ALCOHOL AND HIV1 GP120 INDUCED BRAIN DAMAGE

申请人摘要：进行性脑损伤导致痴呆是一种 艾滋病方面的主要问题。此外，高比例的艾滋病毒感染者 个人消费酒精(乙醇)，通常是过量的。然而， 酒精对与艾滋病毒相关的神经变性的影响在很大程度上显现出来 没有经过研究。HIV-1外壳蛋白gp120可能是一种神经毒素。 潜在的与艾滋病相关的脑损伤。Gp120促进谷氨酸(NMDA) 受体介导的兴奋性毒性，可能是通过刺激胶质细胞释放 释放系数(特别是花生四烯酸)，增加细胞外 谷氨酸。同样，NMDA受体和神经胶质细胞也是已知的酒精靶标。 我们的目标是更好地了解酒精如何影响程度、性质和 Gp120的神经毒性机制。将在AIMS I中探讨这一点 和II用重组gp120和大鼠脑组织切片培养，以及 在AIM III中用gp120转基因小鼠。我们的总体假设是 酒精改变与gp120相关的脑神经退行性变 完全相反的方向，取决于酒精浓度和 曝光方式。有限暴露于亚神经毒性酒精浓度 实际上可能会降低gp120依赖的神经毒性；事实上，这表明 通过我们初步的体外实验。不管酒精的这种影响是 由于胶质细胞数量减少，gp120‘S胶质细胞活动受损，或 将测试对MNDA受体功能的抑制。相比之下，慢性 酒精暴露可能会加剧艾滋病患者的中枢神经系统缺陷，而且在实验上它 加重由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gp120相关的(凋亡性)损伤。如果是这样的话，我们将研究是否 NMDA受体和功能增强，和/或脑水肿(我们 发现是间歇性酒精单独引起细胞毒性的关键因素) 这是这一现象的基础。具体目标一：用大鼠脑测定 器官切片培养酒精暴露的结果在程度上和 Gp120介导的神经变性的类型(凋亡性、坏死性)；目标II：至 解开酒精影响gp120神经毒性的机制 在脑片培养中；以及目的III：确定影响和 酒精对gp120诱导的体外神经变性的作用 在体内复制的转基因小鼠表达脑gp120并显示 神经元损伤。这些研究有可能提供关于 酒精/gp120神经毒性可能有助于了解痴呆症 在酗酒的艾滋病患者身上。

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.