Structure and Design of Cytokine and Chemokine Binding Proteins

细胞因子和趋化因子结合蛋白的结构和设计

• 批准号: 7741162
• 负责人: MARK R WALTER
• 金额: $ 22.62万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-19 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7741162
• 关键词: Abbreviations; Address; Adopted; Amino Acids; Animal Model; Antibodies; Area; Binding Proteins; Biochemical; Biological Assay; Cell Surface Receptors; Cells; Chronic; Discipline; Dithiothreitol; Engineering; Evolution; Feasibility Studies; Gel Chromatography; HIV; HIV Infections; Health; Hepatitis C; Hepatitis C virus; Homo; Human; Immune response; Immune system; Immunosuppressive Agents; Infection; Inhibitory Concentration 50; Interferons; Interleukin-10; Investigation; Libraries; Lymphocytic choriomeningitis virus; Macaca mulatta; Membrane; Methodology; Modeling; Molecular Weight; Mouse Pox Virus; Mus; Oryctolagus cuniculus; Poxviridae; Property; Proteins; Reagent; Relative (related person); Research; Screening procedure; Signal Transduction; Structure; Surface Plasmon Resonance; T-Lymphocyte; Testing; Thioredoxin; Upper arm; Viral; Virus; Work; base; chemokine; cytokine; design; exhaustion; improved; insight; light scattering; maltose-binding protein; novel; prevent; public health relevance; scaffold

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.

描述（由申请人提供）：本提案将使用干扰素-？电虫病毒结合蛋白(IFN-？BPECTV)设计新的细胞因子拮抗剂和改进的研究试剂具有广泛的应用于许多学科。IFN-?的初步结构研究BPECTV揭示了一种新的四聚体结构。该结构将用于设计IFN-？基于bpectv的阻断免疫抑制细胞因子IL-10信号传导的试剂。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，异四聚体D3组装试剂也将在LCMV感染模型中开发和测试。这些研究将验证基于d3的试剂的重要性，并为LCMV诱导t细胞衰竭提供新的见解。这一点很重要，因为人类感染丙型肝炎和艾滋病毒时也会发生t细胞衰竭。公共卫生相关性：本提案将设计和测试基于痘病毒蛋白的细胞因子阻断试剂，有效拮抗细胞因子。这项工作将为更好地研究t细胞衰竭和其他人类健康问题提供新的研究试剂。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。