Overexpression of glycogen synthase kinase 3-beta (GSK-3b) can lead to neuronal apoptosis, and work in the sponsor's lab has demonstrated that GSK-3b activity is upregulated in neurons, following exposure to the candidate HIV-1 neurotoxins Tat and PAF. Furthermore, lithium and valproate treatment both resulted in protection from Tat- and PAF- mediated neurotoxicity. Since lithium and sodium valproate are selective inhibitors of GSK-3b, this suggests that GSK-3b activation may play a role in Tat- and PAF- mediated neurotoxicity. However, lithium and valproate have pleiotropic effects on neurons. Thus, additional experiments are needed to test whether GSK-3b activation may contribute to the neurotoxicity of Tat and PAR Three specific aims are proposed. First, studies will be conducted to test whether other inhibitors of GSK-3b can also protect neurons from PAF- and Tat- induced toxicity. Second, an endogenous inhibitor of GSK-3b (Frat) will be overexpressed in neurons, and cell survival in the presence and absence of PAF and Tat will be quantitated. Third, new inhibitors of GSK-3b will be generated using phage display technology, and the effects of these informational molecules on PAF- and Tat- mediated neurotoxicity will be examined.
| Fan, Shongshan; Maguire, Casey A; Ramirez, Servio H et al. (2005) Valproic acid enhances gene expression from viral gene transfer vectors. J Virol Methods 125:23-33 |
| Ramirez, Servio H; Fan, Shongshan; Maguire, Casey A et al. (2004) Activation of adenosine A2A receptor protects sympathetic neurons against nerve growth factor withdrawal. J Neurosci Res 77:258-69 |
| Fan, Shongshan; Ramirez, Servio H; Garcia, Tatiana M et al. (2004) Dishevelled promotes neurite outgrowth in neuronal differentiating neuroblastoma 2A cells, via a DIX-domain dependent pathway. Brain Res Mol Brain Res 132:38-50 |
