Alcohol-Induced Headaches: An Animal Model

描述（由申请人提供）：在美国有超过120万人感染了人类免疫缺陷病毒（HIV）。酒精滥用在美国也很普遍，超过60%的人口报告在过去一年中饮酒。由于滥用药物和酒精的人有感染艾滋病毒的风险，因此酒精和艾滋病毒之间存在一种共病，这是一种独特的人群，值得调查。因此，研究酒精在艾滋病毒感染期间的影响对于找到治疗这两种疾病的方法是必要的。酒精和HIV都能激活中枢神经系统（CMS）的常驻吞噬细胞小胶质细胞。酒精引起小胶质细胞的氧化应激，而HIV利用小胶质细胞作为复制的载体，由此引起的小胶质细胞感染产生神经毒素和兴奋毒素。尚未研究酒精和HIV或HIV糖蛋白（HIV-gp120）对小胶质细胞的联合作用。拟议的实验将在体外检查小胶质细胞，以确定急性和慢性酒精影响HIV复制的程度以及HIV-gp120的细胞毒性。这些实验将评估细胞死亡和氧化损伤。此外，我们将使用抗氧化剂表达基因传递载体来阐明所涉及的途径并提供潜在的治疗方法。实验的第二部分将利用SV40基因传递载体（SV(gp120)）表达HIV-gp120诱导的慢性CMS损伤大鼠体内模型来模拟HIV脑炎的长期影响。这些动物将接受慢性乙醇治疗，然后颅内注射SV(gp120)，以确定酒精对hiv诱导的CMS损伤进展的影响程度。该研究将阐明酒精和HIV在体内和体外的相互作用，为潜在的治疗方法提供基础。

DESCRIPTION (provided by applicant): More than 1.2 million people in the United States are living with human immunodeficiency virus (HIV). Alcohol abuse is also prevalent in the US with more than sixty percent of the population reporting consuming alcohol over the past year. Since people who abuse drugs and alcohol are at risk for HIV infection, there is a comorbidity between alcohol and HIV which represents a unique population that warrants investigation. Therefore, studying the effects of alcohol during HIV infection is necessary to find treatments that account for both diseases. Both alcohol and HIV activate microglia, the resident phagocytic cells of the central nervous system (CMS). Alcohol causes oxidative stress in microglia whereas HIV uses microglia as a vehicle for replication, and the resulting microglia infection produces neurotoxins and excitotoxins. The combined effects of alcohol and HIV or HIV-glycoproteins (HIV-gp120) on microglia have not been studied. The proposed experiments will examine microglia in vitro to determine the extent to which acute and chronic alcohol impacts HIV replication and the cellular toxicity of HIV-gp120. The experiments will evaluate cell death and oxidative damage. In addition, we will use antioxidant expressing gene delivery vectors to elucidate the pathways involved and provide potential therapeutics. The second portion of the proposed experiments will utilize an in vivo rat model of chronic CMS injury induced by expression of HIV-gp120 using SV40 gene delivery vectors (SV(gp120)) to model the long-term effects of HIV encephalitis. The animals will be treated with chronic ethanol which, followed by an intracranial injection of SV(gp120) to determine the extent to which alcohol impacts the progression of HIV-induced CMS injury. The proposed research will elucidate the interation of alcohol and HIV in vitro and in vivo to provide a foundation for potential therapeutics. Public Health Relevance: The impact that alcohol abuse has on patients with HIV is not well understood. HIV and alcohol abuse, individually, are detrimental to brain function and the combination presents a public health problem. My research focuses on finding the cause of this problem and potential treatments both at the level of the immune cells of the brain and in animals.