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.

摘要：虐待药物是艾滋病毒患者的重要合并症。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有效的心理刺激剂。艾滋病毒和 即使在抗逆转录病毒疗法（CART）的时代，甲基苯丙胺也是认知能力下降的危险因素。这 驱动和/或有助于这种认知能力下降的机制，统称为HIV相关 神经认知障碍（手）并不完全清楚，也不是甲基苯丙胺对艾滋病毒储量的影响。冰毒本身 增强HIV复制。我们将使用两个创新的人源化动物模型来解决 神经胶质细胞，甲基甲基和艾滋病毒储量。 Huastro/HupBMC小鼠，由IPSC-ASSTROCYTES植入 NSG小鼠可以唯一解决星形胶质细胞作为HIV和HIV出口中的储层的作用 进行外围器官（AIM 1），并定义有或没有HIV的Meth对原型功能的影响 星形胶质细胞和大脑稳态（AIM 2）。我们专注于星形胶质细胞，因为它们构成了重要的居民 脑细胞群体并执行重要功能以维持大脑稳态。 HUCD34/NPC模型（CD34 植入神经元祖细胞（NPC）的人源化小鼠将用于评估甲基甲基的作用 随着时间的流逝，中枢神经系统和外围器官的演变（AIM 3）。将这两个模型与资源结合在一起 甲基苯丙胺艾滋病研究中心（TMARC）和NIDA遗传研究中心 在罗格和细胞存储库（RUDCR）中，从甲基甲基/艾滋病毒供体重新编程淋巴细胞，以生成IPSC NPC和/或IPSC-腹膜细胞是用于体外和体内研究的针对性的 中心假设是甲基介导的星形胶质细胞中较大的艾滋病毒储存库，并出口到外围器官 （AIM 1），使星形胶质细胞失调以破坏大脑稳态（AIM 2），并促进更大程度的病毒 中枢神经系统内的进化（目标3）。总之，这些研究对NIDA HIV研究有反应 领域并将提高我们关于滥用药物在艾滋病毒水库，进化和进化中的作用的知识 神经病发生以告知更好的策略以唯一解决HIV阳性药物中的持续HIV 滥用人口。