HIV, Drug Abuse and Neurotoxicity

艾滋病毒、药物滥用和神经毒性

基本信息

批准号：
8447553
负责人：
ANIL KUMAR
金额：
$ 27.47万
依托单位：
UNIVERSITY OF MISSOURI KANSAS CITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8447553
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 Human IL8 gene Illicit Drugs In Vitro Incidence Individual Infection Inflammatory Interleukin-6 Mediating Medical Mental Depression 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 TNF gene Testing Therapeutic Transgenic Mice Tyrosine 3-Monooxygenase Viral Viral Load result Viral Proteins Virus Inhibitors Virus Replication annexin A5 chemokine club drug cytokine design dopamine transporter ecstasy in vivo inhibitor/antagonist men methamphetamine abuse nervous system disorder neuroinflammation neurotoxic neurotoxicity research study virotoxins

项目摘要

Methamphetamine and 3, 4- methylenedioxymethamphetamine (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.

甲基苯丙胺和 3, 4-亚甲二氧基甲基苯丙胺 (MDMA) 是俱乐部中最常见的两种毒品，在年轻一代中很受欢迎。这些非法物质被数百万人使用每年都有人使用，而且它们的使用在同性恋人群中更受欢迎。甲基苯丙胺和 MDMA 已知会引起神经毒性，包括改变大脑结构，尤其是大脑结构。与抑郁和认知问题相关的领域。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，因为 HIV-1 感染发生率较高、病毒载量增加以及神经炎症很明显在吸毒者中。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摇头丸介导的神经毒性中已得到充分证实。然而细胞因子和趋化因子的作用仍有待探索。另一方面，众所周知，艾滋病毒已记录导致 HIV 相关痴呆 (HAD) 和非法物质，尤其是阿片类药物来复合这些效果。两种 HIV 蛋白（Tat 和 gp120）已被详细研究诱发 HAD 的能力。然而，病毒性 Vpr 和 Nef 虽然有所牵连，但尚未对其进行充分研究。在 HAD 中的作用。此外，关于两者之间可能的协同作用，只有有限的信息。一方面是甲基苯丙胺和摇头丸，另一方面是不同的病毒毒素。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摇头丸介导的神经毒性中的作用查明同时使用两种药物是否会增加神经毒性。我们将确定 HIV Vpr 的作用和 Nef 的神经毒性相对而言尚未被探索。我们还将确定是否有非法药物和病毒毒素之间的协同作用以及是否可以通过使用药物消除神经毒性作用拮抗剂和 siRNA。这些体外发现将扩展到体内实验，其中结合将探讨甲基苯丙胺或摇头丸和病毒毒素对 HIV Tat、Nef 和 gp120 的影响转基因小鼠。