IFN-ALPHA AND HIV GP120 IN NEUROAIDS STUDIES

IFN-α 和 HIV GP120 在神经艾滋病研究中的应用

• 批准号: 6751992
• 负责人: IAIN Leslie CAMPBELL
• 金额: $ 18.17万
• 依托单位: UNIVERSITY OF SYDNEY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6751992
• 关键词: AIDS /HIV neuropathy; HIV envelope protein gp120; astrocytes; biological signal transduction; chemokine; cytokine receptors; gene targeting; genetically modified animals; interferon alpha; laboratory mouse; neuropathology; neurotoxicology

Description (Adapted from Applicant's abstract): Individuals infected with the human immunodeficiency virus (HIV-1) frequently exhibit serious, progressive behavioral cognitive and motor deficits (termed NeuroAIDS). In association with pathological changes in the brain. Evidence suggests the pathogenesis of NeuroAIDS involves a combination of neurotoxic pathways mediated by (1) products of the host response exemplified by IFNalpha, released from activated macrophages/microglia and astroglia and (2) HIV-1 products e.g. the envelope protein gp120. As demonstrated in Preliminary Results, transgenic (tg) mice with astrocyte expression of IFNalpha or gp120 recapitulate many of the structural and functional features of NeuroAIDS and will be used in the proposed studies. To determine the nature and mechanisms by with these factors as well as the CXC chemokine IP-10 influence the degree and progression of structural and functional injury in the CNS. The molecular basis for the actions of IFNalpha and gp120 in the CNS are poorly understood and will be examined in relation to the development of neuropathological changes in the tg mice. In studies designed to examine critical signal transduciton pathways, the applicant will determine the nature and role of the signal transducers and activators of transcription (STAT) and suppressors of cytokine signaling ((SOCS) in the development of the clinical, cellular and molecular alterations in the CNS of the IFNalpha and the gp120 tg mice. A multifaceted approach will be employed for these studies which will (I) define the temporal and spatial expression of the STAT and SOCS genes in the CNS and (ii) evaluate the structural consequences of the loss of STAT signaling in the IFNalpha or gp120 tg mice deficient in STAT gene expression. The potential for synergistic/additive neurotoxicity produced when IFNalpha and gp120 are co-expressed in the CNS will be assessed in bi-genic mice co-expressing IFNalpha and gp120 and the structural CNS alterations will be compared with singly tg and wild type mice. The CXC chemokine IP-10 is prominently expressed in the CNS of the IFNalpha and gp120 tg mice and in patients with NeuroAIDS. To ascertain the CNS effects of IP-10, the investigators will utilize tg mice they recently developed exhibiting astrocyte expression of the IP-10 or gene-knockout mice deficient for the expression of the IP-10- receptor CXCR3. These tg and KO mice will be cross bred with IFNalpha or gp120 mice and the structural and functional CNS alterations will be compared with singly tg and wild type mice. To determine the extent to which the structural damage produced y the host and viral factors is reflected in a change in neuronal function, hippocampal slice physiology will be analyzed in the mice described above. The results from this proposal will advance our understanding of the fundamental mechanisms of action of key host and viral factors in the pathogenesis of NeuroAIDS and may help to identify important targets for therapeutic interventions.

描述(改编自申请者摘要)：感染 人类免疫缺陷病毒(HIV-1)通常表现为严重的、进行性的 行为、认知和运动缺陷(称为神经艾滋病)。与……有关 脑部的病变。有证据表明其发病机制 神经艾滋病涉及由(1)介导的神经毒性途径的组合 宿主反应的产物，以IFNpha为例，从激活释放 巨噬细胞/小胶质细胞和星形胶质细胞以及(2)HIV-1产物，如包膜 蛋白gp120。初步结果表明，转基因(TG)小鼠 随着星形胶质细胞表达IFNpha或gp120，概括了许多 神经艾滋病的结构和功能特征，将用于 建议进行的研究。用这些因素来确定疾病的性质和机制 以及CXC趋化因子IP-10影响的程度和进展 中枢神经系统结构和功能损伤。基因的分子基础 IFNpha和gp120在中枢神经系统中的作用尚不清楚，将被 检查与三叉神经痛神经病变发生发展的关系 老鼠。在旨在研究关键信号转导通路的研究中， 申请人将确定信号传感器的性质和作用，并 转录激活因子(STAT)和细胞因子信号抑制因子 ((SOCS)在临床、细胞和分子改变的发展中) 在IFNpha和gp120转基因小鼠的中枢神经系统中。多方面的方法将 用于这些研究，这些研究将(I)定义时间和空间 STAT和SOCS基因在中枢神经系统中的表达及(Ii)评估 IFNpha或gp120中STAT信令丢失的结构后果 转基因小鼠STAT基因表达缺失。潜在的 干扰素α和gp120联合应用时产生的协同/相加神经毒性 在中枢神经系统中共表达将在双基因小鼠中进行评估 IFNAlpha和gp120以及结构CNS的改变将与 单甘油三酯和野生型小鼠。CXC趋化因子IP-10显著表达 在IFNpha和gp120转基因小鼠以及神经艾滋病患者的中枢神经系统中。至 为了确定IP-10对中枢神经系统的影响，研究人员将利用TG小鼠 新近发现星形胶质细胞表达IP-10或 IP-10受体CXCR3表达缺失的基因敲除小鼠。 这些Tg和KO小鼠将与IFNpha或gp120小鼠杂交，并 结构和功能中枢神经系统的改变将与单独的甘油三酯和 野生型小鼠。以确定结构损伤产生的程度 宿主和病毒因素反映在神经功能的变化上， 对上述小鼠的海马片生理学进行分析。这个 这一提议的结果将促进我们对基本问题的理解 关键宿主和病毒因子在猪瘟发病中的作用机制 神经艾滋病，可能有助于确定治疗的重要靶点 干预措施。