AIDS DEMENTIA--MOLECULAR AND CELLULAR MECHANISMS

这是我们的NIMH中心补助金（MH 47690_）的竞争性续订请求 艾滋病痴呆症：分子和细胞机制。 目前， 多学科研究中心自成立以来，积极开展 中枢神经系统表现的分子和细胞机制 通过高度集中的HIV比较评价慢病毒感染 神经心理学和睡眠中断定义的脑病理生理学 神经行为学、电生理学、病毒学和免疫学 猴免疫缺陷病毒（SIV）感染的表现，以及 猫免疫缺陷病毒（FIV）以及过- 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， 星形胶质细胞或其它CNS细胞。 根据本中心的进展， 在艾滋病研究工作的总体范围内， 将在未来5年内进行的工作将侧重于确定 早期中枢神经系统变化的分子和细胞机制， 比较这些动物模型与艾滋病毒的趋同表现， 病理生理机制，并评估潜在的药物治疗 用于逆转或减弱 慢病毒感染 因此，现请求为6个核心项目提供资金， 项目和12个独立的，但高度合作的研究组成部分。 两个组成部分将扩展HIV相关CNS的最新进展 功能障碍，比较传统的神经心理测试电池与 CANTAB是一种自动神经心理评估电池， 该中心的SUV中枢神经系统研究，并检查睡眠中断， 早期HIV血清转换患者，其神经心理作用 性能，其短期治疗，以及最近发现的 血浆细胞因子与CNS EEG活动的相关性。 两个高度互动的 组成部分将侧重于SIV感染恒河猴。 一个最近 发达的，小胶质细胞衍生的神经侵入性，神经毒性SIV股票将 在神经行为和生理动物模型中进行评价， 定量监测以表征CNS的时间进程 FIV的表现。 将研究功能修饰的FIV突变体 评估脑细胞感染性和神经毒力的模式 根据临床和神经系统进展、睡眠中断、EEG和事件 相关电位; 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TNF α或 NMDA受体拮抗剂，单独或组合对FIV诱导的 将研究神经系统疾病。 五个啮齿类动物项目将研究 特定细胞类别内的特定分子介质。 三个项目 将使用转基因小鼠突变体来过表达特定的细胞因子， 天然蛋白质或病毒蛋白质（IFN γ在视杆细胞和视锥细胞中的表达; 星形胶质细胞表达HIV gp 120、IL 6或IFN α或人CD 4， 脑小胶质细胞/巨噬细胞或神经元中的人淀粉样前体蛋白） 单独或组合使用，以确定潜在的机制 神经病理生理学在缺乏直接慢病毒感染的情况下， 神经元 第四个项目将检查细胞因子IL 1-β，TNF α， 和IL 6，以及HIV糖蛋白对小脑神经元发育的影响。 体外 第五个将利用新开发的分子发现 技术，以确定由激活的小胶质细胞表达的mRNA，确定 它们与单核细胞/巨噬细胞谱系的其他细胞的关系，以及 在细胞因子暴露或病毒感染期间， 感染 总之，这一系列高度互动的研究 研究将进一步阐明艾滋病相关的神经认知的性质， 和运动功能障碍，并提供动物模型，其中特定的早期 HIV、SIV和FIV常见的可逆病理过程可能减缓 或者颠倒。 此外，这些研究可能会阐明其他无法解释的 基本神经元-神经胶质细胞-免疫系统相互作用的方面， 以及神经精神疾病的基础 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.