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

• 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
• 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

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.

HIV感染中枢神经系统(CNS)引起的神经认知障碍的流行 正在增加。巨噬细胞是HIV在中枢神经系统内的主要靶点，在HIV诱导的过程中发挥着非常核心的作用 神经发病机制。它们抵抗艾滋病毒的细胞病变效应，并在更长的时间内产生病毒 因此，时间成为了病毒的庇护所。甲基苯丙胺(Meth)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重手部疾病。如果有效的治疗方案对 Hand正在开发更好地了解这些水库中病毒发病机制的潜力 治疗策略是必要的。了解神经毒性的分子机制 由HIV-1和Meth在大脑中，目前的提议集中在一个重要的和新兴的参与者，称为 在HIV的发病机制中，细胞外小泡(EVS)也常被称为“外体”或“微泡”。我们的 初步研究表明，Meth可促进EV的生物生成和巨噬细胞的释放。因此， 这项提议的中心假设是进一步了解Meth和HIV如何影响EV 巨噬细胞的生物发生和释放，因此可加剧艾滋病毒相关 神经发病机制。我们将在两个特定目标下研究这一假设：特定目标1将确定 Meth通过破译其对运输所需的内体分选复合体(ESCRT)依赖和独立途径的影响，在EV的生物发生和巨噬细胞释放中的作用。具体目标2是 旨在研究EVS对HIV疾病进展和中枢神经系统潜伏期的影响 采用一系列生化和细胞检测方法建立小鼠模型。本项目圆满完成 将提供关于Meth如何影响EV生物发生的重要新信息，以及进一步我们的 了解HIV感染的巨噬细胞释放的EV货物对再激活和 中枢神经系统的潜伏期。