COCAINE USE AND HIV ANTIRETROVIRAL THERAPY EFFICACY IN THE CNS

可卡因的使用和 HIV 抗逆转录病毒治疗在中枢神经系统中的疗效

• 批准号: 10226215
• 负责人: Dionna Whitney Williams
• 金额: $ 24.26万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226215
• 关键词: ABCB1 gene; Address; Affect; Anti-Retroviral Agents; Area; Autopsy; Award; Blood - brain barrier anatomy; Brain; Bypass; CYP3A4 gene; Characteristics; Cocaine; Cocaine Users; Cognitive deficits; Consequences of HIV; Cytochrome P450; Dementia; Development; Disease Progression; Dose; Drug Efflux; Drug Transport; Effectiveness; Ensure; Environment; Enzymes; Exhibits; Family; Foundations; Genetic; Genetic Polymorphism; Goals; HIV; HIV Infections; HIV antiretroviral; HIV-1; HIV-associated neurocognitive disorder; Human; Image; Impaired cognition; Incidence; Individual; Innate Immune Response; International; Life Expectancy; Local Therapy; Macaca; Mass Spectrum Analysis; Mediating; Mentorship; Metabolic Pathway; Metabolism; Methodology; Microglia; Minor; Modality; Modeling; Molecular Biology; Multidrug Resistance-Associated Proteins; Neuraxis; Neurologic; Neurons; Neuropathogenesis; OATP Transporters; Pathogenesis; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacogenetics; Pharmacology; Phase; Plasma; Prevalence; Primary Infection; Quality of life; RNA Interference; Research; Research Personnel; Resources; Risk; SIV; Series; Severities; Spatial Distribution; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Substance abuse problem; Therapeutic; Training; Treatment Efficacy; Universities; Viral Load result; Viral reservoir; Viremia; Virus; Virus Replication; Work; antiretroviral therapy; blood-brain barrier permeabilization; brain parenchyma; career development; cellular targeting; cocaine use; cognitive function; comorbidity; drug abuser; experience; macrophage; mass spectrometric imaging; meetings; neuroinflammation; non-drug; pandemic disease; programs; research and development; response; seropositive; skills; substance abuser; therapeutic target

Project Summary/Abstract Human immunodeficiency virus-1 (HIV) enters the central nervous system (CNS) early after primary infection and results in a spectrum of cognitive deficits, collectively termed HIV associated neurocognitive disorders (HAND). While successful in reducing peripheral viral loads to undetectable levels, antiretroviral therapy (ART) does not effectively quell CNS viremia to the same extent. As a result, ART has not decreased the prevalence of HAND, which continues to increase as the life expectancy for seropositive individuals rises. HIV-infected substance abusers exhibit more severe cognitive impairment compared with their non-drug abusing counterparts. Specifically, cocaine use is associated with an accelerated incidence and progression of HAND. This occurs, in part, due to cocaine-mediated increases in HIV replication and resultant blood-brain barrier perturbations, neuroinflammatory responses, and neuronal damage that contribute to the sequelae characteristic of HAND. To understand more fully the impact of cocaine use on the pathogenesis of HAND, I will examine three major mechanisms by which cocaine may interfere with ART effectiveness in the CNS. In Aim 1, I will evaluate the impact of cocaine on ART metabolism by HIV infected macrophages/microglia. These analyses will occur during the K99 phase. Aim 2 will also be performed during the K99 phase, where I will determine the distribution of ART in the brain during comorbid HIV infection and cocaine use by mass spectrometric imaging. In the R00 phase of the award, I will characterize the association between polymorphisms in drug metabolizing enzymes and HAND during Aim 3. Finally, Aim 4 will be performed in the remainder of the R00 phase where I will evaluate the transport of ART across the BBB in the context of cocaine. My past experience with the blood-brain barrier, HAND, and substance abuse will be combined with my current training in CNS-specific innate immune responses and the molecular biology of HIV pathogenesis. However, I require additional training in pharmacology of ART, mass spectrometric modalities, and pharmacogenetics. The institutional resources and outstanding mentorship available at the Johns Hopkins University provide a supportive and rich training environment in which to develop an independent research program. In the K99 phase, I will receive mentorship from a team of distinguished leaders in their respective fields: Drs. Clements, Bumpus, McArthur, and Haughey. Under their guidance and with their support, I will receive technical training in experimental concepts and development of appropriate methodologies, which will be complimented by networking opportunities at national and international scientific meetings. Successful completion of the mentorship, didactic training, research, and career development activities afforded by this K99/R00 Pathway to Independence Award will provide the strong foundation necessary for my successful transition to an independent investigator.

项目摘要/摘要 原发性感染后，人类免疫缺陷病毒1（HIV）早期进入中枢神经系统（CNS） 并导致多种认知缺陷，共同称为HIV相关的神经认知障碍 （手）。虽然成功地将外围病毒负荷降低到无法检测到的水平，但抗逆转录病毒疗法（ART） 在同一程度上没有有效地平息CNS病毒血症。结果，艺术没有降低流行率 随着血清反应阳性个体的预期寿命的增长，它继续增加。感染HIV 与非药物滥用相比，药物滥用者表现出更严重的认知障碍 同行。具体而言，可卡因的使用与手的加速发病率和进展有关。 这部分是由于可卡因介导的HIV复制增加和导致的血脑屏障的增加而发生的 扰动，神经炎症反应和神经元损伤有助于后遗症 手的特征。为了更充分地了解可卡因对手发病机理的影响，I 将检查可卡因可能干扰中枢神经系统的艺术有效性的三种主要机制。在 AIM 1，我将评估可卡因对HIV感染巨噬细胞/小胶质细胞的影响。这些 分析将在K99阶段进行。 AIM 2也将在K99阶段进行，我将在这里进行 确定合并症HIV感染期间大脑中艺术在大脑中的分布和质量可卡因的使用 光谱成像。在奖励的R00阶段，我将表征 在AIM 3期间，药物代谢酶和手的多态性。最后，AIM 4将在 在R00阶段的其余部分，我将在该阶段评估艺术在BBB中的运输 可卡因。我过去对血脑屏障，手和滥用药物的经历将与 我目前在CNS特异性的先天免疫反应和HIV发病机理的分子生物学方面的训练。 但是，我需要在艺术药理学，质谱模式和 药物遗传学。约翰·霍普金斯（Johns Hopkins）提供的机构资源和杰出指导 大学提供了一个支持性丰富的培训环境，可以在其中开发独立研究 程序。在K99阶段，我将从各自的杰出领导人团队中获得指导 字段：Drs。 Clements，Bumpus，McArthur和Haughey。在他们的指导下，在他们的支持下，我将 接受实验概念和开发适当方法的技术培训，这将 在国家和国际科学会议上的网络机会表示赞赏。成功的 完成指导，教学培训，研究和职业发展活动的完成 K99/R00独立奖奖将为我的成功提供必要的基础 过渡到独立研究者。