Alcohol Abuse and HIV-mediated Neurotoxicity

酒精滥用和艾滋病毒介导的神经毒性

基本信息

批准号：
8410167
负责人：
ANIL KUMAR
金额：
$ 33.75万
依托单位：
UNIVERSITY OF MISSOURI KANSAS CITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-10 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8410167
关键词：
AIDS Dementia Complex AIDS/HIV problem Address Affect Agonist Alcohol abuse Alcohol consumption Alcohol dependence Alcohols American Apoptosis Astrocytes Biological Models Blood - brain barrier anatomy Brain CCL2 gene CCL3 gene CCL4 gene CXCL10 gene Cell Adhesion Molecules Cells Development Disease Disease Progression Ethanol Metabolism Extravasation Glutamates HIV HIV Envelope Protein gp120 HIV Seropositivity HIV-1 Health Human IL8 gene In Vitro Individual Inflammatory Interleukin-8 Interleukins Knowledge Laboratories Measures Mediating Mus Neuraxis Neurocognitive Neurologic Manifestations Neuronal Plasticity Neurons Oxidative Stress PPAR gamma Permeability Peroxisome Proliferator-Activated Receptors Population Prevalence Production Property Public Health RANTES RNA Reporting Role Small Interfering RNA TNF gene Testing Transfection Transgenic Mice United States Viral Viral Genes Viral Proteins alcohol effect alcohol exposure chemokine chronic alcohol ingestion cytokine design extracellular in vivo in vivo Model mouse model neuroinflammation neuron apoptosis neurotoxic neurotoxicity research study tissue culture virotoxins

项目摘要

DESCRIPTION (provided by applicant): Alcohol abuse remains one of the major health problems with approximately 14 million Americans (<5% of total population) suffering from alcohol abuse. However, the prevalence of chronic alcohol consumption among HIV-positive individuals has been reported to be between 29 and 60% in US. In view of emerging results from several laboratories, it is becoming clear that alcohol abuse contributes to HIV replication, disease progression and development of HIV-associated dementia. Furthermore both alcohol and HIV are independently known to be neurotoxic, but it is not known with certainty whether they will have synergistic effect in alcohol addicted HIV-1 positive individuals and cause increased production of proinflammatory. This application is designed to address this gap in the existing knowledge. We will study the combined effect of the alcohol and 2 virotoxins (HIV-1 gp120 and Tat,) on cytokine as well chemokine production, markers of oxidative stress, apoptosis, PPAR-? in astrocytes/neurons, and whether these detrimental effects can be abrogated by use of the antagonists of alcohol metabolism, the virotoxin-specific siRNAs and PPAR-? agonists. These in vitro studies will be extended to in vivo situation where effect of chronic alcohol consumption will be studied in HIV-1 Tat and gp120 transgenic mice. These mice will be used for assessment of cytokine and chemokine expression, neuronal apoptosis in brain as well as leakage in the blood brain barrier and whether use of alcohol antagonist and PPAR-? agonists will abrogate the alcohol-mediated neurotoxicity. PUBLIC HEALTH RELEVANCE: This application proposes to dissect mechanism of increased neuroinflammation in alcohol-dependent HIV-1-infected individuals. We will study the role of proinflammatory cytokines and chemokine and whether their over-expression in the CNS leads to increased neurotoxicity. We will also determine role of antagonist of alcohol metabolism, siRNA and PPAR-gamma agonists in the management of neuroinflammation. These in vitro results will be extended to an in vivo model system using transgenic mice.

描述（由申请人提供）：酗酒仍然是大约1400万美国人（占总人口的5％）遭受酗酒的主要健康问题之一。然而，据报道，在美国，HIV阳性个体中长期饮酒的患病率在29％至60％之间。鉴于几个实验室的新兴结果，很明显，酗酒有助于HIV复制，疾病进展和与HIV相关痴呆的发育。此外，酒精和艾滋病毒都是独立的神经毒性的，但尚不确定它们是否会在酒精中具有协同作用上瘾的HIV-1阳性个体并导致促炎的产生增加。该应用程序旨在解决现有知识中的这一差距。我们将研究酒精和2种病毒毒素（HIV-1 GP120和TAT）对细胞因子以及趋化因子产生，氧化应激，凋亡，PPAR-的标志的综合作用。在星形胶质细胞/神经元中，以及这些有害作用是否可以通过使用酒精代谢的拮抗剂，病毒毒素特异性siRNA和PPAR-的拮抗剂来消除。激动剂。这些体外研究将扩展到体内状况，其中将在HIV-1 TAT和GP120转基因小鼠中研究慢性饮酒的作用。这些小鼠将用于评估细胞因子和趋化因子表达，脑中神经元细胞凋亡以及血脑屏障中的泄漏以及是否使用酒精拮抗剂和PPAR-？激动剂将废除酒精介导的神经毒性。公共卫生相关性：该应用建议剖析酒精依赖性HIV-1感染者神经炎症增加的机制。我们将研究促炎细胞因子和趋化因子的作用，以及它们在中枢神经系统中的过表达是否导致神经毒性增加。我们还将确定酒精代谢，siRNA和PPAR-GAMMA激动剂在神经炎症管理中的作用。这些体外结果将扩展到使用转基因小鼠的体内模型系统。