AIDS DEMENTIA--MOLECULAR AND CELLULAR MECHANISMS

这是我们国家卫生研究院中心补助金(MH 47690_)的竞争性续订申请 艾滋病痴呆症：分子和细胞机制：目前由 多学科研究中心自成立以来一直积极追求 中枢神经系统疾病表现的分子和细胞机制 慢病毒感染与HIV高度聚焦的对比评价 神经心理和睡眠障碍所定义的大脑病理生理学 神经行为、电生理、病毒学和免疫学 感染猴免疫缺陷病毒(SIV)的表现，以及 猫免疫缺陷病毒(FIV)以及转基因小鼠 表达介导炎症和免疫的细胞因子 反应，或神经元中慢病毒包膜的选定糖蛋白， 星形胶质细胞或其他中枢神经系统细胞。根据该中心内部的进展情况，以及 关于艾滋病研究总体努力的研究进展，研究 在接下来的5年内，将重点确定 早期中枢神经系统改变的分子和细胞机制，以提炼和 将这些动物模型与HIV进行比较，以寻找趋同的表现 病理生理机制，并评估潜在的药物治疗 对于早期中枢神经系统表现的逆转或减弱 慢病毒感染。因此，现在请拨6个核心的经费 项目和12个独立但高度协作的研究组成部分。 两个组成部分将扩大艾滋病毒相关中枢神经系统的最新进展 功能障碍，将传统的神经心理测试电池与 CanTab，一种自动化的神经心理评估电池，在 该中心的SUV中枢神经系统研究，并检查睡眠中断在 早期HIV血清转换患者在神经心理学中的作用 性能及其短期治疗，以及最近发现的一种 血浆细胞因子与中枢神经系统脑电活动的相关性两个高度互动 各部分将重点关注SIV感染猕猴的情况。A最近 开发的小胶质细胞来源的神经侵袭性、神经毒性的SIV股票将 在神经行为和生理动物模型中进行评估 定量监测表征中枢神经系统的时间进程 FIV的表现。将研究功能修饰的FIV突变体 关于评估的脑细胞感染性和神经毒力的模式 根据临床和神经进展、睡眠障碍、脑电和事件 相关电位；一项FIV小胶质细胞研究将尝试复制 在SIV模型中获得的增强的神经毒力，以及抗TNFα或 NMDA受体拮抗剂单独或联合应用于FIV诱导 将对神经系统疾病进行研究。将对啮齿动物的五个项目进行检查 确定的细胞类别内的特定分子介体。三个项目 将使用转基因小鼠突变体来过度表达特定的细胞因子， 天然蛋白或病毒蛋白(IFNGamma在杆状和锥体中表达； HIV gp120、IL6或IFNα的星形细胞表达 脑小胶质细胞/巨噬细胞或神经元中的人淀粉样前体蛋白) 单独或组合以确定潜在的机制 无慢病毒直接感染的神经病理生理学 神经元。第四个项目将研究细胞因子IL1-β，TNFpha， 和IL6，以及HIV糖蛋白对小脑神经元发育的影响 体外培养。第五个将利用新发展的分子发现 鉴定激活的小胶质细胞表达的mRNAs的技术，确定 它们与单核/巨噬细胞谱系中其他细胞的关系，以及 在细胞因子暴露或病毒感染期间其基因表达模式的变化 感染。总而言之，这一系列高度互动的重点研究 研究将进一步澄清艾滋病相关神经认知的性质 和运动功能障碍，并提供了特定早期的动物模型 HIV、SIV和FIV常见的可逆病理过程可能会放缓 或者颠倒过来。此外，这些研究可能会启发其他无法解释的问题。 基本神经元-神经胶质-免疫系统相互作用的自然界 大脑驻留的小胶质细胞，以及神经精神障碍的基础 来历不明。

This is a competitive renewal request for our NIMH Center Grant (MH 47690_ "AIDS Dementia: Molecular and Cellular Mechanisms:. This currently funded multidisciplinary Research Center has since its inception actively pursued the molecular and cellular mechanisms underlying the CNS manifestations of lentivirus infection by a highly focused comparative evaluation of HIV brain pathophysiology as defined by neuropsychological and sleep disruption with neurobehavioral, electrophysiological, virological and immunological manifestations of infection with Simian Immunodeficiency Virus (SIV), and Feline Immunodeficiency Virus (FIV) as well as transgenic mice over- expressing either the cytokines mediating inflammatory and immune responses, or selected glycoproteins of the lentivirus envelope in neurons, astrocytes or other CNS cells. Based on progress within this Center, and on research developments within the overall AIDS research effort, research to be conducted over the next 5 year period will focus on determination of the molecular and cellular mechanisms of early CNS changes, to refine and compare these animal models with HIV for convergent manifestations of pathophysiological mechanisms, and to evaluate potential drug treatments for the reversal or attenuation of the early CNS manifestation of lentivirus infection. Accordingly, funding is now requested for 6 Core projects and 12 individual, but highly collaborative research components. Two components will extend recent progress in HIV-associated CNS dysfunctions, comparing conventional neuropsychological test batteries with CANTAB, an automated neuropsychological assessment battery developed within this Center for SUV CNS studies, and examining the disruption of sleep in early HIV sero-converting patients, its role in neuropsychological performance, and its short term treatment, as well as a recently discovered plasma cytokine correlation with CNS EEG activity. Two highly interactive components will focus on SIV infection of rhesus macaque. A recently developed, micro-glia derived neuroinvasive, neurovirulent SIV stock will be evaluated in a neurobehavioral and physiological animal model with quantitative monitoring to characterize the time course of the CNS manifestations of FIV. Functionally modified FIV mutants will be studied for patterns of brain cellular infectivity and neurovirulence as assessed by clinical and neurologic progress, sleep disruption, EEG and event related potentials; an FIV microglia study will attempt to replicate the enhanced neurovirulence obtained in the SIV Model, and anti TNFalpha or NMDA receptor antagonists, alone or in combination on FIV-induced neurologic disease will be studied. Five projects in rodents will examine specific molecular mediators within defined cell classes. Three projects will employ transgenic mouse mutants to overexpress specific cytokines, natural proteins or viral proteins (IFNgamma expression in rods and cones; astrocytic expression of HIV gp120, IL6 or IFNalpha or either human CD4 on brain microglia/macrophages or human amyloid precursor protein in neurons) either singly or in combination to identify the mechanisms underlying neuropathophysiology int he absence of direct lentivirus infection of neurons. A fourth project will examine the cytokines IL1-beta, TNFalpha, and IL6, as well as HIV glycoproteins on cerebellar neuronal development in vitro. The fifth will utilize newly developed molecular discovery techniques to identify mRNAs expressed by activated microglia, determine their relationships to other cells of the monocyte/macrophage lineage, and changes in their gene expression patterns during cytokine exposure or virus infection. Together, this focused array of highly interactive research studies will further clarify the nature of AIDS-associated neurocognitive and motor dysfunctions, and provide animal models in which specific early reversible pathological processes common to HIV, SIV and FIV may be slowed or reversed. In addition, these studies may illuminate other unexplained aspects of fundamental neuronal-glial-immune system interaction, the nature of brain resident microglia, and the basis for neuropsychiatric disorders of unknown origin.