Methamphetamine, Brain Endothelial TLR3 Signaling and HIV

甲基苯丙胺、脑内皮 TLR3 信号转导和 HIV

• 批准号: 8659645
• 负责人: Jieliang Li
• 金额: $ 7.78万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8659645
• 关键词: Acquired Immunodeficiency Syndrome; Astrocytes; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Injuries; Dementia; Disease; Drug abuse; Endothelial Cells; Epidemic; HIV; High Prevalence; Homeostasis; Human; Individual; Inflammation; Inflammatory; Interferons; Mediating; Methamphetamine; Microglia; NIH Program Announcements; Natural Immunity; Neuraxis; Neurocognitive; Neuronal Injury; Pathway interactions; Pericytes; Permeability; Play; Production; Public Health; Publications; Publishing; Risk; Role; Sentinel; Series; Signal Transduction; United States; Virion; Virus Diseases; Virus Replication; Work; base; brain tissue; cell injury; human TLR3 protein; immune activation; insight; macrophage; methamphetamine abuse; monocyte; neurotoxic; neurotoxicity; pathogen; protective effect; public health relevance; response

DESCRIPTION (provided by applicant): Methamphetamine (METH) abuse and human immunodeficiency virus (HIV) infection produce a "double epidemic" in the United States, which is a serious global concern to public health. METH abuse and HIV infection are both recognized as major causes of neurocognitive diseases. METH use can increase the risk of acquiring HIV and enhance brain injury in the context of HIV infection. However, it is unclear about the mechanisms by which METH and/or HIV impair the central nervous system (CNS). Human brain microvascular endothelial cells (HBMEC) have been well known as main components of the blood-brain barrier (BBB) and play a key role in protecting the CNS from pathogen invasion. Recently, we identified HBMEC as an important bystander in inhibiting HIV replication in macrophages, as Toll-like receptor 3 (TLR3) signaling of HBMEC could activate IFN pathway, inducing the expression of the cellular HIV restriction factors. In the proposed studies, we will determine whether METH and/or HIV compromise TLR3 signaling-mediated immune activation of HBMEC and HBMEC-mediated anti-HIV activity. The overarching hypothesis of this R03 proposal is that METH and/or HIV impair TLR3 signaling of HBMEC, diminishing HBMEC-mediated innate immunity against HIV. We propose two specific aims: 1) to determine the effect of METH and/or HIV on TLR3 signaling of HBMEC-mediated anti-HIV activity; 2) to examine the impact of METH and/or HIV on BBB permeability in the context of TLR3 signaling of HBMEC, and whether TLR3 signaling of HBMEC has protective effect on METH and/or HIV-mediated neuronal injury. Given the high prevalence of METH use and its implication in HIV-associated dementia, the proposed studies are timely and important, which should provide insight of the role of HBMEC in BBB innate immunity in the context of METH use and/or HIV infection.

描述（由申请人提供）：甲基苯丙胺（METH）滥用和人类免疫缺陷病毒（HIV）感染在美国造成“双重流行”，这是一个严重的全球公共卫生问题。甲基苯丙胺滥用和艾滋病毒感染都被认为是神经认知疾病的主要原因。甲基苯丙胺的使用会增加感染艾滋病毒的风险，并在艾滋病毒感染的情况下增加脑损伤。然而，METH和/或HIV损害中枢神经系统（CNS）的机制尚不清楚。人脑微血管内皮细胞（HBMEC）是血脑屏障（BBB）的主要组成部分，在保护中枢神经系统免受病原体侵袭方面起着关键作用。最近，我们发现HBMEC作为抑制HIV在巨噬细胞中复制的重要旁观者，因为HBMEC的Toll样受体3（TLR 3）信号传导可以激活IFN途径，诱导细胞HIV限制因子的表达。在拟议的研究中，我们将确定METH和/或HIV是否损害TLR 3信号介导的HBMEC免疫激活和HBMEC介导的抗HIV活性。该R 03提案的首要假设是METH和/或HIV损害HBMEC的TLR 3信号传导，从而降低HBMEC介导的针对HIV的先天免疫。我们提出两个具体目标：1）确定METH和/或HIV对HBMEC介导的抗HIV活性的TLR 3信号传导的影响; 2）在HBMEC的TLR 3信号传导的背景下检查METH和/或HIV对BBB通透性的影响，以及HBMEC的TLR 3信号传导是否对METH和/或HIV介导的神经元损伤具有保护作用。鉴于METH使用的高流行率及其在HIV相关性痴呆中的意义，拟议的研究是及时和重要的，这应该提供在METH使用和/或HIV感染的背景下HBMEC在BBB先天免疫中的作用的见解。