HIV-Tat蛋白与甲基苯丙胺协同激活TRPM2通道增强氧化应激和炎症反应损伤血脑屏障的机制研究

HIV-Tat蛋白是艾滋病痴呆的重要致病因子，能直接损伤血脑屏障。甲基苯丙胺（METH）滥用对HIV感染者的血脑屏障有显著的协同损害作用，氧化应激和神经炎症扮演重要角色，但其调控机制不清楚。研究表明，瞬时受体电位通道蛋白2（TRPM2）可增强氧化应激、释放细胞因子及介导神经炎症的发生。我们前期发现，HIV-Tat蛋白与METH协同增加TRPM2蛋白的表达，因此，我们推测TRPM2通道可能是HIV-Tat蛋白与METH协同损伤血脑屏障的潜在机制靶点。本项目采用hCMEC/D3内皮细胞和NHA星形胶质细胞共培养及树鼩为研究对象，从行为学、神经生物学及分子生物学等多角度，证明HIV-Tat蛋白与METH协同激活TRPM2通道增强内皮细胞氧化应激反应，激活的TRPM2通道同时调控NF-κB信号通路，释放炎症因子，从而协同损伤血脑屏障，旨在为毒品滥用的艾滋病痴呆患者的发病机制和防治提供新的依据。

HIV-Tat protein is an important pathogenic factor of AIDS dementia, which can directly damage the blood-brain barrier. Methamphetamine (METH) abuse has a significant synergistic effect on BBB damage in HIV-infected patients. However the synergistic and regulatory mechanisms are unclear. Our previous studies found that oxidative stress and neuroinflammation played a key role in the synergistic damage to the blood-brain barrier by HIV-Tat protein and methamphetamine induced, and transient receptor potential channel 2 (TRPM2) may be involved in the regulation of the above synergistic damage to the blood-brain barrier. TRPM2 may also activate the NF-κB pathway, which results in glial cells to release a large number of inflammatory factors, to further damage the blood brain barrier. In this study, we will use some technologies including molecular biology, neurobiology and so on, to detect hCMEC/D3 and NHA cell lines as well as tree shrews in vivo and in vitro, aim to solve the following scientific problems. Firstly, TRPM2 channel regulates the oxidative stress response of HIV-Tat protein and METH induced BBB damage. Secondly, TRPM2 channel regulates the NF-κB signaling pathway, which releases a large number of inflammatory factors, and then the blood-brain barrier is further damaged. This study aims to provide a new basis and target for the prevention and treatment of AIDS and dementia patients with drug abuse.