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.

中枢神经系统（CNS）HIV感染导致的神经认知障碍的患病率 正在增加。巨噬细胞是CNS内HIV的主要靶点，在HIV诱导的免疫应答中起着非常重要的作用。 神经发病机制它们对HIV的细胞病变效应具有抵抗力，并在较长时间内产生病毒。 时间因此成为病毒的避难所。滥用药物，如甲基苯丙胺（冰毒）已被证明， 通过增加巨噬细胞中的病毒复制进一步加重HAND。如果有效的治疗方案 HAND将更好地了解这些储库中的病毒发病机制， 需要治疗性治疗策略。了解神经毒性的分子机制 目前的建议集中在一个重要的和新兴的球员，称为 在HIV发病机制中，细胞外囊泡（EV）通常也被称为“外来体”或“微囊泡”。我们 初步研究表明，Meth可以增加EV的生物合成和从巨噬细胞的释放。因此 该建议的中心假设是进一步了解甲基苯丙胺与艾滋病毒如何影响EV 生物合成和巨噬细胞的释放，因此可以加剧艾滋病毒相关的 神经发病机制我们将在两个具体目标下研究这一假设：具体目标1将确定 Meth在EV生物发生和巨噬细胞释放中的作用，通过解读其对转运所需的内体分选复合物（ESCRT依赖性和非依赖性途径）的作用。具体目标2是 旨在研究EV在HIV疾病进展和CNS潜伏期中的作用， 小鼠模型，采用一系列的生化和细胞分析。顺利完成该项目 将提供重要的新信息，如何甲基影响EV生物发生，以及进一步我们 了解从HIV感染的巨噬细胞释放的EV货物对再活化的影响， CNS潜伏期。