Astrocyte connexin43 containing channels amplify CNS dysfunction in NeuroAIDS
含有通道的星形胶质细胞连接蛋白 43 会放大 NeuroAIDS 中的中枢神经系统功能障碍
基本信息
- 批准号:8467056
- 负责人:
- 金额:$ 13.98万
- 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:2012-05-07 至 2013-06-30
- 项目状态:已结题
- 来源:
- 关键词:AIDS neuropathyAddressAnimal ModelAnimalsAnti-Retroviral AgentsApoptosisAreaAstrocytesBlood - brain barrier anatomyBrainCell DeathCell surfaceCellsCentral Nervous System InfectionsCharacteristicsCognitive deficitsCollaborationsCommunicationConnexin 43CytoplasmDataDementiaDevelopmentEndothelial CellsExtracellular SpaceFunctional disorderGap JunctionsGoalsHIVHIV-1Homologous GeneHumanImmuneImmune responseImpaired cognitionIn VitroIndividualInfectionInflammationInflammatoryInvestigationKnockout MiceLettersLifeMediatingMicrogliaMicroinjectionsMinorMolecularMusNervous System PhysiologyNervous System TraumaNeuraxisNeurodegenerative DisordersNeurologicNeurologic DysfunctionsNeuronsNeuropathogenesisPathogenesisPathway interactionsPersonsPlayPopulationPrevalencePrincipal InvestigatorProductionProteinsPublic HealthPublicationsRegulationResearchRoleSignal TransductionTechniquesTimeToxic effectUniversitiesViralVirus Diseasesantiretroviral therapybasegap junction channelhealth organizationin vivoinhibitor/antagonistmacrophagemigrationmotor deficitmotor impairmentmouse modelnervous system disorderneuronal survivalnew therapeutic targetnovelprogramsresearch studysuccesstherapy developmenttool
项目摘要
DESCRIPTION (provided by applicant): As of 2010, an estimated 34 million persons worldwide were living with human immunodeficiency virus (HIV) infection (Word Health Organization and UN estimations). Early after primary infection, HIV enters the CNS and causes cognitive and motor impairment in 30-60% of infected individuals, even in the antiretroviral era. As infected individuals are living longer, the prevalence of neurological complications due to HIV CNS infection has increased. The cellular basis and mechanisms by which HIV-1 causes neuropathogenesis, or NeuroAIDS, are still not well understood. Astrocytes are key cells in the CNS that regulate BBB integrity, CNS inflammation, immune responses and neuronal survival. HIV only infects a small percentage of these cells and minimal to undetectable viral production is detected. Nevertheless, our data demonstrate for first time that HIV infected astrocytes, through gap junction channels and perhaps hemichannels, can amplify inflammation and CNS damage. We hypothesize that Cx43 containing gap junctions (GJ) and hemichannels (uHC) amplify intercellular signals generated in few HIV infected astrocytes to surrounding uninfected cells resulting in cellular toxicity, BBB disruption and secretion of DKK1 leading to the CNS dysfunction often observed in the HIV infected population even in the current antiretroviral era, where viral replication is minimal. To address this hypothesis we will expand upon our extensive Preliminary Studies demonstrating the participation of these channels in astrocyte, neuronal and blood brain barrier (BBB) dysfunction, as well in amplification of cell activation and inflammation
in HIV infected astrocytes and in uninfected cells. These data will characterize novel pathways of HIV toxicity within the brain and will identify the role of these channels in CNS dysfunction. The results obtained from this proposal should indicate potential novel therapeutic targets to limit the devastating consequences of NeuroAIDS. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page
描述(由申请人提供):截至2010年,全球估计有3400万人感染了人类免疫缺陷病毒(HIV)(世界卫生组织和联合国估计)。初次感染后早期,艾滋病毒进入中枢神经系统,导致30%-60%的感染者认知和运动障碍,即使在抗逆转录病毒时代也是如此。随着感染者寿命的延长,由艾滋病毒中枢神经系统感染引起的神经系统并发症的患病率也增加了。HIV-1引起神经发病或神经艾滋病的细胞学基础和机制仍不是很清楚。星形胶质细胞是中枢神经系统中调节血脑屏障完整性、中枢神经系统炎症、免疫反应和神经元存活的关键细胞。艾滋病毒只感染这些细胞中的一小部分,并检测到极少或无法检测到的病毒产生。然而,我们的数据首次表明,感染HIV的星形胶质细胞,通过缝隙连接通道,可能还有半脑沟,可以放大炎症和中枢神经系统的损伤。我们推测,含有缝隙连接(GJ)和半通道(UHC)的Cx43将少数HIV感染的星形胶质细胞产生的细胞间信号放大到周围的未感染细胞,导致细胞毒性、血脑屏障中断和Dkk1的分泌,导致即使在当前病毒复制最少的抗逆转录病毒时代,HIV感染人群中也经常观察到中枢神经系统功能障碍。为了解决这一假设,我们将扩展我们广泛的初步研究,证明这些通道参与星形胶质细胞、神经元和血脑屏障(BBB)功能障碍,以及细胞激活和炎症的放大
在感染艾滋病毒的星形胶质细胞和未感染的细胞中。这些数据将描述HIV在大脑中毒性的新途径,并将确定这些途径在中枢神经系统功能障碍中的作用。从这项提议中获得的结果应该表明潜在的新的治疗目标,以限制神经艾滋病的破坏性后果。PHS 398/2590(06/09版)页面续格式页面
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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Eliseo A Eugenin其他文献
Eliseo A Eugenin的其他文献
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{{ truncateString('Eliseo A Eugenin', 18)}}的其他基金
Metabolic strategies to eliminate CNS Myeloid Viral Reservoirs
消除中枢神经系统骨髓病毒库的代谢策略
- 批准号:
10630131 - 财政年份:2021
- 资助金额:
$ 13.98万 - 项目类别:
Metabolic strategies to eliminate CNS Myeloid Viral Reservoirs
消除中枢神经系统骨髓病毒库的代谢策略
- 批准号:
10458785 - 财政年份:2021
- 资助金额:
$ 13.98万 - 项目类别:
Metabolic strategies to eliminate CNS Myeloid Viral Reservoirs
消除中枢神经系统骨髓病毒库的代谢策略
- 批准号:
10327167 - 财政年份:2021
- 资助金额:
$ 13.98万 - 项目类别:
Role of pannexin-1 hemichannels in NeuroAIDS
pannexin-1 半通道在 NeuroAIDS 中的作用
- 批准号:
10166965 - 财政年份:2018
- 资助金额:
$ 13.98万 - 项目类别:
Role of pannexin-1 hemichannels in NeuroAIDS
pannexin-1 半通道在 NeuroAIDS 中的作用
- 批准号:
9271671 - 财政年份:2017
- 资助金额:
$ 13.98万 - 项目类别:
Astrocyte connexin43 containing channels amplify CNS dysfunction in NeuroAIDS
含有通道的星形胶质细胞连接蛋白 43 会放大 NeuroAIDS 中的中枢神经系统功能障碍
- 批准号:
8329102 - 财政年份:2012
- 资助金额:
$ 13.98万 - 项目类别:
Astrocyte connexin43 containing channels amplify CNS dysfunction in NeuroAIDS
含有通道的星形胶质细胞连接蛋白 43 会放大 NeuroAIDS 中的中枢神经系统功能障碍
- 批准号:
9914883 - 财政年份:2012
- 资助金额:
$ 13.98万 - 项目类别:
Astrocyte connexin43 containing channels amplify CNS dysfunction in NeuroAIDS
含有通道的星形胶质细胞连接蛋白 43 会放大 NeuroAIDS 中的中枢神经系统功能障碍
- 批准号:
8826812 - 财政年份:2012
- 资助金额:
$ 13.98万 - 项目类别:
Astrocyte connexin43 containing channels amplify CNS dysfunction in NeuroAIDS
含有通道的星形胶质细胞连接蛋白 43 会放大 NeuroAIDS 中的中枢神经系统功能障碍
- 批准号:
8793824 - 财政年份:2012
- 资助金额:
$ 13.98万 - 项目类别:
Astrocyte connexin43 containing channels amplify CNS dysfunction in NeuroAIDS
含有通道的星形胶质细胞连接蛋白 43 会放大 NeuroAIDS 中的中枢神经系统功能障碍
- 批准号:
9321162 - 财政年份:2012
- 资助金额:
$ 13.98万 - 项目类别:
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