Role of GSK-3beta in HIV 1 induced neuronal damage

描述：（由申请人提供）：

DESCRIPTION: (Provided by applicant): A significant proportion of individuals infected with human immunodeficiency virus type-1 (HIV-1) will develop HIV-associated dementia (HAD). Neuronal injury and cell death are thought to contribute to the pathogenesis of this disorder, and these events are believed to occur in response to the production and release of both viral and cellular gene products; collectively, these molecules are referred to as candidate HIV neurotoxins. We have evidence that two well-characterized candidate HIV-1 neurotoxins (HIV-1 Tat and platelet activating factor, or PAF) up-regulate the activity of glycogen synthase kinase 3-beta (GSK-3beta) in neurons. Furthermore, the toxic effects of Tat and PAF can be eliminated by inhibition of GSK-3beta. These findings suggest the following hypothesis: that activation of GSK-3beta may contribute to neuronal death and damage in the context of HAD. This hypothesis will be tested experimentally through the studies set forth in this proposal. Specifically, the contribution of GSK-3beta activation to the activity of candidate HIV neurotoxins will be examined, using intracellular molecular inhibitors of GSK-3beta (Frat and a dominant-negative GSK-3beta mutant). Analysis of the mechanism(s) involved in GSK-3beta mediated neuronal apoptosis and neuronal damage will then be examined, with emphasis on beta-catenin, protein tau, and the antiapoptotic transcription factor, NFKB. Finally, experiments will be conducted to identify novel peptides capable of disrupting the interaction between GSK-3beta and the scaffolding protein, Axin. This interaction is known to be necessary for phosphorylation of many key substrate molecules of GSK-3beta, and is therefore expected to represent an important and useful therapeutic target that may lead to new insights into the design of neuroprotective molecules for use in HAD and other neurodegenerative disorders.