Oligodendrocyte damage and dysfunction in HIV associated neurocognitive disorder

HIV相关神经认知障碍中的少突胶质细胞损伤和功能障碍

• 批准号: 10609743
• 负责人: JUDITH B GRINSPAN
• 金额: $ 11.04万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-16 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10609743
• 关键词: Animal Model; Brain; Cell Culture System; Cell Death; Cellular Stress; Cuprizone; Data; Demyelinations; Development; Dose; Exhibits; Functional disorder; Generations; Genes; HIV; HIV Infections; HIV Seropositivity; HIV-associated neurocognitive disorder; Human; Image Analysis; In Vitro; Integrase Inhibitors; Lesion; Lipids; Lopinavir; Maintenance; Membrane; Modeling; Mus; Myelin; Myelin Basic Proteins; Myelin Proteins; Myelin Sheath; Neurodegenerative Disorders; Nucleosides; Oligodendroglia; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Protease Inhibitor; Regulation; Reporting; Reverse Transcriptase Inhibitors; Ritonavir; Rodent Model; Severities; Thick; Time; Viral; antiretroviral therapy; astrogliosis; cell type; intravenous administration; myelination; neuroinflammation; neuropathology; oligodendrocyte precursor; protein expression; remyelination; transcriptome; white matter; white matter change; white matter damage

Despite effective viral control by Antiretroviral therapy (ART), HIV associated neurocognitive disorder (HAND) persists in 30-50% of patients. In the ART era, neuropathology has shifted from a rapidly progressing encephalitic condition to a prolonged neurodegenerative disease with pathologic features including astrogliosis, microgliosis, dendritic damage, and especially white matter deficits. White matter alterations include decreased myelin sheath thickness, myelin lesions, and abnormal myelin protein expression. The severity of white matter damage correlates with the amount of time on ART therapy. Transcriptome analysis of HIV patients on ART revealed decreases in genes associated with oligodendrocyte maturation and myelination. Using a well-characterized oligodendrocyte culture model, we have recently reported that representative drugs from the protease inhibitor class of ART (ritonavir and lopinavir) inhibit differentiation of oligodendrocyte precursors to mature oligodendrocytes in a dose-dependent manner, independent of cell death. Intravenous administration of ritonavir to mice for only two weeks significantly decreased the expression of several myelin proteins. Further, myelin basic protein (MBP) was significantly decreased in the cortex of HIV patients who were on ART and exhibited HAND. These findings are the first to demonstrate on an experimental level that ART can disrupt myelin development and maintenance. We hypothesize that ART compounds alter oligodendrocyte differentiation, function, and survival, contributing to the persistence of HAND in the post-ART era. Our new preliminary data suggest that a subset of drugs from the nucleoside reverse transcriptase inhibitor (NRTI) class and from the integrase inhibitor class also decrease oligodendrocyte differentiation in vitro. In this proposal, we will use our oligodendrocyte cell culture system to identify mechanisms by which ART drugs decrease oligodendrocyte maturation, including lipid regulation and cellular stress pathways in oligodendrocytes, which regulate myelin membrane generation. The second aim of this proposal will examine whether ART drugs can impede remyelination after a demyelinating insult using small animal model of HIV-induced neuroinflammation and the cuprizone model of demyelination. The third aim will compare white matter changes in our rodent model with human patients using image analysis. Results from these aims should help devise more rational drug therapies without myelin deficits to reduce HAND.

尽管通过抗逆转录病毒疗法（ART）有效控制病毒，但HIV相关的神经认知障碍（Hand） 30-50％的患者持续存在。在艺术时代，神经病理学已经从快速发展 具有病理特征的长时间神经退行性疾病的脑病状况 星形胶质细胞增多，小胶质细胞增多，树突状损害，尤其是白质缺陷。白质改变 包括减少髓鞘层厚度，髓磷脂病变和异常髓磷脂蛋白表达。这 白质损害的严重程度与艺术疗法的时间相关。转录组分析 HIV患者的ART患者显示，与少突胶质细胞成熟和 髓鞘。使用特征良好的少突胶质细胞培养模型，我们最近报告说 来自蛋白酶抑制剂类（Ritonavir和Lopinavir）的代表性药物抑制了分化的 以剂量依赖性的方式对成熟的少突胶质细胞的少突胶质细胞前体，与细胞无关 死亡。静脉注射利托那韦仅向小鼠施用仅两周，显着降低了表达 几种髓磷脂蛋白。此外，HIV皮质中的髓磷脂碱性蛋白（MBP）显着降低 正在艺术并展示手的患者。这些发现是第一个在 艺术可以破坏髓磷脂的发育和维护的实验水平。我们假设艺术 化合物改变了少突胶质细胞的分化，功能和生存，有助于手的持久性 在艺术后时代。我们的新初步数据表明，来自核苷反面的药物子集 转录酶抑制剂（NRTI）类别和整合酶抑制剂类别也降低了少突胶质细胞 体外分化。在此提案中，我们将使用少突胶质细胞培养系统来识别 ART药物减少少突胶质细胞成熟的机制，包括脂质调节和细胞 少突胶质细胞中的应力途径，这些途径调节髓鞘膜产生。第二个目标 提案将检查艺术药物在使用小的侮辱性侮辱后是否会阻碍透明度 HIV引起的神经炎症和脱髓鞘模型的动物模型。第三个目标 使用图像分析将啮齿动物模型中的白质变化与人类患者进行比较。结果 这些目标应有助于在没有髓磷脂缺陷的情况下设计更多理性的药物疗法以减少手。