Structure and Design of Cytokine and Chemokine Binding Proteins

描述(由申请人提供)：本提案将使用干扰素-？ECV结合蛋白设计新的细胞因子拮抗剂和改良的研究试剂，具有广泛的学科应用。BPECTV的初步结构研究揭示了一种新的四聚体结构。该结构将用于设计基于BPECTV的干扰素试剂，阻断免疫抑制细胞因子IL-10的信号。这些基于痘病毒的IL-10阻断蛋白将被测试其解决小鼠慢性LCMV感染的能力。利用计算和文库筛选方法，还将开发异四聚体D3组装试剂，并在LCMV感染模型中进行测试。这些研究将验证基于D3的试剂的重要性，并为LCMV诱导的T细胞衰竭提供新的见解。这一点很重要，因为在人类感染丙型肝炎和艾滋病毒期间也会发生T细胞耗尽。与公共卫生相关：这项提案将设计和测试细胞因子阻断试剂，这种试剂基于痘病毒中能有效拮抗细胞因子的蛋白质。这项工作将提供新的研究试剂，以更好地研究T细胞耗竭和人类健康中的许多其他问题。特别是，这些研究可以帮助我们了解如何利用免疫系统来消除丙型肝炎和/或艾滋病毒感染。

DESCRIPTION (provided by applicant): This proposal will use the interferon-? binding protein from ectromelia virus (IFN-?BPECTV) to design new cytokine antagonists and improved research reagents with broad applications to many disciplines. Preliminary structural studies on IFN-?BPECTV have revealed a novel tetrameric structure. The structure will be used to engineer IFN-?BPECTV-based reagents that block signaling by the immunosuppressive cytokine, IL-10. These poxvirus-based IL-10 blocking proteins will be tested for their ability to resolve chronic LCMV infections in mice. Using computational and library screening methodology, hetero-tetrameric D3 assembly reagents will also be developed and tested in the LCMV infection model. These studies will validate the importance of D3-based reagents and provide new insights into LCMV induced T-cell exhaustion. This is important as T-cell exhaustion also occurs during hepatitis C and HIV infections in humans. PUBLIC HEALTH RELEVANCE: This proposal will design and test cytokine blocking reagents that are based on proteins in poxviruses that efficiently antagonize cytokines. This work will provide new research reagents to better study T-cell exhaustion and a broad number of other problems in human health. In particular, these studies could help us understand how to harness the immune system to eliminate hepatitis C and/or HIV infections.