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：
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
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：
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

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.

摘要：滥用药物是艾滋病毒感染者的一个重要合并症。冰毒尤其是（冰毒），它是一种强效精神兴奋剂，经常在艾滋病毒/艾滋病人群中滥用。艾滋病毒和即使在联合抗逆转录病毒疗法（cART）时代，冰毒也是认知能力下降的危险因素。这驱动和/或促成这种认知能力下降的机制，统称为艾滋病毒相关性神经认知障碍 (HAND) 尚不完全清楚，冰毒对 HIV 病毒库的影响也不完全清楚。冰毒本身增强HIV复制。我们将使用两种创新的人性化动物模型来解决两者之间的界面神经胶质细胞、冰毒和艾滋病毒储存库。 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（目标 1），并确定有或没有 HIV 的情况下冰毒对周围器官原型功能的影响星形胶质细胞和大脑稳态（目标 2）。我们关注星形胶质细胞，因为它们是重要的居民脑细胞群并执行维持大脑稳态的重要功能。 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冰毒对艾滋病毒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结合起来转化甲基苯丙胺艾滋病研究中心 (TMARC) 和 NIDA 遗传研究中心在罗格斯大学和细胞储存库 (RUDCR) 对来自冰毒/艾滋病毒捐献者的淋巴细胞进行重新编程，以生成 IPSC NPC 和/或 IPSC-星形胶质细胞作为体外和体内研究的目标提供了一个强大的工具来解决我们的问题中心假设是，冰毒介导星形胶质细胞中更大的艾滋病毒储存库并进入外周器官（目标 1），失调星形胶质细胞以破坏大脑稳态（目标 2），并促进更大程度的病毒传播 CNS 内的进化（目标 3）。总之，这些研究响应了 NIDA HIV 研究的高优先级领域，并将增进我们对滥用药物对艾滋病毒储存、进化和感染的作用的了解。神经发病机制为更好的策略提供信息，以独特地解决艾滋病毒阳性药物中持续存在的艾滋病毒虐待人口。