Development of Brain Organoids to Study the Impact of HIV-1, Drugs of Abuse and Aging on Cognitive Impairment
开发大脑类器官来研究 HIV-1、滥用药物和衰老对认知障碍的影响
基本信息
- 批准号:10208846
- 负责人:
- 金额:$ 73.49万
- 依托单位:
- 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:2020-07-15 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAddressAdultAffectAgeAgingAlkaloidsAutologousBioinformaticsBrainBrain regionCCL2 geneCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCell Culture TechniquesCell LineCell physiologyCellsCellular ImmunologyCerebral cortexCerebrumCicatrixCocaineComplexCytotoxic T-LymphocytesDementiaDevelopmentDisease modelDrug AddictionDrug ScreeningEffectivenessEffector CellEngineeringExhibitsExposure toFOXO3A geneGene ExpressionGene Expression ProfileGenesGenetic TranscriptionGoalsHIVHIV-1HIV-associated neurocognitive disorderHealthcare SystemsHeterogeneityHippocampus (Brain)HumanImageImmuneImpaired cognitionIn VitroIndividualInfectionInterdisciplinary StudyInterleukin-1 betaInternetLeadLinkMediatingMethodsMicrogliaMicroscopyModelingMolecular VirologyNervous System TraumaNeurocognitive DeficitNeuroectodermNeurogliaNeuronsOrganoidsPathogenesisPathway interactionsPeripheral Blood Mononuclear CellPharmaceutical PreparationsPhenotypeProcessProsencephalonReporterReproducibilityResidual stateRewardsRoleSignaling ProteinSteroidsStructureSubstance abuse problemSystemTNF geneTechnologyTestingToxic effectVariantViral ProteinsVirusaging brainanalogantiretroviral therapycell behaviorcell killingcognitive testingcombinatorialcortistatindrug of abusehindbraininduced pluripotent stem cellinnovationinsightlongevity genemicroscopic imagingmouse modelneural networkneuroimmunologyneuroinflammationneurotoxicitynonhuman primatenovelnovel strategiesnovel therapeuticssingle cell analysisstem cell technologystimulant abusetat Proteintranscriptometranscriptome sequencinguptake
项目摘要
PROJECT ABSTRACT
HIV-1 associated neuroinflammation and neurotoxicity lead to cognitive impairments (HIV-1-associated
neurocognitive disorders or HAND) even in those under suppressive antiretroviral therapy (ART). As people
living with HIV-1 age, a compounding effect is occurring, with age associated dementia added to HAND,
leading to a complex web of neurocognitive deficit. This will have tremendous implications for health care
systems not only in the USA but also in the developing world. How HAND develops, and how it could be
modified remain mysterious, largely because It has been very difficult to study HIV-1 infection and HAND in the
human brain. Over the past few years new developments in stem cell technologies have permitted the
differentiation of “cerebral organoids” from induced pluripotent stem cells (iPSCs), and these cultures can be
grown in vitro in conditions that promote three-dimensional expansion of neuroectoderm, in cerebral organoid
or “miniature brain” forms. Cerebral organoids are heterogeneous and form a variety of brain regions, including
ventral forebrain, cerebral cortex, hippocampus, and mid- and hindbrain boundary. They exhibit neurons that
are functional and capable of electrical excitation, and develop microglia. These brain organoids also resemble
human cortical development at the gene expression level, and allow in depth analysis of neural networks, cell
behavior, drug screening, disease modeling, and variations in brain development. While brain-region
composition varies in organoids from different iPSC lines, regional gene-expression patterns remain largely
reproducible across individuals. These create unparalleled new opportunities to study HIV-1 infection of the
brain. We propose to develop our iPSC derived organoid model which incorporates microglia, into one that
better represents an adult mature brain that can support robust HIV-1 infection. With this model, we can test
whether different viruses lead to differential neurotoxicity and if cells other than microglia can be latently
infected with virus. We will test how individual proteins from the virus, including HIV-1 Tat causes neurological
damage, and how ART or drugs such as Didehydro-Cortistatin A (dCA), which cross-neutralizes Tat activity,
affects the process. Interestingly, exposure to Tat also potentiates cocaine-mediated reward mechanisms,
which further promotes HAND, revealing a complex web of interactions between HIV-1 infection and drugs of
substance abuse. We will determine how Tat and cocaine collaborate in neurological damage and determine if
dCA can reverse it. As cerebral organoids provide a model for HIV-1 latency in the brain we can test whether
administration of dCA, can “block-and-lock” any residual virus, and finally whether HIV-1 specific cytotoxic T
cells (CTL) can eliminate virus in the organoid. Together, these studies promise to provide novel insights into
the pathogenesis of HAND, Tat mediated neurotoxicity, effects of cocaine, and the potential link between these
processes. Finally, the model promises to add exciting findings on HIV-1 latency in the brain, and if it can be
silenced or eliminated.
项目摘要
项目成果
期刊论文数量(0)
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DOUGLAS F NIXON其他文献
DOUGLAS F NIXON的其他文献
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{{ truncateString('DOUGLAS F NIXON', 18)}}的其他基金
The Role of Transposable Elements in Healthy Aging and in Alzheimer's Disease
转座元件在健康衰老和阿尔茨海默病中的作用
- 批准号:
10670482 - 财政年份:2022
- 资助金额:
$ 73.49万 - 项目类别:
Development of Brain Organoids to Study the Impact of HIV-1, Drugs of Abuse and Aging on Cognitive Impairment
开发大脑类器官来研究 HIV-1、滥用药物和衰老对认知障碍的影响
- 批准号:
10398244 - 财政年份:2020
- 资助金额:
$ 73.49万 - 项目类别:
Development of Brain Organoids to Study the Impact of HIV-1, Drugs of Abuse and Aging on Cognitive Impairment
开发大脑类器官来研究 HIV-1、滥用药物和衰老对认知障碍的影响
- 批准号:
10063343 - 财政年份:2020
- 资助金额:
$ 73.49万 - 项目类别:
Genetic Risk of HIV Acquisition: Mechanisms of Resilience
感染艾滋病毒的遗传风险:恢复机制
- 批准号:
10077116 - 财政年份:2020
- 资助金额:
$ 73.49万 - 项目类别:
Development of Brain Organoids to Study the Impact of HIV-1, Drugs of Abuse and Aging on Cognitive Impairment
开发大脑类器官来研究 HIV-1、滥用药物和衰老对认知障碍的影响
- 批准号:
10613440 - 财政年份:2020
- 资助金额:
$ 73.49万 - 项目类别:
Genetic Risk of HIV Acquisition: Mechanisms of Resilience
感染艾滋病毒的遗传风险:恢复机制
- 批准号:
10251347 - 财政年份:2020
- 资助金额:
$ 73.49万 - 项目类别:
Elimination of HIV using HERV specific T cells
使用 HERV 特异性 T 细胞消除 HIV
- 批准号:
9744988 - 财政年份:2019
- 资助金额:
$ 73.49万 - 项目类别:
HIV induced anti-cancer HERV immunity in prostate, breast and colon cancers
HIV 诱导前列腺癌、乳腺癌和结肠癌中的抗癌 HERV 免疫
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9315726 - 财政年份:2016
- 资助金额:
$ 73.49万 - 项目类别:
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