Human/Animal Brain Chimera in drugs of abuse and HIV
滥用药物和艾滋病毒中的人/动物脑嵌合体
基本信息
- 批准号:10543385
- 负责人:
- 金额:$ 52.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-15 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:AIDS populationAIDS/HIV problemAbstinenceAcquired Immunodeficiency SyndromeAddressAffectAnimal ModelAnimalsAreaAstrocytesAutopsyBiological AssayBiologyBloodBlood - brain barrier anatomyBrainCD34 geneCell modelCellsChimera organismCollaborationsDNA RepositoryDrug abuseEngraftmentEvolutionFunctional disorderGene Expression ProfileGenetic TranscriptionGenetic studyGenotypeGluesHIVHIV InfectionsHIV SeronegativityHIV SeropositivityHIV-associated neurocognitive disorderHomeostasisHumanImmunofluorescence ImmunologicImpaired cognitionIn SituIn VitroIndividualInfectionInflammatoryInflammatory ResponseInvadedKineticsKnowledgeLeadLearningLinkLymphocyteMETH abuserMediatingMediator of activation proteinMethamphetamineModelingMolecularMusNational Institute of Drug AbuseNational Institute of Neurological Disorders and StrokeNeurocognitive DeficitNeurodegenerative DisordersNeurogliaNeuronal InjuryNeuropathogenesisNeurotransmittersOrganPeripheralPeripheral Blood Mononuclear CellPersonsPharmaceutical PreparationsPhenotypePopulationResearchResourcesRisk FactorsRoleTechniquesTestingTimeTissuesUnited States National Institutes of HealthViralabuse victimantiretroviral therapyblood-brain barrier disruptionbrain cellbrain tissuecell repositorycohortcomorbiditydrug of abuseexperiencegenetic signaturegenome sequencinghuman modelhumanized mouseimmunoregulationin vitro activityin vivoinduced pluripotent stem cellinnovationmethamphetamine effectmethamphetamine usemethamphetamine usermouse modelneglectnerve stem cellneurotrophic factorneurotropicnewsnext generationnovelpsychostimulantrepairedresponsetool
项目摘要
Abstract: Drugs of abuse are a significant comorbidity among people living with HIV. Methamphetamine
(Meth), in particular, is a potent psychostimulant frequently abused in the HIV/AIDS population. Both HIV and
Meth are risk factors for cognitive decline even in the era of combination antiretroviral therapy (cART). The
mechanism(s) that drive and/or contribute to this cognitive decline, collectively known as HIV-Associated
Neurocognitive Impairment (HAND), are not entirely clear nor is the impact of Meth on HIV reservoir. Meth itself
enhances HIV replication. We will use two innovative humanized animal models to address the interface between
glial cells, Meth and HIV reservoir. huAstro/HuPBMC mice, generated by engraftment of IPSC-astrocytes into
NSG mice, can uniquely address the role of astrocytes as a reservoir for HIV and in HIV egress out of the brain
to peripheral organs (Aim 1) and define the effect of Meth with or without HIV on prototypical functions of
astrocyte and brain homeostasis (Aim 2). We focus on astrocytes because they constitute a significant resident
brain cell population and perform vital functions to maintain brain homeostasis. The HuCD34/NPC model (CD34
humanized mice engrafted with neuronal progenitor cells (NPCs) will be used to assess the role of Meth on HIV
evolution over time in the CNS and peripheral organs (Aim 3). Combining these two models with the resources
of the Translational Methamphetamine AIDS Research Center (TMARC) and the NIDA center for genetic studies
at Rutgers and cell repository (RUDCR) to reprogram lymphocytes from Meth/HIV donors to generate IPSC then
NPC and/or IPSC-astrocytes as targeted for in vitro and in vivo studies provides a powerful tool to address our
central hypothesis that Meth mediates a greater HIV reservoir in astrocytes and egress into peripheral organs
(Aim 1), dysregulate astrocytes to disrupt brain homeostasis (Aim 2), and promote s greater extent of viral
evolution within the CNS (Aim 3). Together, these studies are responsive to NIDA HIV research high priority
areas and will advance our knowledge regarding the role of drugs of abuse on HIV reservoir, evolution, and
neuropathogenesis to inform better strategies to uniquely address persistent HIV among the HIV positive drug
abusing population.
翻译后摘要:药物滥用是艾滋病毒感染者之间的一个显着的并发症。甲基苯丙胺
特别是,甲基苯丙胺是一种在艾滋病毒/艾滋病人群中经常滥用的强效精神兴奋剂。HIV和
即使在联合抗逆转录病毒治疗(cART)的时代,冰毒也是认知能力下降的危险因素。的
驱动和/或促成这种认知下降的机制,统称为HIV相关
神经认知障碍(HAND),也不完全清楚甲基苯丙胺对艾滋病毒库的影响。甲基苯丙胺本身
增强艾滋病毒复制。我们将使用两种创新的人性化动物模型来解决
神经胶质细胞冰毒和艾滋病病毒库huAstro/HuPBMC小鼠,通过将IPSC-星形胶质细胞植入
NSG小鼠可以独特地解决星形胶质细胞作为HIV储存库和HIV从大脑中排出的作用
外周器官(目的1),并确定甲基苯丙胺与或不与艾滋病毒对原型功能的影响,
星形胶质细胞和脑内环境稳定(Aim 2)。我们关注星形胶质细胞是因为它们是
脑细胞群和执行重要功能,以维持大脑的稳态。HuCD 34/NPC模型(CD 34
植入神经元祖细胞(NPC)的人源化小鼠将用于评估甲氧苯丙胺对艾滋病毒的作用
CNS和外周器官随时间的演变(目的3)。将这两种模型与资源相结合
转译甲基苯丙胺艾滋病研究中心(TMARC)和NIDA遗传研究中心
在Rutgers和细胞库(RUDCR)重新编程来自Meth/HIV供体的淋巴细胞以产生IPSC,然后
作为体外和体内研究的靶向的NPC和/或IPSC-星形胶质细胞提供了一个强大的工具来解决我们的问题。
中心假设,甲基介导星形胶质细胞中更大的HIV库并进入外周器官
(Aim 1),星形胶质细胞失调,破坏脑内稳态(目的2),并促进更大程度的病毒感染。
CNS内的进化(目标3)。总之,这些研究是响应NIDA艾滋病毒研究的高度优先事项
并将促进我们对滥用药物对艾滋病毒储存库,演变和
神经发病机制,为更好的策略提供信息,以独特地解决HIV阳性药物中持续存在的HIV
滥用人口。
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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Lena Al-Harthi其他文献
Lena Al-Harthi的其他文献
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{{ truncateString('Lena Al-Harthi', 18)}}的其他基金
Human/Animal Brain Chimera in drugs of abuse and HIV
滥用药物和艾滋病毒中的人/动物脑嵌合体
- 批准号:
10683363 - 财政年份:2022
- 资助金额:
$ 52.86万 - 项目类别:
Dynamic interaction between HIV in the CNS and peripheral organs
HIV在中枢神经系统和周围器官中的动态相互作用
- 批准号:
10063582 - 财政年份:2019
- 资助金额:
$ 52.86万 - 项目类别:
Dynamic interaction between HIV in the CNS and peripheral organs
HIV在中枢神经系统和周围器官中的动态相互作用
- 批准号:
10524054 - 财政年份:2019
- 资助金额:
$ 52.86万 - 项目类别:
Dynamic interaction between HIV in the CNS and peripheral organs
HIV在中枢神经系统和周围器官中的动态相互作用
- 批准号:
10305639 - 财政年份:2019
- 资助金额:
$ 52.86万 - 项目类别:
Neuroimmune axis in HAND and HIV persistence in the brain
HAND 中的神经免疫轴和大脑中的 HIV 持续存在
- 批准号:
10088477 - 财政年份:2017
- 资助金额:
$ 52.86万 - 项目类别:
Neuroimmune axis in HAND and HIV persistence in the brain
HAND 中的神经免疫轴和大脑中的 HIV 持续存在
- 批准号:
9474682 - 财政年份:2017
- 资助金额:
$ 52.86万 - 项目类别: