HIV, Drug Abuse and Neurotoxicity

描述（申请人提供）：甲基苯丙胺和3，4-亚甲二氧基甲基苯丙胺（MDMA）是两种最常见的俱乐部毒品，在年轻一代中非常流行。这些非法物质每年被数百万人使用，它们的使用在同性恋人群中更受欢迎。已知甲基苯丙胺和MDMA都会引起神经毒性，包括大脑结构的变化，特别是在与抑郁症和认知问题有关的区域。有间接证据表明，甲基苯丙胺和二亚甲基双氧安非他明可能影响艾滋病毒1阳性吸毒者的病程，这一点可以从吸毒者中艾滋病毒1感染的发病率较高、病毒载量增加以及神经炎症等方面得到证明。多巴胺（DA），多巴胺转运蛋白（DT），酪氨酸羟化酶（TH）和氧化应激标志物的作用是很好地建立在甲基苯丙胺和MDMA介导的神经毒性。然而，细胞因子和趋化因子的作用仍在探索中。另一方面，已知艾滋病毒会引起艾滋病毒相关性痴呆症（HAD），而非法药物，特别是阿片类药物，已被证明会加剧这些影响。两种HIV蛋白（达特和gp 120）诱导HAD的能力已被详细研究。然而，病毒Vpr和Nef，虽然牵连，但没有很好地研究其在HAD中的作用。此外，关于甲基苯丙胺和二亚甲基双氧安非他明与不同病毒毒素之间可能的协同作用，现有的信息有限。在这个建议中，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，并找出同时使用2种药物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。这些体外发现将扩展到体内实验，其中将在HIV达特、Nef和gp 120转基因小鼠中探索甲基苯丙胺或MDMA和病毒毒素的联合作用。公共卫生相关性：本申请提出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消除神经毒性的潜力。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.