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：
8542738
负责人：
ANIL KUMAR
金额：
$ 31.6万
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/8542738
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 public health relevance 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.

描述（由申请人提供）：酗酒仍然是主要的健康问题之一，约有 1400 万美国人（占总人口的 5%）患有酗酒问题。然而，据报道，美国 HIV 阳性人群中长期饮酒的患病率在 29% 至 60% 之间。鉴于多个实验室的新结果，越来越明显的是，酗酒会导致艾滋病毒复制、疾病进展和艾滋病毒相关痴呆症的发生。此外，酒精和艾滋病毒都被独立地知道具有神经毒性，但尚不清楚它们是否会在酒精中产生协同作用 HIV-1 阳性个体上瘾并导致促炎物质产生增加。该应用程序旨在解决现有知识中的这一空白。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、氧化应激标志物、细胞凋亡、PPAR-？星形胶质细胞/神经元中的有害影响是否可以通过使用酒精代谢拮抗剂、病毒毒素特异性 siRNA 和 PPAR- 来消除？激动剂。这些体外研究将扩展到体内情况，在 HIV-1 Tat 和 gp120 转基因小鼠中研究长期饮酒的影响。这些小鼠将用于评估细胞因子和趋化因子表达、脑中神经元凋亡以及血脑屏障渗漏以及是否使用酒精拮抗剂和PPAR-？激动剂将消除酒精介导的神经毒性。