Structure-Function Analytics Core

结构-功能分析核心

• 批准号: 10258149
• 负责人: GEORGIA Doris TOMARAS
• 金额: $ 76.49万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-25 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10258149
• 关键词: Animal Model; Antibodies; Antibody Response; Antigen-Antibody Complex; Antigens; Antiviral Agents; Architecture; Binding; Biochemical; Biological; Biological Models; Biology; Biophysics; Blood; Cells; Cellular Structures; Characteristics; Clinic; Complex; Computing Methodologies; Data; Data Analyses; Dissection; Effector Cell; Epitopes; Equilibrium; Extracellular Domain; Fc Receptor; Fc(alpha) receptor; Gene Expression Profiling; Genetic Transcription; Goals; HIV Antibodies; HIV-1; High Pressure Liquid Chromatography; Human; Immune; Immunoglobulin A; Immunoglobulin G; Immunoglobulins; Immunologic Receptors; In Situ; In Vitro; Infection; Inflammation; Infusion procedures; Knowledge; Lead; Macaca mulatta; Maps; Mediating; Methods; Modeling; Molecular; Monoclonal Antibodies; Outcome; Peptides; Phenotype; Play; Polymeric Immunoglobulin Receptors; Polysaccharides; Population; Post-Translational Protein Processing; Recombinants; Regimen; Resolution; Role; Sampling; Specificity; Standardization; Structure; Therapeutic Studies; Tissues; Translating; Vaccine Design; Vaccines; Variant; Viral Antibodies; Viral Load result; base; cell type; diverse data; env Gene Products; experimental study; glycosylation; human model; immunoprophylaxis; in vivo; insight; interest; mouse model; neonatal Fc receptor; nonhuman primate; polyclonal antibody; programs; protective efficacy; receptor; receptor binding; response; vaccine trial

ABSTRACT_Core 2 Considerable evidence suggests a role for diverse antibody (Ab) activities, including Fc receptor (FcR)- mediated functions in viral load reduction and in blocking HIV-1 acquisition. Although the role of FcR-effector function in antiviral activity holds across multiple model systems and Abs, mechanistic insights are complicated by species-specific solutions to balancing potent Ab effector activity with damaging inflammation, distinct epitope-, effector-, and Ab-specific factors, as well as distinctions between the effector mechanisms available in blood and tissue. Despite evolutionary proximity, significant differences between Rhesus macaque (RM) and human Ab biology that manifest in different functional characteristics of the Ab isotypes and subclasses, FcRs expressed on innate immune cells, and their biological interplay. This program will expand this map of how antiviral activity against HIV-1 is accomplished by diverse effector mechanisms, involving engagement of different soluble factors and effector cell populations, and distinctive immunoglobulin types in immune-complexes that vary in their overall architecture and biological activity, in both humans and RM. There is a continuing need to define this biology in humans and animal models in order to effectively translate insights gained from emerging protective and therapeutic studies to the clinic, and fuel impactful Ab immunoprophylaxis, cure strategies, and vaccine designs. The Structure-Function Analytics Core will support Projects 1, 2, and 3 and play a key role in achieving Program Goals by providing unifying structural, biophysical, biochemical, and data analysis of the Ab features and Fv and Fc interactions that underpin potent antiviral activities. Aim 1. Define the biophysical basis of potent antiviral Ab activity. Aim 2: Define the structural basis of potent antiviral Ab activity. Aim 3. Model the knowledge of immune cells and Ab features to define optimal antiviral activities.

摘要_核心2 相当多的证据表明，不同的抗体（Ab）活性，包括Fc受体（FcR）- 介导的病毒载量减少和阻断HIV-1获得的功能。尽管FcR效应子的作用 抗病毒活性中的功能在多个模型系统和Ab中成立，机制见解是复杂的 通过物种特异性解决方案来平衡有效的Ab效应子活性与破坏性炎症， 表位、效应子和抗体特异性因子，以及可用效应子机制之间的区别 在血液和组织中。 尽管进化上接近，但恒河猴（RM）和人类Ab之间的显著差异 生物学表现为Ab同种型和亚类的不同功能特征，FcRs表达 以及它们之间的生物学相互作用。这个项目将扩展抗病毒药物 抗HIV-1的活性是通过不同的效应机制来实现的，涉及不同的 可溶性因子和效应细胞群，以及免疫复合物中独特的免疫球蛋白类型， 在人类和RM中，它们的整体结构和生物活性各不相同。持续需要 在人类和动物模型中定义这种生物学，以便有效地转化从新兴的 保护和治疗研究的临床，燃料有影响力的抗体免疫预防，治愈策略， 疫苗设计 结构-功能分析核心将支持项目1、2和3，并在实现目标方面发挥关键作用 通过提供Ab特征的统一结构、生物物理、生物化学和数据分析，实现计划目标 以及支持有效抗病毒活性的Fv和Fc相互作用。 目标1。定义有效抗病毒抗体活性的生物物理基础。 目的2：明确抗病毒抗体活性的结构基础. 目标3。对免疫细胞和抗体特征的知识进行建模，以确定最佳的抗病毒活性。