Effect of Methamphetamine and/or HIV on Human iPSCs-derived microglia and Neuron

甲基苯丙胺和/或 HIV 对人 iPSC 衍生的小胶质细胞和神经元的影响

基本信息

批准号：
10210377
负责人：
WENZHE HO
金额：
$ 19.81万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10210377
关键词：
AIDS prevention Address Autopsy Biological Assay Biopsy Brain Cause of Death Cell Line Cells Cessation of life Development Drug abuse Enzyme-Linked Immunosorbent Assay GAG Gene Gene Expression HIV HIV Core Protein p24 HIV Infections HIV-associated neurocognitive disorder Human ITGAM gene Immunity In Vitro Individual Inflammasome Interleukin-18 Life Expectancy Methamphetamine MicroRNAs Microglia Modeling National Institute of Drug Abuse Natural Immunity Neurons Neurotoxins Pathogenesis Pathologic Patients Prevalence Publishing Rattus Research Project Grants Role Stains TREM2 gene United States Viral Western Blotting drug of abuse in vitro Model induced pluripotent stem cell insight interest macrophage methamphetamine abuse methamphetamine effect methamphetamine use monocyte neuron loss neurotoxic neurotoxicity peripheral blood psychostimulant success

项目摘要

Abstract METH, a potent addictive psychostimulant, is one of the most commonly abused drugs in the United States. METH abuse is highly prevalent in HIV-infected individuals, which presents unique challenges for HIV prevention and treatment. Given the overlap impact of METH use and HIV on neuronal damage in the CNS, it becomes urgent to understand the role of interplays between METH and HIV in the pathogenesis of HIV- associated neurocognitive disorders (HAND). However, studies of HAND have been hampered by difficulties in collecting primary microglial and neuronal cells from autopsy or biopsy of HIV patients. Recent success in generating microglia and neurons from human induced pluripotent stem cell lines (iPSCs) now offers a great opportunity to study the direct interactions between HIV-infected microglia and neurons. The proposed studies will use iPSC-derived microglia (iPSC-MG) and neuron (iPSC-N) to examine our overall hypothesis that METH and/or HIV inhibit the intracellular HIV restriction factors and induce the inflammasomes and neurotoxic miRNAs in iPSC-MG, which facilitate HIV infection/replication in iPSC-MG and promote the death of iPSC-N. We propose two specific aims to address this hypothesis: Aim 1 To determine whether METH enhances HIV infection/replication in iPSC-MG. Mechanistically, we will examine whether METH and/or HIV inhibit the intracellular HIV restriction factors in iPSC-MG; Aim 2 To determine whether METH and/or HIV infection induce expression of the inflammasomes and neurotoxic miRNAs in iPSC-MG and promote the death of IPSC-N. This project fits well to the NIDA’s recent interests in studying the impact of drug abuse and/or HIV on human iPSC-derived CNS cells. The information resulting from the proposed studies using the iPSC-MG and iPSC-N will provide important insights on how the interplays of two major pathologic factors (HIV and METH) in the CNS compromise the intracellular anti-HIV immunity of microglia and induce neuronal death, which are the key mechanisms for HIV infection/persistence in the brain and development of HAND.

抽象的冰毒是一种强效成瘾性精神兴奋剂，是美国最常滥用的药物之一。冰毒滥用在艾滋病毒感染者中非常普遍，这给艾滋病毒带来了独特的挑战鉴于冰毒的使用和艾滋病毒对中枢神经系统神经元损伤的重叠影响，迫切需要了解 METH 和 HIV 之间的相互作用在 HIV 发病机制中的作用相关的神经认知障碍（HAND）然而，HAND 的研究因困难而受到阻碍。从艾滋病毒患者的尸检或活检中收集原代小胶质细胞和神经元细胞最近取得了成功。从人类诱导多能干细胞系（iPSC）生成小胶质细胞和神经元现在提供了一个很好的方法研究艾滋病毒感染的小胶质细胞和神经元之间直接相互作用的机会。将使用 iPSC 衍生的小胶质细胞 (iPSC-MG) 和神经元 (iPSC-N) 来检验我们的总体假设：METH 和/或HIV抑制细胞内HIV限制因子并诱导炎症小体和神经毒性 iPSC-MG 中的 miRNA，促进 iPSC-MG 中的 HIV 感染/复制并促进 iPSC-N 的死亡。我们提出两个具体目标来解决这一假设：目标 1 为了确定 METH 是否会从机制上增强 iPSC-MG 中的 HIV 感染/复制。检查 METH 和/或 HIV 是否抑制 iPSC-MG 中的细胞内 HIV 限制因子；目标 2 确定 METH 和/或 HIV 感染是否诱导炎症小体和 iPSC-MG 中的神经毒性 miRNA 会促进 IPSC-N 的死亡。该项目非常符合 NIDA 最近研究药物滥用和/或艾滋病毒对人类影响的兴趣 iPSC 衍生的 CNS 细胞的信息来自使用 iPSC-MG 和 iPSC-N 的拟议研究。将提供关于两种主要病理因素（HIV 和 METH）如何相互作用的重要见解中枢神经系统损害小胶质细胞的细胞内抗HIV免疫并诱导神经元死亡，这是关键 HIV 感染/大脑持续存在和 HAND 发展的机制。