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: 10543385
• 负责人: Lena Al-Harthi
• 金额: $ 52.86万
• 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/10543385
• 关键词: AIDS population; AIDS/HIV problem; Abstinence; 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-associated neurocognitive disorder; Homeostasis; Human; Immunofluorescence Immunologic; Impaired cognition; In Situ; In Vitro; Individual; Infection; Inflammatory; Inflammatory Response; Invaded; Kinetics; Knowledge; Lead; Learning; Link; Lymphocyte; METH abuser; Mediating; Mediator of activation protein; 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; 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; methamphetamine effect; methamphetamine use; methamphetamine user; mouse model; neglect; nerve stem cell; neurotrophic factor; neurotropic; news; next generation; novel; psychostimulant; repaired; response; 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.

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。