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
• 负责人: Lena Al-Harthi
• 金额: $ 55.28万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10683363
• 关键词: AIDS population; Acquired Immunodeficiency Syndrome; Address; Affect; Animal Model; Animals; Area; Astrocytes; Autopsy; Biological Assay; Biology; Blood; Blood - brain barrier anatomy; Brain; CD34 gene; Cell model; Cells; Chimera organism; Collaborations; DNA Repository; Drug abuse; Engraftment; Evolution; Functional disorder; Gene Expression Profile; Genetic Transcription; Genetic study; Genotype; Glues; HIV; HIV Infections; HIV Seronegativity; HIV Seropositivity; HIV envelope protein; HIV-associated neurocognitive disorder; HIV/AIDS; Homeostasis; Human; Immunofluorescence Immunologic; Impaired cognition; In Situ; In Vitro; Individual; Infection; Inflammatory; Inflammatory Response; Invaded; Kinetics; Knockout Mice; Knowledge; Learning; Link; Lymphocyte; METH abuser; Mediating; Mediator; Methamphetamine; Modeling; Molecular; Mus; National Institute of Drug Abuse; National Institute of Neurological Disorders and Stroke; Neurocognitive Deficit; Neurodegenerative Disorders; Neuroglia; Neuronal Injury; Neuropathogenesis; Neurotransmitters; Organ; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Phenotype; Population; Research; Resources; Risk Factors; Role; Techniques; Testing; Time; Tissues; United States National Institutes of Health; Viral; abuse victim; antiretroviral therapy; astrocyte progenitor; blood-brain barrier disruption; brain cell; brain tissue; cell repository; cohort; comorbidity; drug of abuse; experience; genetic signature; genome sequencing; human model; humanized mouse; immunoregulation; in vitro activity; in vivo; induced pluripotent stem cell; innovation; long term abstinence; lymphocyte trafficking; methamphetamine effect; methamphetamine use; methamphetamine user; mouse model; neglect; nerve stem cell; neurotrophic factor; neurotropic; news; next generation; novel; programs; psychostimulant; repaired; tool

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.

摘要：滥用药物是艾滋病毒携带者中的一种重要共病。甲基苯丙胺 特别是，(冰毒)是一种在艾滋病毒/艾滋病人群中经常滥用的强有力的精神刺激剂。艾滋病毒和艾滋病 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。这个 推动和/或促成这种认知能力下降的机制(S)，统称为艾滋病毒相关 神经认知障碍(HAND)，既不完全清楚，也不清楚甲基苯丙胺对艾滋病毒蓄积物的影响。冰毒本身 增强艾滋病毒复制。我们将使用两个创新的人性化动物模型来解决 胶质细胞、甲胎蛋白和艾滋病毒储存库。HuAstro/HuPBMC小鼠，通过将iPSC-星形胶质细胞移植到 NSG小鼠，可以独一无二地解决星形胶质细胞作为HIV储存库和HIV从大脑中流出的作用 外周器官(目标1)，并确定有或没有HIV对Meth原型功能的影响 星形胶质细胞与脑内稳态(目标2)。我们关注星形胶质细胞，因为它们构成了一个重要的居民 脑细胞数量和执行重要功能，以维持大脑的动态平衡。HuCD34/NPC模型(CD34 植入神经前体细胞的人源化小鼠将被用来评估Meth对HIV的作用 中枢神经系统和外周器官随时间的演变(目标3)。将这两个模型与资源相结合 翻译甲基苯丙胺艾滋病研究中心(TMARC)和NIDA遗传学研究中心 在罗格斯大学和细胞库(RUDCR)重新编程来自Meth/HIV捐赠者的淋巴细胞以生成IPSC，然后 作为体外和体内研究靶点的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 中心假设Meth在星形胶质细胞中介导了更大的HIV储存库，并向外周器官输出 (目标一)，失调星形胶质细胞破坏脑内稳态(目标二)，促进S更大程度地感染病毒 中枢神经系统内的进化(目标3)。总之，这些研究是对NIDA艾滋病毒研究的高度重视 并将促进我们对滥用药物在艾滋病毒储存、进化和 神经发病机制提供更好的战略，以独特地解决艾滋病毒阳性药物中的持久性艾滋病毒 虐待人口。