HIV, Drug Abuse and Neurotoxicity

描述（由申请人提供）：甲基苯丙胺和3,4 -亚甲基二氧基甲基苯丙胺（MDMA）是两种最常见的俱乐部毒品，非常受年轻一代的欢迎。每年都有数以百万计的人使用这些非法药物，而且在同性恋人群中使用更为普遍。已知甲基苯丙胺和MDMA都会引起神经毒性，包括大脑结构的改变，尤其是与抑郁和认知问题相关的区域。有间接证据表明，甲基苯丙胺和MDMA可能影响HIV-1阳性吸毒者的病程，这一点可以从吸毒者中HIV-1感染发生率较高、病毒载量增加以及神经炎症中得到证明。多巴胺（DA）、多巴胺转运体（DT）、酪氨酸羟化酶（TH）和氧化应激标志物在甲基苯丙胺和mdma介导的神经毒性中的作用已经得到了很好的证实。然而，细胞因子和趋化因子在其中的作用尚不明确。另一方面，已知艾滋病毒会导致与艾滋病毒相关的痴呆（HAD），非法物质，特别是阿片类药物已被证明会加剧这些影响。对两种HIV蛋白（Tat和gp120）诱导HAD的能力进行了详细的研究。然而，病毒Vpr和Nef虽然有牵连，但它们在HAD中的作用还没有得到很好的研究。此外，关于甲基苯丙胺和MDMA与不同病毒毒素之间可能的协同作用的信息有限。在本提案中，我们将确定细胞因子和趋化因子在甲基苯丙胺和mdma介导的神经毒性中的作用，并找出两种药物同时使用是否会增加神经毒性。我们将确定HIV Vpr和Nef在神经毒性中的作用，这是相对未被探索的。我们还将确定非法药物和病毒毒素之间是否存在协同作用，以及是否可以通过使用拮抗剂和siRNA来消除神经毒性作用。这些体外研究结果将扩展到体内实验，在HIV Tat， Nef和gp120转基因小鼠中探索甲基苯丙胺或MDMA和病毒毒素的联合效应。公共卫生相关性：本应用旨在剖析细胞因子和趋化因子在甲基苯丙胺和mdma介导的神经毒性中的作用。实验还计划阐明病毒蛋白（HIV Vpr和Nef）在HAD中的作用，以及俱乐部药物和病毒毒素之间是否存在协同作用，以诱导神经毒性。我们还将测试药理学抑制剂和病毒siRNA的潜力，以消除神经毒性。体外结果将扩展到使用转基因小鼠的模型系统。

DESCRIPTION (provided by applicant): Methamphetamine and 3, 4- methylenedioxy methamphetamine (MDMA) are two most common club drugs, and are very popular among younger generation. These illicit substances are used by millions of people every year and their use is more popular among gay population. Both methamphetamine and MDMA are known to cause neurotoxicity including changes in structure of the brain, especially in the areas associated with depression and cognitive problems. There is indirect evidence that Methamphetamine and MDMA might affect course of the disease among HIV-1 positive drug-users as evident by higher incidence of HIV-1 infection and increased viral load and as well as neuroinflammation among drug users. Role of dopamine (DA), dopamine transporter (DT), tyrosine hydroxylase (TH) and oxidative stress markers is well established in methamphetamine and MDMA-mediated neurotoxicity. However role of cytokine and chemokine remains under explored. On the other hand HIV is known to cause HIV-associated dementia (HAD) and illicit substances especially opiates have been documented to compound these effects. Two HIV proteins (Tat and gp120) have been studied in great detail for their ability to induce HAD. However, viral Vpr and Nef, though implicated, but not very well studied for their role in HAD. Furthermore, there is only limited information available regarding possible synergy between methamphetamine and MDMA on one hand and different virotoxins on the other. In this proposal we will determine role of cytokines and chemokine in methamphetamine and MDMA-mediated neurotoxicity and find out whether concurrent use of 2 drugs increases neurotoxicity. We will determine role of HIV Vpr and Nef in neurotoxicity which has been relatively unexplored. We will also determine whether there is synergy between illicit drugs and virotoxins and whether neurotoxic effect can be abrogated by use of antagonist and siRNA. These in vitro findings will be extended to in vivo experiments wherein combined effect of methamphetamine or MDMA and virotoxins will be explored in HIV Tat, Nef and gp120 transgenic mice. PUBLIC HEALTH RELEVANCE: This application proposes to dissect role of the cytokine(s) and chemokine(s) in methamphetamine and MDMA-mediated neurotoxicity. Experiments are also planned to elucidate the role of viral proteins (HIV Vpr and Nef) in HAD, and whether there is synergy between club drugs and virotoxins for their ability to induce neurotoxicity. We will also test pharmacological inhibitors and viral siRNA for their potential to abrogate neurotoxicity. In vitro results will be extended to a model system using transgenic mice.