P74 NTR and its Role in Regeneration: Potential Neuroprotective Effects

p75NTR is an important neurotrophin receptor and plays a crucial role in many diverse functions in neurons. In the peripheral nervous system (PNS), p75NTR is known to enhance myelin formation and promote regeneration when it binds to various neurotrophins. However, in the central nervous system (CNS), p75NTR expression affects neuron survival in contrasting fashions depending on the ligand it binds and the other receptors with which it interacts. Recent evidence points to p75NTR as a potential neuron survival promoting receptor when activated in tandem with the apoptotic p75NTR pathway induced by NGF and nitric oxide (NO). Whether p75NTR expression can promote neuron survival or regeneration in a growth inhibitory and apoptotic environment such as the CNS remains unknown. We hypothesize that over-expression of p75NTR will increase neuron survival under otherwise apoptotic and growth inhibitory conditions. To support this hypothesis, we will over- and under-express p75NTR in CNS and PNS neurons both in vitro and in vivo. In vitro experiments will apply PNS and CNS specific neuron cultures with siRNA induced p75NTR under-expression or promoter induced p75NTR over- expression in the presence and absence of p75NTR ligands. In vivo experiments will apply a tetracycline induced Cre/LoxP mouse model to over and under express p75NTR and its ligands in both PNS and CNS. We will measure neuron survival using azino-bis (ethylbenzothiazoline-6-sulphonic acid) enzyme-linked immunoabsorbant assay and the CellTiterGlo ATP assay. Our experiments should reveal a possible means of preventing CNS neuron death in cases of injury or neurodegeneration