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

描述：（申请人提供）： 很大一部分感染人类免疫缺陷病毒的人 1型病毒（HIV-1）将发展为HIV相关性痴呆（HAD）。神经元 损伤和细胞死亡被认为是导致这种疾病的发病机制。 疾病，这些事件被认为是在响应生产 以及病毒和细胞基因产物的释放;总的来说，这些 分子被称为候选HIV神经毒素。 我们有证据表明，两个充分表征的候选HIV-1神经毒素（HIV-1 达特和血小板活化因子，或PAF）上调的活性， 神经元中的糖原合成酶激酶3-β（GSK-3 β）。此外，有毒 达特和PAF的作用可通过抑制GSK-3 β而消除。这些 研究结果提出了以下假设：GSK-3 β的激活可能 在HAD的背景下，导致神经元死亡和损伤。这一假设 将通过本提案所述的研究进行实验测试。 具体地说，GSK-3 β激活对 候选的HIV神经毒素将被检查，使用细胞内分子 GSK-3 β抑制剂（Frat和显性阴性GSK-3 β突变体）。 GSK-3 β介导神经元凋亡的机制分析 然后将检查神经元损伤，重点是β-连环蛋白， tau蛋白和抗凋亡转录因子NF κ B。最后， 将进行实验以鉴定能够破坏 GSK-3 β和支架蛋白Axin之间的相互作用。这 已知相互作用对于许多关键底物磷酸化是必需的 GSK-3 β的分子，因此预计将代表一个重要的 和有用的治疗目标，可能会导致新的见解设计 用于HAD和其它神经退行性疾病的神经保护分子 紊乱

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.