BIOCHEMISTRY OF CCR5/CXCR4/GP120 SIGNAL TRANSDUCTION

CCR5/CXCR4/GP120 信号转导的生物化学

• 批准号: 6607451
• 负责人: CRAIG GERARD
• 金额: $ 30.61万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-03 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6607451
• 关键词: HIV envelope protein gp120; HIV envelope protein gp41; HIV infections; affinity chromatography; binding sites; biological signal transduction; chemokine; conformation; cytokine receptors; genetic library; genetically modified animals; helper T lymphocyte; laboratory mouse; polymerase chain reaction; protein structure function; receptor binding; respiratory infections

This proposal seeks to address two current hypotheses regarding the role of chemokines and their receptors in viral disease pathogenesis. The first hypothesis is that the chemokine receptors bear discrete structural features which recognize the bind a conformationally protected feature on the gp120 molecule (exposed after CD4 binding). Interaction at this binding site directly leads to the fusion event mediated by gp41. The second hypotheses is that chemokines responding to virally infected cells are essential to shape the immune response by recruitment of specific host defense cells in a coordinated fashion. In the case of HIV-1 infection, identification of the chemokine response in the lung may be of significance in understanding the pulmonary consequences of the infection. Two specific aims are proposed as means to gather additional information regarding these hypotheses. Aim 1 will identify and characterize single chain antibodies from a phage display library which specifically recognize the gp120/CD4 complex in an effort to identify more precisely the co-receptor binding sites for R5 and X4 envelope glycoproteins. Aim 2 will examine the role of chemokines in viral host defense in the lung using a transgenic mouse bearing an inducible chemokine antagonist or lacking a Th1 polarized receptor CXCR3. Information gathered in this proposal may be of importance in the development of therapeutic strategies to control HIV disease.

该提案旨在解决目前关于趋化因子及其受体在病毒性疾病发病机制中的作用的两个假设。第一个假设是趋化因子受体具有离散的结构特征，其识别结合gp120分子上的构象保护特征（在CD4结合后暴露）。该结合位点的相互作用直接导致 gp41 介导的融合事件。第二个假设是，对病毒感染细胞做出反应的趋化因子对于通过以协调的方式招募特定宿主防御细胞来形成免疫反应至关重要。在 HIV-1 感染的情况下，识别肺部趋化因子反应对于了解感染的肺部后果可能具有重要意义。提出了两个具体目标作为收集有关这些假设的额外信息的手段。目标 1 将鉴定和表征来自噬菌体展示文库的单链抗体，该抗体特异性识别 gp120/CD4 复合物，以更精确地鉴定 R5 和 X4 包膜糖蛋白的共受体结合位点。目标 2 将使用带有诱导型趋化因子拮抗剂或缺乏 Th1 极化受体 CXCR3 的转基因小鼠来检查趋化因子在肺部病毒宿主防御中的作用。本提案中收集的信息对于制定控制艾滋病毒疾病的治疗策略可能很重要。