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

描述：(申请人提供)： 感染人类免疫缺陷的人中有相当大比例 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情况的原因之一。 无序，这些事件被认为是对生产的反应 和释放病毒和细胞基因产品；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，两种特征良好的候选HIV-1神经毒素(HIV-1 TAT和血小板激活因子(PAF)上调血管活性 神经元中的糖原合成酶激酶3-β(GSK-3β)。此外，有毒的 TAT和PAF的作用可通过抑制GSK-3β来消除。这些 研究结果提出了以下假设：GSK-3β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 将通过这项提案中提出的研究进行实验测试。 具体地说，GSK-3β的激活对 候选HIV神经毒素将被检测，使用细胞内分子 GSK-3β的抑制剂(Frat和显性阴性的GSK-3β突变体)。 GSK-3β诱导神经细胞凋亡的机制分析(S) 然后将检查神经元损伤，重点是β-连环蛋白， 蛋白tau和抗凋亡转录因子NFKB。最后， 将进行实验以确定能够破坏的新型多肽 GSK-3β与支架蛋白Axin之间的相互作用。这 已知相互作用对于许多关键底物的磷酸化是必要的 GSK-3β分子，因此有望代表一种重要的 和有用的治疗目标，可能会导致对设计的新见解 用于HAD和其他神经退行性变的神经保护分子 精神错乱。

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.