytes. Our overall hypothesis is that TrkA/p75 crosstalk takes the form of direct, competitive regulation at a particular point in the pathway upstream of JNK. To test this hypothesis, the following specific aims are proposed:
Aim 1 to test whether p75 signaling is required for apoptosis. We will investigate whether oligodendrocytes die in the absence of p75, and whether we can reconstitute the missing effect by introducing back into the p75-/- oligodendrocytes the full-length p75 of the mutant p75 lacking the signaling domain.
Aim 1 1: to test whether Rac functions as the upstream regulator in the JNK pathway and whether TrkA and p75 regulate Rac activity oppositely.
Aim 1 11: to investigate the mechanisms whereby Trk-A mediated PI-3kinase activity suppresses JNK activation. The outcome of this study will result in significant advancement of the current knowledge of NGF signaling by elucidating the basic biochemical mechanisms behind the complex interplay between TrkA and p75. In addition, delineation of the process controlling the precise balance between cell death and survival by NGF may lead to the development of potential therapeutic agents for many degenerative diseases whose etiology may reflect a dis-regulation in this balance.
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