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

基本信息

批准号：
10095867
负责人：
JUDITH B GRINSPAN
金额：
$ 42.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-25 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10095867
关键词：
Address Adult Affect Animal Model Attenuated Behavioral Brain Cell Culture System Cell Death Cells Cellular Stress Cognitive Complement Cuprizone Data Demyelinations Development Diffusion Magnetic Resonance Imaging Dose Exhibits Functional disorder Funding Gene Expression Generations Genes Goals HIV HIV Infections HIV Protease Inhibitors HIV Seropositivity HIV antiretroviral HIV tat Protein HIV therapy HIV-associated neurocognitive disorder Human Image Analysis Impaired cognition In Vitro Incidence Injury Integrase Inhibitors Intravenous Lesion Lipids Lopinavir Maintenance Measures Membrane Meta-Analysis Modeling Molecular Mus Myelin Myelin Basic Proteins Myelin Proteins Myelin Sheath Neurodegenerative Disorders Neurons Nucleosides Oligodendroglia Pathologic Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Protease Inhibitor Recovery Regulation Reporting Reverse Transcriptase Inhibitors Ritonavir Rodent Rodent Model Role Severities Structure Testing Therapeutic Intervention Thick Time Viral antiretroviral therapy astrogliosis biological adaptation to stress cell type clinically significant cohort compliance behavior design imaging study in vitro Model in vivo inflammatory marker intravenous administration lipid metabolism macrophage member motor disorder myelination neuroimaging marker neuroinflammation neuropathology non-invasive monitor oligodendrocyte precursor protein expression remyelination response success transcriptome white matter white matter change white matter damage

项目摘要

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。