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

计划主任/首席研究员（最后，第一，中间）：豪瑟，库尔特·F。和纳普，帕梅拉·E。 即使在接受的患者中，与HIV相关的神经认知障碍（Hand）仍然是一个严重的临床问题 滥用优化的购物车和艾滋病毒感染的人面临更大的手动风险。 Opates可以直接通过 粒神经胶质上的µ型受体（MOR），以扩增继发性神经毒性作用。损害的概念 寡头（OLS）在HIV中增加了神经系统缺陷，即使白质缺陷也很大 感染后很早就发生。重要的是，我们的实验工作表明OLS容易受到病毒的影响 蛋白质或HIV暴露。转基因小鼠的7 d共同暴露于HIV-1 TAT±吗啡损害OLS，这 裸露的细胞结构/超微结构异常，caspase-3和Tunel表达升高，后者 指示死亡（69;图1）。 OLS是唯一响应急性TAT和 吗啡共曝光。在体外，Tat杀死了发展中的OLS，而成熟的OLS则显示出髓磷脂的损失 膜;这两个结果均与Ca2+ - 和Glur介导的机制有关（84）。 ol损坏，另外 对于血管/血脑屏障的损害，在成像研究中始终注意到髓磷脂苍白。 我们的中心假设是HIV-1 TAT与优化相互作用，以直接损害表达Mor的OL。 由于未成熟的OLS表达了MOR，并且优先容易受到HIV/TAT的影响，因此我们预测髓磷脂修复 过程特别脆弱。本文中，我们提出了一个全面的形态和功能 评估由急性和慢性（≤3个月）HIV/TAT引起的OL和髓磷脂损害的时间过程 吗啡共曝光。鸦片暴露是间歇性的，可以更好地建模注射吸毒者的接触 （IDU）谁染上了艾滋病毒。在两性中都进行了研究，因为髓鞘化受性类固醇的影响。这 中央假设在3个相关目的中进行了检验。 AIM 1开发了与优化相关OL的详尽图片和 使用HIV-1 TAT模型原位髓磷脂损伤。使用电生理学评估功能；损坏 白质区和OLS通过组织学，高分辨率DT-MRI和拖拉机/连通性评估， 立体和电子显微镜。血脑屏障泄漏所评估的血管变化是 在组织学上监测并与脱髓鞘区域相关。在AIM 2中，将MOR从OLS删除到测试 是否通过对体内OLS的直接作用发生扩展相互作用；吗啡±HIV，TAT的直接作用 在表达Mor的GP120和GP120体外比较了人类OLS。 AIM 3测试结构和功能 撤回吗啡后的恢复。这些全面的研究回答了有关OL/髓鞘的关键问题 脆弱性及其在联合艾滋病毒（HIV/TAT）结合后恢复的潜力并优化侮辱。 OMB编号0925-0001/0002（Rev. 03/16批准通过10/31/2018）页面延续格式页面