IFN-ALPHA AND HIV GP120 IN NEUROAIDS STUDIES

描述（改编自申请人的摘要）：感染该病毒的个人 人类免疫缺陷病毒 (HIV-1) 经常表现出严重、进行性的症状 行为认知和运动缺陷（称为 NeuroAIDS）。与 大脑的病理变化。有证据表明发病机制 NeuroAIDS 涉及由 (1) 介导的神经毒性途径的组合 宿主反应的产物，以 IFNα 为代表，从激活的细胞中释放出来 巨噬细胞/小胶质细胞和星形胶质细胞和 (2) HIV-1 产品，例如信封 蛋白质 gp120。如初步结果所示，转基因 (tg) 小鼠 星形胶质细胞表达 IFNα 或 gp120 概括了许多 NeuroAIDS 的结构和功能特征，并将用于 拟议的研究。通过这些因素来确定性质和机制 以及CXC趋化因子IP-10影响程度和进展 中枢神经系统的结构和功能损伤。的分子基础 IFNα 和 gp120 在 CNS 中的作用尚不清楚，有待进一步研究 检查与 tg 神经病理学变化的发展有关 老鼠。在旨在检查关键信号转导途径的研究中， 申请人将确定信号传感器的性质和作用，以及 转录激活剂 (STAT) 和细胞因子信号转导抑制剂 （（SOCS）在临床、细胞和分子改变的发展中 在 IFNα 和 gp120 tg 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 CNS 中的表达，并且 (ii) 评估 IFNα 或 gp120 中 STAT 信号丢失的结构后果 STAT 基因表达缺陷的 tg 小鼠。的潜力 当 IFNα 和 gp120 作用时产生协同/累加神经毒性 中枢神经系统中的共表达将在双基因小鼠共表达中进行评估 IFNα 和 gp120 以及 CNS 结构的改变将与 单独 tg 和野生型小鼠。 CXC 趋化因子 IP-10 显着表达 在 IFNα 和 gp120 tg 小鼠以及 NeuroAIDS 患者的中枢神经系统中。至 为了确定 IP-10 对 CNS 的影响，研究人员将使用 tg 小鼠 最近开发的星形胶质细胞表达 IP-10 或 IP-10 受体 CXCR3 表达缺陷的基因敲除小鼠。 这些 tg 和 KO 小鼠将与 IFNα 或 gp120 小鼠杂交， 中枢神经系统结构和功能的改变将与单独的 tg 和 野生型小鼠。确定结构损坏的程度 y 宿主和病毒因素反映在神经元功能的变化中， 将在上述小鼠中分析海马切片生理学。的 该提案的结果将增进我们对基本原理的理解 关键宿主和病毒因素在发病机制中的作用机制 NeuroAIDS 可能有助于确定重要的治疗靶点 干预措施。

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.