ALCOHOL AND HIV1 GP120 INDUCED BRAIN DAMAGE

申请人摘要：导致痴呆的进行性脑损伤是一种 主要关注艾滋病。此外，艾滋病毒感染者的比例很高， 个人饮酒（乙醇），通常是滥用量。然而，在这方面， 酒精对与艾滋病毒相关的神经变性的影响很大程度上显现出来 未经研究。HIV-1外壳蛋白gp 120可能是一种神经毒素 潜在的艾滋病相关脑损伤GP 120促进谷氨酸（NMDA） 受体介导的兴奋性毒性，可能通过刺激神经胶质细胞释放 释放因子（特别是花生四烯酸），增加细胞外 谷氨酸盐。同样，NMDA受体和神经胶质细胞是已知的酒精靶点。 我们的目标是更好地了解酒精如何影响程度，性质和 GP 120的神经毒性机制将在第一个目标中处理这一问题 和II用重组gp 120和大鼠脑器官型切片培养物，和 在AIM III中用gp 120转基因小鼠。我们的总体假设是 酒精改变与gp 120相关的脑神经变性， 直径相反的方向，取决于酒精浓度和 曝光模式。有限暴露于亚神经毒性酒精浓度 实际上可以减少依赖gp 120的神经毒性;事实上，这表明 通过我们初步的体外实验酒精的这种作用是否 由于神经胶质数量减少，gp 120神经胶质作用受损，或 将测试MNDA受体功能的抑制。相反，慢性 酒精暴露可能会加重艾滋病患者的中枢神经系统缺陷， 加剧了由MNDA或谷氨酸引起的兴奋性毒性。因此，我们预计， 长期或严重的间歇性酒精暴露会增加神经元 与GP 120相关的（凋亡）损伤。如果是这样，我们将研究是否 NMDA受体和功能增强，和/或脑水肿（我们 发现是单独偶发性酒精引起细胞毒性的关键因素） 这一现象的基础。具体目的一：用大鼠脑组织测定 器官型切片培养的结果，酒精暴露的程度和 gp 120介导的神经退行性变类型（凋亡，坏死）;目的II： 阐明酒精影响gp 120神经毒性的机制 目的三：确定是否影响和 乙醇对gp 120诱导的体外神经变性的作用。 在转基因小鼠体内复制， 神经元损伤这些研究有可能提供以下信息： 酒精/gp 120神经毒性可能有助于理解痴呆症 饮酒的艾滋病患者。

APPLICANT'S ABSTRACT: Progressive brain damage leading to dementia is a major concern in AIDS. Furthermore, a high percentage of HIV-infected individuals consume alcohol (ethanol), often in abusive amounts. However, alcohol's effects on neurodegeneration associated with HIV appear largely unstudied. The HIV-1 coat protein, gp120, is a possible neurotoxin underlying AIDS-related brain damage. GP120 promotes glutamate (NMDA) receptor-mediated excitotoxicity, presumably via stimulating glia to release release factors (esp. Arachidonic acid) that increase extracellular glutamate. Likewise, NMDA receptors and glia are known alcohol targets. Our goal is to better understand how alcohol affects the extent, nature and mechanisms of neurotoxicity due to gp120. This will be approached in AIMS I and II with recombinant gp120 and rat brain organotypic slice cultures, and in AIM III with gp120 transgenic mice. Our overall hypothesis is that alcohol modifies brain neurodegeneration associated with gp120 in diametrically opposite directions, depending on alcohol concentrations and mode of exposure. Limited exposure to subneurotoxic alcohol concentrations may actually reduce gp120-dependent neurotoxicity; indeed, this is indicated by our preliminary in vitro experiments. Whether this effect of alcohol is due to reduced glial number, impairment of gp120's glial actions, or inhibition of MNDA receptor function will be tested. In contrast, chronic alcohol exposure may worsen CNS deficits in AIDS, and experimentally it exacerbates excitotoxicity due to MNDA or glutamate. Thus we anticipate that long-term or severe episodic alcohol exposure will increase neuronal (apoptotic) damage associated with gp120. If so, we will examine if augmentations in NMDA receptors and function, and/or brain edema (which we find to be a key factor in cytotoxicity caused by episodic alcohol alone) underlie the phenomenon. Specific Aim I is: To determine with rat brain organotypic slice cultures the outcome of alcohol exposure on the extent and type (apoptotic, necrotic) of gp120-mediated neurodegeneration; Aim II: To unravel the mechanisms through which alcohol affects the gp120 neurotoxicity in the brain slice cultures; and AIM III: To ascertain if the effects and actions of alcohol on gp120-induced neurodegeneration in vitro are reproduced in vivo in transgenic mice that express brain gp120 and show neuronal damage. The studies have the potential of providing information on alcohol/gp120 neurotoxicity that could be useful in understanding dementia in alcohol-consuming AIDS patients.