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:10609743
- 负责人:
- 金额:$ 11.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Animal ModelBrainCell Culture SystemCell DeathCellular StressCuprizoneDataDemyelinationsDevelopmentDoseExhibitsFunctional disorderGenerationsGenesHIVHIV InfectionsHIV SeropositivityHIV-associated neurocognitive disorderHumanImage AnalysisIn VitroIntegrase InhibitorsLesionLipidsLopinavirMaintenanceMembraneModelingMusMyelinMyelin Basic ProteinsMyelin ProteinsMyelin SheathNeurodegenerative DisordersNucleosidesOligodendrogliaPathologicPathway interactionsPatientsPharmaceutical PreparationsPharmacotherapyProtease InhibitorRegulationReportingReverse Transcriptase InhibitorsRitonavirRodent ModelSeveritiesThickTimeViralantiretroviral therapyastrogliosiscell typeintravenous administrationmyelinationneuroinflammationneuropathologyoligodendrocyte precursorprotein expressionremyelinationtranscriptomewhite matterwhite matter changewhite 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.
尽管抗逆转录病毒治疗(ART)有效控制病毒,但HIV相关神经认知障碍(HAND)
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JUDITH B GRINSPAN其他文献
JUDITH B GRINSPAN的其他文献
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{{ truncateString('JUDITH B GRINSPAN', 18)}}的其他基金
Effects of HIV and ART on myelination in the adolescent
HIV 和 ART 对青少年髓鞘形成的影响
- 批准号:
10258486 - 财政年份:2021
- 资助金额:
$ 11.04万 - 项目类别:
Effects of HIV and ART on myelination in the adolescent
HIV 和 ART 对青少年髓鞘形成的影响
- 批准号:
10556341 - 财政年份:2021
- 资助金额:
$ 11.04万 - 项目类别:
Effects of HIV and ART on myelination in the adolescent
HIV 和 ART 对青少年髓鞘形成的影响
- 批准号:
10377541 - 财政年份:2021
- 资助金额:
$ 11.04万 - 项目类别:
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:
10095867 - 财政年份:2020
- 资助金额:
$ 11.04万 - 项目类别:
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:
8410133 - 财政年份:2012
- 资助金额:
$ 11.04万 - 项目类别:
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:
8879215 - 财政年份:2012
- 资助金额:
$ 11.04万 - 项目类别:
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:
9085413 - 财政年份:2012
- 资助金额:
$ 11.04万 - 项目类别:
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:
10318942 - 财政年份:2012
- 资助金额:
$ 11.04万 - 项目类别:
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:
8698817 - 财政年份:2012
- 资助金额:
$ 11.04万 - 项目类别:
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:
8511840 - 财政年份:2012
- 资助金额:
$ 11.04万 - 项目类别:
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