IFN-ALPHA AND HIV GP120 IN NEUROAIDS STUDIES

描述（改编自申请人摘要）：感染 人免疫缺陷病毒（HIV-1）经常表现出严重、进行性 行为认知和运动缺陷（称为NeuroAIDS）。结合 大脑的病理变化。有证据表明， 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，例如IFN α，从活化的 巨噬细胞/小胶质细胞和星形胶质细胞，以及（2）HIV-1产物，例如包膜 蛋白质gp 120。如初步结果所示，转基因（tg）小鼠 星形胶质细胞表达IFN α或gp 120， 神经艾滋病的结构和功能特点，并将用于 建议的研究。通过对这些因素的综合分析， 以及CXC趋化因子IP-10的影响， CNS的结构和功能损伤。的分子基础 IFN α和gp 120在CNS中的作用知之甚少， 检查与TG中神经病理学变化的发展相关 小鼠在旨在检查关键信号转导途径的研究中， 申请人将确定信号换能器的性质和作用， 转录激活因子（STAT）和细胞因子信号转导抑制因子 （（SOCS）在临床、细胞和分子改变的发展中 在IFN α和gp 120 tg小鼠的CNS中。多方面的方法将 这些研究将（I）定义时间和空间 STAT和SOCS基因在CNS中的表达，以及（ii）评估 IFN α或gp 120中STAT信号传导丢失的结构后果 tg小鼠STAT基因表达缺陷。的潜力 当IFN α和gp 120被 将在共表达以下蛋白的双基因小鼠中评估CNS中共表达的 IFN α和gp 120以及结构性CNS改变将与 单独的TG和野生型小鼠。CXC趋化因子IP-10显著表达于 在IFN α和gp 120 tg小鼠以及NeuroAIDS患者的CNS中。到 为了确定IP-10的CNS作用，研究人员将利用tg小鼠， 最近开发的表现出IP-10的星形胶质细胞表达， IP-10受体CXCR 3表达缺陷的基因敲除小鼠。 这些tg和KO小鼠将与IFN α或gp 120小鼠杂交， 结构和功能的中枢神经系统的改变将与单一的tg和 野生型小鼠以确定结构损坏的程度 由于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 这项建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急性胰腺炎发病机制中的作用机制 神经艾滋病，可能有助于确定治疗的重要目标 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.