Prediction and Perturbation of Epitopes by Modeling and Immune Responses

通过建模和免疫反应预测和扰动表位

• 批准号: 8897074
• 负责人: WILLIAM R. SCHIEF
• 金额: $ 53.07万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8897074
• 关键词: Affect; Algorithm Design; Algorithms; Antibodies; Antibody Response; Antibody Specificity; Antigen Targeting; Antigen-Antibody Complex; Antigens; Back; Benchmarking; Binding; Binding Sites; Biochemical; Biological Models; Cell surface; Characteristics; Clinical; Collaborations; Communicable Diseases; Complex; Computer Simulation; Computing Methodologies; Data; Data Set; Databases; Dengue; Dengue Virus; Development; Distal; Ebola virus; Engineering; Ensure; Epitopes; Evaluation; Glycoproteins; Head; Human; Immune response; Immune system; Immunity; Immunization; Immunology; In Vitro; Infection; Influenza Hemagglutinin; Investigation; Libraries; Maps; Medical; Methods; Modeling; Monoclonal Antibodies; Mus; Polysaccharides; Property; Proteins; Protocols documentation; Reproduction; Serum; Specificity; Structural Models; Structure; Surface; Surface Properties; Techniques; Testing; Vaccination; Vaccine Antigen; Vaccines; Viral; Viral Antigens; Virus; base; biodefense; design; feeding; human subject; improved; influenzavirus; method development; model design; neutralizing monoclonal antibodies; novel; novel vaccines; pathogen; receptor binding; research study; response; vaccine development

This project (Project 3 of a three project proposal entitled "Structure based design of antibodies and vaccines" responding to the RFA-AI-14-028 “Modeling Immunity for Biodefense”) will develop computational methods to predict the epitope specificity of antibody immune responses to structural antigens, will develop computational methods to design structurally stable antigens with customized surfaces to enable focusing of antibody immune responses to preselected epitopes, and will test these methods by experiment, by assessing immune responses to designed model antigens. The primary model system will be the head domain of influenza hemagglutinin and the focus will be on the epitopes within and around the receptor binding site, but other model systems will include neutralizing epitopes of glycoproteins from dengue virus and ebola virus. To assist computational methods development, in vitro cell surface display methods will be employed to improve the properties of designed antigens, and those results will feed back to guide algorithmic improvements. Likewise, results from immunization studies will feed back to guide refinement of the methods. The project 3 specific aims are: (1) Develop and benchmark computational methods to predict epitope immuno-visibility (2) Develop computational methods to design structurally stable epitope-focused immunogens and experimentally test those methods by evaluating immune responses to designed model antigens (3) Develop computational methods to resurface immunogens to focus immune responses to preselected epitopes, and test those methods by evaluating immune responses to designed model antigens. .

本项目（题为“基于结构的建筑设计"的三个项目提案中的项目3） 抗体和疫苗”响应RFA-AI-14-028“免疫建模 生物防御”）将开发计算方法来预测 抗体免疫反应的结构抗原，将开发计算方法 设计具有定制表面的结构稳定的抗原， 抗体免疫反应预选表位，并将测试这些方法， 实验，通过评估对设计的模型抗原的免疫应答。主 模型系统将是流感血凝素的头部域，重点将是 在受体结合位点内和周围的表位上，但其他模型系统将 包括来自登革热病毒和埃博拉病毒糖蛋白的中和表位。到 辅助计算方法的发展，体外细胞表面展示方法将成为 用于改善设计抗原的特性，这些结果将有助于 来指导算法的改进同样，免疫研究的结果将 反馈以指导方法的改进。该项目的3个具体目标是：（1） 开发和基准计算方法，以预测表位免疫可见性（2） 开发计算方法来设计结构稳定的表位聚焦 免疫原和实验测试这些方法，通过评估免疫反应， 设计的模型抗原（3）开发计算方法来重新浮现免疫原 将免疫反应集中在预先选择的表位上，并通过以下方式测试这些方法： 评价对设计的模型抗原的免疫应答。 .