HIV, Drug Abuse and Neurotoxicity

艾滋病毒、药物滥用和神经毒性

• 批准号: 7685746
• 负责人: ANIL KUMAR
• 金额: $ 29.8万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7685746
• 关键词: AIDS Dementia Complex; AIDS/HIV problem; Acute; Address; Affect; Area; Astrocytes; Biological Assay; Biological Models; Body Weight decreased; Brain; CCL2 gene; Categories; Chronic; Coculture Techniques; Cognition; Cognitive; Consumption; Development; Disease; Disease Progression; Dopamine; Dose; Drug abuse; Drug user; Epidemiologic Studies; Feline Immunodeficiency Virus; Gays; Generations; HIV; HIV Envelope Protein gp120; HIV tat Protein; HIV-1; Hand; Human; IL8 gene; Illicit Drugs; In Vitro; Incidence; Individual; Infection; Inflammatory; Interleukin-6; Mediating; Medical; Methamphetamine; Neurons; Neuropathogenesis; Opiates; Oxidative Stress; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Population; Prevalence; Property; Proteins; RNA; Role; Severities; Small Interfering RNA; Staining method; Stains; Structure; Testing; Therapeutic; Transgenic Mice; Tyrosine 3-Monooxygenase; Viral; Viral Load result; Viral Proteins; Virus Inhibitors; Virus Replication; annexin A5; chemokine; club drug; cytokine; depression; design; dopamine transporter; ecstasy; in vivo; inhibitor/antagonist; men; methamphetamine abuse; methamphetamine exposure; nervous system disorder; neuroinflammation; neurotoxic; neurotoxicity; public health relevance; research study; virotoxins

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.

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，并且在同性恋人群中更受欢迎。众所周知，甲基苯丙胺和摇头丸都会引起神经毒性，包括大脑结构的变化，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 可能会影响 HIV-1 阳性吸毒者的病程，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就证明了这一点。多巴胺 (DA)、多巴胺转运蛋白 (DT)、酪氨酸羟化酶 (TH) 和氧化应激标记物在甲基苯丙胺和 MDMA 介导的神经毒性中的作用已得到充分证实。然而细胞因子和趋化因子的作用仍有待探索。另一方面，已知 HIV 会导致 HIV 相关痴呆 (HAD)，而非法物质（尤其是阿片类药物）已被证明会加剧这些影响。两种 HIV 蛋白（Tat 和 gp120）诱导 HAD 的能力已被详细研究。然而，病毒 Vpr 和 Nef 虽然有所涉及，但对其在 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存在的协同作用，目前的信息有限。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，并找出同时使用两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，这方面的研究相对较少。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 消除神经毒性作用。这些体外研究结果将扩展到体内实验，其中将在 HIV Tat、Nef 和 gp120 转基因小鼠中探索甲基苯丙胺或 MDMA 和病毒毒素的联合作用。公共健康相关性：本申请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。还计划进行实验来阐明病毒蛋白（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。我们还将测试药物抑制剂和病毒 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。