SDF-1 and neurogenesis in HIV-1 associated dementia
SDF-1 和 HIV-1 相关痴呆的神经发生
基本信息
- 批准号:8266024
- 负责人:
- 金额:$ 36.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-07-01 至 2014-02-28
- 项目状态:已结题
- 来源:
- 关键词:AIDS Dementia ComplexAcuteAffectAlzheimer&aposs DiseaseAnimalsApoptosisAreaAstrocytesAutopsyBasal GangliaBiological AssayBrainCXCR4 ReceptorsCXCR4 geneCathepsin GCell Culture SystemCell CycleCell Differentiation processCell ProliferationCell SurvivalCell physiologyCellsCentral Nervous System Viral DiseasesCerebrospinal FluidChemotactic FactorsChemotaxisChronicCleaved cellCoculture TechniquesConfocal MicroscopyCyclin D1DataDementiaDetectionDevelopmentDiseaseEncephalitisEnvironmentEnzymesEventGelatinase AGene ClusterGenerationsGoalsGrowth FactorHIVHIV-1HarvestHealthHigh Pressure Liquid ChromatographyHippocampus (Brain)HomeostasisHumanImmuneImmunohistochemistryImpairmentIn Situ HybridizationIn Situ Nick-End LabelingIn VitroIndividualInfectionInflammationInflammatoryInjection of therapeutic agentInterleukin-12InterleukinsInvestigationKineticsKnock-outKnockout MiceLabelLeukocyte ElastaseLifeLigandsLipopolysaccharidesMatrix MetalloproteinasesMeasurementMediatingMedical centerMethodsMicrogliaMitogen-Activated Protein KinasesModalityModelingModificationMonitorMononuclearMultiple SclerosisMusNebraskaNervous system structureNeurodegenerative DisordersNeurogliaNeuronal DifferentiationNeuronal InjuryNeuronsNeuropathogenesisNeurovirologyOligodendrogliaParkinson DiseasePathologyPathway interactionsPatientsPeptidesPhagocytesPhaseProcessProductionPropertyProteinsRNARecombinantsRegulationResearchResourcesReverse Transcriptase Polymerase Chain ReactionRodent ModelRoleSCID MiceSignal PathwaySignal TransductionSiteSmall Interfering RNAStaining methodStainsStromal Cell-Derived Factor 1SystemTNF geneTechniquesTestingTherapeuticThickThymidineTimeTissuesTranscriptUniversitiesWestern BlottingWorkastrogliosisbrain tissuecell motilitychemokinechemokine receptorcytokinedeprivationgliogenesisimmune activationimmunocytochemistryin vivoinjuredinjury and repairliquid chromatography mass spectrometrymacrophagemigrationmonocytemouse modelnerve stem cellneurogenesisneurotoxicnovel therapeuticsoverexpressionpreventrelating to nervous systemrelease factorrepairedresearch studyresponsesingle photon emission computed tomographytissue repairtranscription factortreatment effect
项目摘要
DESCRIPTION (provided by applicant): Neural progenitor cells (NPC) are present throughout life and replenish neurons and glia (astrocytes and oligodendrocytes) through neurogenesis, a process that requires proper migration, proliferation and differentiation of NPC. Neurogenesis appears to be dysfunctional in neurodegenerative disorders including HIV-1 associated dementia (HAD), Alzheimer's and Parkinson's diseases, where dead or injured neurons are not replaced. HAD is a neurodegenerative disorder where HIV-1-infected and activated brain mononuclear phagocytes (MP; perivascular macrophages and microglia) mediate inflammatory conditions that alter brain homeostasis. We recently demonstrated that HIV-1-infected and activated macrophages inhibit neurogenesis but enhance gliogenesis. We propose this gliogenesis is mediated through brain inflammation attributable to the dysregulation of stromal cell-derived factor 1 (SDF-1). SDF-1 is an endogenous ligand for the chemokine receptor, CXCR4, which is highly expressed on human NPC and mediates NPC migration. Improper SDF-1 and CXCR4 function can affect neural repair by impairing NPC migration. SDF-1 is released in response to glial activation, mediated by inflammatory cytokines from HIV-1-infected and activated MP such as Interleukin one beta (IL-12). SDF-1 is elevated in the cerebrospinal fluid of HAD patients. Activated matrix metalloproteinase-2 (MMP-2) is produced by HIV-1 infected and activated MP and cleaves SDF-1 resulting in a neurotoxic fragment. This proposal will examine the role of HIV-1-infected and activated macrophage in brain inflammation and their effects on neurogenesis. We hypothesize HIV-1-infected and immune- activated MP inhibit neuronal differentiation and promote gliogenesis. Specifically, we propose this shift in neurogenesis is dependent upon SDF-1 produced by activated astrocytes. This gliogenesis may be a consequence of modification/degradation of SDF-1 by factors released from HIV-1-infected MP leading to impairment of normal SDF-1/CXCR4 mediated NPC migration, survival, proliferation and differentiation, generating an environment detrimental to CNS repair. Using our human NPC culture system in a severe combined immune deficient (SCID) HIV-1 encephalitis (HIVE) mouse model, this project will mimic HIV-1-infection and immune-activation of brain MP and investigate the effect of CNS inflammation on neurogenesis. Elucidating the mechanisms of SDF-1/CXCR4 influence on neurogenesis may identify new therapeutic strategies for treating HAD and other neurodegenerative disorders. PUBLIC HEALTH RELEVANCE Globally, about 40 million people are infected with HIV. 10-20% of these individuals will eventually develop HIV-associated dementia (HAD). This work will elucidate mechanisms through which neurogenesis is affected by HAD, which could identify new therapeutic strategies for treating HAD and other neurodegenerative disorders.
描述(由申请人提供):神经祖细胞(NPC)存在于整个生命过程中,并通过神经发生补充神经元和神经胶质细胞(星形胶质细胞和少突胶质细胞),这是一个需要NPC适当迁移、增殖和分化的过程。神经发生似乎在神经退行性疾病中功能障碍,包括HIV-1相关痴呆(HAD),阿尔茨海默病和帕金森病,其中死亡或受伤的神经元没有被替换。HAD是一种神经退行性疾病,其中HIV-1感染和激活的脑单核吞噬细胞(MP;血管周围巨噬细胞和小胶质细胞)介导改变脑内稳态的炎性病症。我们最近发现,HIV-1感染和激活的巨噬细胞抑制神经发生,但增强胶质细胞的生成。我们提出这种胶质细胞生成是通过脑炎症介导的,可归因于基质细胞衍生因子1(SDF-1)的失调。SDF-1是趋化因子受体CXCR 4的内源性配体,CXCR 4在人NPC上高度表达并介导NPC迁移。不适当的SDF-1和CXCR 4功能可以通过损害NPC迁移来影响神经修复。SDF-1在神经胶质细胞活化时释放,由HIV-1感染和活化MP的炎性细胞因子如白细胞介素1 β(IL-12)介导。SDF-1在HAD患者的脑脊液中升高。活化的基质金属蛋白酶-2(MMP-2)由HIV-1感染和活化的MP产生,并切割SDF-1,产生神经毒性片段。这项建议将研究HIV-1感染和激活的巨噬细胞在脑炎症中的作用及其对神经发生的影响。我们假设HIV-1感染和免疫激活的MP抑制神经元分化并促进胶质细胞生成。具体来说,我们提出这种神经发生的转变依赖于活化的星形胶质细胞产生的SDF-1。这种胶质细胞生成可能是由HIV-1感染的MP释放的因子修饰/降解SDF-1的结果,导致正常SDF-1/CXCR 4介导的NPC迁移、存活、增殖和分化受损,产生对CNS修复有害的环境。利用我们的人NPC培养系统在严重联合免疫缺陷(SCID)HIV-1脑炎(HIVE)小鼠模型中,本项目将模拟HIV-1感染和脑MP的免疫激活,并研究CNS炎症对神经发生的影响。阐明SDF-1/CXCR 4影响神经发生的机制可能会为治疗HAD和其他神经退行性疾病找到新的治疗策略。全球约有4000万人感染艾滋病毒。这些人中有10-20%最终会发展为艾滋病毒相关性痴呆(HAD)。这项工作将阐明神经发生受HAD影响的机制,这可以确定治疗HAD和其他神经退行性疾病的新治疗策略。
项目成果
期刊论文数量(0)
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Jialin Charles Zheng其他文献
Jialin Charles Zheng的其他文献
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{{ truncateString('Jialin Charles Zheng', 18)}}的其他基金
Glutaminase and its neurotoxic link to HAND
谷氨酰胺酶及其与 HAND 的神经毒性联系
- 批准号:
9357733 - 财政年份:2016
- 资助金额:
$ 36.02万 - 项目类别:
Glutaminase and its neurotoxic link to HAND
谷氨酰胺酶及其与 HAND 的神经毒性联系
- 批准号:
9146113 - 财政年份:2016
- 资助金额:
$ 36.02万 - 项目类别:
ACTIVITY MODULATION OF PROTEIN KINASE AND PHOSPHATASE
蛋白激酶和磷酸酶的活性调节
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8362286 - 财政年份:2011
- 资助金额:
$ 36.02万 - 项目类别:
ACTIVITY MODULATION OF PROTEIN KINASE AND PHOSPHATASE
蛋白激酶和磷酸酶的活性调节
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8170287 - 财政年份:2010
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$ 36.02万 - 项目类别:
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HIV 1 引起的神经元损伤的细胞机制
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7959385 - 财政年份:2009
- 资助金额:
$ 36.02万 - 项目类别:
SDF-1 and neurogenesis in HIV-1 associated dementia
SDF-1 和 HIV-1 相关痴呆的神经发生
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7869501 - 财政年份:2008
- 资助金额:
$ 36.02万 - 项目类别:
SDF-1 and neurogenesis in HIV-1 associated dementia
SDF-1 和 HIV-1 相关痴呆的神经发生
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7647340 - 财政年份:2008
- 资助金额:
$ 36.02万 - 项目类别:
HIV-1 Clade Diversity and Macrophage Mediated Neurotoxicity in HIV-1 Dementia
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- 批准号:
7612649 - 财政年份:2008
- 资助金额:
$ 36.02万 - 项目类别:
SDF-1 and neurogenesis in HIV-1 associated dementia
SDF-1 和 HIV-1 相关痴呆的神经发生
- 批准号:
8026004 - 财政年份:2008
- 资助金额:
$ 36.02万 - 项目类别:
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HIV 1 引起的神经元损伤的细胞机制
- 批准号:
7719942 - 财政年份:2008
- 资助金额:
$ 36.02万 - 项目类别:
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