cART effects on glial cells

cART对神经胶质细胞的影响

基本信息

批准号：
9925543
负责人：
Lena Al-Harthi
金额：
$ 23.55万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9925543
关键词：
AIDS dementia Acquired Immunodeficiency Syndrome Address Adverse effects Aging Anti-Retroviral Agents Antigen Presentation Apoptosis Astrocytes Astrocytosis Biological Assay Blood - brain barrier anatomy Cell Culture Techniques Cell Cycle Arrest Cell Survival Cells Chronic Communication Complication Data Dementia Development Diabetes Mellitus Disease Drug Combinations Drug usage Elderly Endothelial Cells Equilibrium Equus caballus Flow Cytometry Fumarates Functional disorder Future General Population Glutamates HIV HIV Infections HIV-associated neurocognitive disorder Health Homeostasis Hypertension Immune response In Vitro Incidence Individual Inflammatory Ions Knockout Mice Knowledge Lamivudine Microglia Mitochondria Morbidity - disease rate Morphology Mus Nerve Degeneration Neuraxis Neurocognitive Deficit Neurodegenerative Disorders Neuroglia Neurons Neuropathogenesis Oxidative Stress Pathogenesis Patients Persons Phagocytosis Pharmaceutical Preparations Pharmacotherapy Phenotype Physiological Population Property Prophylactic treatment Propidium Diiodide Proteins Regimen Series Source Stimulus Tenofovir Testing Therapeutic Time Toxic effect Treatment Efficacy Viral Viremia Virus antiretroviral therapy brain cell brain tissue cell type comorbidity cytokine design efavirenz emtricitabine experimental study extracellular high risk high risk population humanized mouse immune function improved in vivo inflammatory marker macrophage monocyte mortality mouse model neurocognitive disorder neuroinflammation neuropsychiatry neurotoxic novel novel strategies pandemic disease pre-exposure prophylaxis prevent repaired side effect transmission process truvada uptake virtual

项目摘要

Combination antiretroviral therapy (cART) is appropriately credited with dramatically curbing the AIDS pandemic and is increasingly being used as a prophylactic treatment to prevent HIV transmission among “at high-risk” populations. Despite these therapeutic advances, HIV infection is associated with a number of co-morbid conditions, the most notable of which is a spectrum of neurocognitive disorders termed HIV Associated Neurodegenerative Disorders (HAND). The contribution of HIV vs. cART on HAND is not clear. cART, independent of HIV, may negatively impact cells of the Central Nervous System (CNS). While some studies demonstrated direct neurotoxic effects of cART, little is known about their impact on macro and micro glial cells (e.g. astrocytes and microglia/macrophages, respectively). Glial cells coordinate immunologic responses and communication with neurons and endothelial cells. Dysregulation of glial cells is associated with a number of neurodegenerative diseases, including HAND. In this application, in Aim 1 we will determine the impact of cART (Atripla and Triumeq) on the phenotype and function of astrocytes, microglia, and monocyte- derived macrophages (MDMs). In Aim 2, we will determine the impact of cART on glia and neuroinflammation in vivo humanized mice. Collectively, these studies will reveal the impact of cART on glial cells and its subsequent effects on neuronal health and blood brain barrier integrity as well as inform combination of antiretrovirals that will retain therapeutic efficacy with minimal CNS dysregulation.

抗逆转录病毒疗法（CART）的合理记录在巨大的遏制下适当地记入 AIDS大流行，越来越多地用作预防治疗以预防HIV “高风险”人群之间的传播。尽管有这些治疗性进展，但艾滋病毒感染与许多合并症有关，其中最值得注意的是神经认知疾病称为HIV相关的神经退行性疾病（手）。这艾滋病毒与购物车的贡献尚不清楚。独立于艾滋病毒的购物车可能负面撞击中枢神经系统（CNS）的细胞。一些研究证明了直接 CART的神经毒性作用，对它们对宏观和微神经胶质细胞的影响知之甚少（例如星形胶质细胞和小胶质细胞/巨噬细胞）。神经胶质细胞协调免疫学反应和与神经元和内皮细胞的通讯。神经胶质细胞的失调是与许多神经退行性疾病有关，包括手。在此应用程序中目标1我们将确定卡车（Atripla和Triumeq）对表型的影响星形胶质细胞，小胶质细胞和单核细胞衍生巨噬细胞（MDMS）的功能。在AIM 2中，我们将确定购物车对胶质和神经炎症的影响人源化的小鼠。总的来说，这些研究将揭示推车对神经胶质细胞及其ITS的影响随后对神经元健康和血脑屏障完整性的影响，并告知抗逆转录病毒的组合将保留最小CNS治疗效率失调。