Role of extracellular vesicles in methamphetamine and HIV induced neurotoxicity

细胞外囊泡在甲基苯丙胺和 HIV 诱导的神经毒性中的作用

基本信息

批准号：
9929090
负责人：
Fatah Kashanchi
金额：
$ 0.43万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9929090
关键词：
AIDS dementia AIDS/HIV problem Acceleration Address Affect Amphetamines Animals Apoptosis Biochemical Biogenesis Biology Blood Brain Cell Death Cell Line Cells Cellular Assay Central Nervous System Diseases Central Nervous System Infections Chronic Communication Comorbidity Complex Data Disease Progression Exhibits Gene Expression Goals HIV HIV Infections HIV-1 HIV-associated neurocognitive disorder High Prevalence Human Impaired cognition Infection Laboratories Light Mediator of activation protein Membrane Methamphetamine Modeling Modification Molecular Mus N-terminal Names Nervous System Trauma Neuraxis Neurologic Neuropathogenesis Pathogenesis Pathway interactions Play Prevalence Psychomotor Impairments Publishing Reporting Resistance Risk Role Series Sorting - Cell Movement Structure Testing Therapeutic Therapeutic Intervention Time Treatment Protocols Viral Viral Pathogenesis Virus Virus Latency Virus Replication Work antiretroviral therapy design drug of abuse effective therapy exosome experimental study extracellular vesicles humanized mouse illicit drug use interest macrophage methamphetamine abuse methamphetamine effect methamphetamine exposure microvesicles monocyte mouse model nef Protein nervous system disorder neuroAIDS neurocognitive disorder neurotoxic neurotoxicity novel prevent psychostimulant screening synergism treatment strategy vesicular release

项目摘要

The prevalence of neurocognitive disorders that result from HIV infection of the central nervous system (CNS) is increasing. Macrophages, the primary target for HIV within the CNS, play a very central role in HIV-induced neuropathogenesis. They are resistant to the cytopathic effect of HIV and produce virus for longer periods of time thus serving as viral sanctuaries. Drugs of abuse such as methamphetamine (Meth) have been shown to further exacerbate HAND by increasing viral replication in the macrophages. If effective treatment regimens for HAND are to be developed a better understanding of viral pathogenesis in these reservoirs for potential therapeutic treatment strategies is needed. To understand the molecular mechanisms underlying neurotoxicity by HIV-1 and Meth in the brain, the current proposal focuses on one important and emerging player called extracellular vesicles (EVs) also often referred to as “exosomes” or “microvesicles” in HIV pathogenesis. Our preliminary studies indicate that Meth can increase EV biogenesis and release from macrophages. Thus the central hypothesis of this proposal is to further understand how Meth in conjunction with HIV affects EV biogenesis and release from macrophages and consequently can exacerbate HIV associated neuropathogenesis. We will investigate this hypothesis under two specific aims: Specific Aim 1 will identify the role of Meth in EV biogenesis and release from macrophages through deciphering its effect on endosomal-sorting complex required for transport (ESCRT) dependent and independent pathways. Specific Aim 2 is designed to study the effects of EVs in HIV disease progression and latency in the CNS using a humanized mouse model by employing a series of biochemical and cellular assays. Successful completion of this project will provide important new information on how Meth influences EV biogenesis and as well as further our understanding on the impact of the released EV cargo from HIV infected macrophages on re-activation and latency in CNS.

由中枢神经系统（CNS）引起的神经认知疾病的患病率正在增加。巨噬细胞是中枢神经系统内艾滋病毒的主要目标，在艾滋病毒诱导的神经病发生。它们对HIV的细胞质效应具有抗性，并在更长的时间内产生病毒时间因此是病毒庇护所。甲基苯丙胺（甲基苯丙胺）等滥用药物已被证明通过增加巨噬细胞中的病毒复制，进一步加剧了手。如果有效的治疗方案要在这些储层中更好地理解对病毒发病机理的更好理解需要治疗策略。了解神经毒性的分子机制由HIV-1和大脑中的甲基甲基在HIV发病机理中，细胞外蔬菜（EV）通常也称为“外部”或“微泡”。我们的初步研究表明，甲基甲基苯丙胺可以增加EV生物发生并从巨噬细胞中释放。那是该提案的中心假设是进一步了解甲基甲基与HIV的结合如何影响EV 生物发生和从巨噬细胞释放，因此可能加剧与HIV相关的HIV 神经病发生。我们将在两个具体目的下调查这一假设：具体目标1将确定 Meth在EV生物发生中的作用并通过破译其对转运（ESCRT）依赖性和独立途径所需的内体分类复合物的影响而从巨噬细胞中释放。具体目标2是旨在研究使用人源化的中枢神经系统中电动汽车在艾滋病毒疾病进展和潜伏期的影响小鼠模型通过采用一系列生化和细胞测定法。成功完成该项目将提供有关甲基甲基甲基影响ev生物发生以及进一步的重要新信息了解来自艾滋病毒感染巨噬细胞对重新激活和中枢神经系统的延迟。