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

基本信息

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
项目类别：
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

项目摘要

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艾滋病毒感染者面临更大的阿片类药物风险。 µ-阿片受体（MOR）对神经胶质细胞放大继发性神经毒性作用的概念。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重要的是，我们的实验工作表明，OL 很容易受到病毒的感染。转基因小鼠同时暴露于 HIV-1 Tat ± 吗啡 7 天会损害 OLs，从而导致 OLs 损伤。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 是响应急性 Tat 和原位死亡的唯一 CNS 细胞类型。在体外与吗啡共暴露时，Tat 会杀死发育中的 OL，而成熟的 OL 则会出现髓鞘质损失。此外，这两种结果都与 Ca2+- 和 GluR 介导的机制有关 (84)。血管/血脑屏障损伤，始终会导致影像学研究中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在此，我们提出了全面的形态和功能。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联合暴露是间歇性的，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）研究针对两性进行，因为髓鞘形成受到性类固醇的影响。中心假设在 3 个相关目标中得到检验，目标 1 全面了解阿片类药物相关的 OL 和使用 HIV-1 Tat 模型对髓磷脂原位损伤进行电生理学损伤评估；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，通过血脑屏障渗漏评估血管变化。进行组织学监测并与脱髓鞘区域相关。在目标 2 中，从 OL 中删除 MOR 进行测试。阿片类药物的相互作用是否通过对体内 OL 的直接作用而发生；吗啡 ± HIV、Tat 的直接作用； Aim 3 测试了表达 MOR 的人类 OL 上的 gp120 和 gp120 的结构和功能。这些全面的研究回答了有关 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