HIV opiate interactions in white matter pathology

HIV阿片类药物在白质病理学中的相互作用

• 批准号: 9419501
• 负责人: Kurt F Hauser
• 金额: $ 52.94万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9419501
• 关键词: Abstinence; Acute; Address; Area; Astrocytes; Biochemical; Blood - brain barrier anatomy; Blood Vessels; Brain; CASP3 gene; Cells; Cessation of life; Chronic; Clinical; Complement; Contracts; Demyelinations; Disease; Electron Microscopy; Electrophysiology (science); Exhibits; Exposure to; Extravasation; Genetic study; Golgi Apparatus; Gonadal Steroid Hormones; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Histologic; Histology; Histopathology; Human; In Situ; In Situ Nick-End Labeling; In Vitro; Infection; Inflammatory; Injecting drug user; Injection of therapeutic agent; Injury; Intervention; LoxP-flanked allele; Magnetic Resonance Imaging; Mediating; Membrane; Microglia; Modeling; Monitor; Morphine; Morphology; Mus; Myelin; Myelin Proteins; Neuroglia; Neurologic Deficit; Neurons; Oligodendroglia; Opiates; Opioid Receptor; Outcome; Pallor; Pathology; Patients; Persons; Principal Investigator; Process; Production; Recovery; Recovery of Function; Resolution; Risk; Role; Symptoms; Testing; Therapeutic; Time; Toxic effect; Transgenic Mice; Viral Proteins; Virion; Withdrawal; Withdrawal Symptom; Work; antiretroviral therapy; cell type; design; imaging study; immunocytochemistry; in vivo; indexing; injured; killings; macrophage; myelination; neurotoxic; opioid abuse; programs; repaired; response; sex; therapy design; tractography; ultra high resolution; white matter

Program Director/Principal Investigator (Last, First, Middle): Hauser, Kurt F. & Knapp, Pamela E. HIV-associated neurocognitive disorder (HAND) remains a serious clinical problem even in patients receiving cART, and HIV-infected persons who abuse opiates are at greater risk for HAND. Opiates can act directly via µ-opiate receptors (MOR) on glia to amplify secondary neurotoxic effects. The concept that damage to oligodendroglia (OLs) adds to neurologic deficits in HIV is largely unexplored, even though white matter deficits occur quite early after infection. Importantly, our experimental work shows that OLs are vulnerable to viral protein or HIV exposure. A 7 d co-exposure of transgenic mice to HIV-1 Tat ± morphine damages OLs, which exhibit cytoarchitectural/ultrastructural anomalies, and elevated caspase-3 and TUNEL expression, the latter indicating OL death (69; Fig 1). OLs are the only CNS cell type that die in situ in response to acute Tat and morphine coexposure. In vitro, Tat kills developing OLs, while mature OLs instead show a loss of myelin membrane; both outcomes are related to Ca2+- and GluR-mediated mechanisms (84). OL damage, in addition to vascular/blood brain barrier damage, would contribute to myelin pallor consistently noted in imaging studies. Our central hypothesis is that HIV-1 Tat interacts with opiates to directly injure MOR-expressing OLs. Since immature OLs express MOR and are preferentially vulnerable to HIV/Tat, we predict that myelin repair processes are especially vulnerable. Herein, we propose a comprehensive morphological and functional assessment of the time course of OL and myelin damage caused by acute and chronic (≤3 month) HIV/Tat and morphine coexposure. Opiate exposure is intermittent to better model the exposure of injection drug users (IDUs) who contract HIV. Studies are done in both sexes, as myelination is influenced by sex steroids. The central hypothesis is tested in 3 related aims. Aim 1 develops a thorough picture of opiate-related OL and myelin damage in situ using an HIV-1 Tat model. Function is assessed using electrophysiology; damage to white matter tracts and OLs is assessed by histology, high resolution DT-MRI and tractography/connectivity, stereology, and electron microscopy. Vascular changes as assessed by blood-brain barrier leakiness are monitored histologically and correlated with areas of demyelination. In Aim 2, MOR is deleted from OLs to test whether opiate interactions occur via direct actions on OLs in vivo; the direct effects of morphine ± HIV, Tat and gp120 on MOR-expressing, human OLs are compared in vitro. Aim 3 tests structural and functional recovery after morphine is withdrawn. These comprehensive studies answer critical questions about OL/myelin vulnerability and the potential for their recovery after combined HIV/Tat and opiate insults. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page

项目总监/首席研究员（最后、第一、中间）：Hauser, Kurt F. & Knapp, Pamela E. 即使在接受治疗的患者中，HIV 相关神经认知障碍 (HAND) 仍然是一个严重的临床问题 cART 和滥用阿片类药物的 HIV 感染者发生 HAND 的风险更大。阿片类药物可以直接通过 神经胶质细胞上的μ阿片受体（MOR）可放大继发性神经毒性作用。损害的概念 尽管白质缺陷，少突神经胶质细胞（OLs）会增加艾滋病毒的神经缺陷，但在很大程度上尚未被探索 感染后很早就发生。重要的是，我们的实验工作表明，OL 很容易受到病毒的影响 蛋白质或艾滋病毒暴露。转基因小鼠同时暴露于 HIV-1 Tat ± 吗啡 7 天会损害 OLs， 表现出细胞结构/超微结构异常，并且 caspase-3 和 TUNEL 表达升高，后者 表明 OL 死亡（69；图 1）。 OL 是唯一一种响应急性 Tat 和原位死亡的中枢神经系统细胞类型。 吗啡共暴露。在体外，Tat 会杀死发育中的 OL，而成熟的 OL 则表现出髓磷脂的损失 膜;这两种结果都与 Ca2+- 和 GluR 介导的机制有关 (84)。 OL伤害，另外 血管/血脑屏障损伤，会导致影像学研究中一致注意到的髓磷脂苍白。 我们的中心假设是 HIV-1 Tat 与阿片类药物相互作用，直接损伤表达 MOR 的 OL。 由于未成熟的 OL 表达 MOR 并且更容易感染 HIV/Tat，因此我们预测髓磷脂修复 进程特别容易受到攻击。在此，我们提出了一种全面的形态和功能 评估急性和慢性（≤3个月）HIV/Tat引起的OL和髓磷脂损伤的时间过程 吗啡共暴露。阿片剂暴露是间歇性的，以更好地模拟注射吸毒者的暴露情况 感染艾滋病毒的人（注射吸毒者）。研究在两性中进行，因为髓鞘形成受到性类固醇的影响。这 中心假设在 3 个相关目标中进行检验。目标 1 全面了解阿片类药物相关的 OL 和 使用 HIV-1 Tat 模型进行原位髓磷脂损伤。使用电生理学评估功能；损害 通过组织学、高分辨率 DT-MRI 和纤维束成像/连接性评估白质纤维束和 OL， 体视学和电子显微镜。通过血脑屏障渗漏评估的血管变化是 进行组织学监测并与脱髓鞘区域相关。在目标 2 中，MOR 从 OL 中删除以进行测试 阿片类药物的相互作用是否通过直接作用于体内 OL 发生；吗啡的直接影响 ± HIV、Tat 和 gp120 在表达 MOR 的人类 OL 上进行了体外比较。目标 3 测试结构和功能 吗啡戒断后恢复。这些综合研究回答了有关 OL/髓磷脂的关键问题 艾滋病毒/塔特和阿片类药物联合伤害后的脆弱性和康复潜力。 OMB 编号 0925-0001/0002（修订版 03/16 已批准至 10/31/2018） 页面延续格式页面