Structure-Function Analytics Core

结构-功能分析核心

基本信息

批准号：
10670249
负责人：
GEORGIA Doris TOMARAS
金额：
$ 100.92万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10670249
关键词：
Animal Model Antibodies Antibody Response Antigen-Antibody Complex Antigens Architecture Binding Biochemical Biological Biological Models Biology Biophysics Blood Cells Characteristics Clinic Complex Computing Methodologies Data Data Analyses Dissection Effector Cell Epitopes 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 Viral Antibodies Viral Load result Viral Physiology cell type data integration 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

项目摘要

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 大量证据表明多种抗体 (Ab) 活性发挥作用，包括 Fc 受体 (FcR) - 介导的病毒载量减少和阻止 HIV-1 获得的功能。尽管 FcR 效应子的作用抗病毒活性的功能跨多个模型系统和抗体，机制见解很复杂通过物种特异性解决方案来平衡有效的抗体效应子活性与破坏性炎症，不同表位、效应器和抗体特异性因素，以及可用效应器机制之间的区别在血液和组织中。尽管在进化上接近，恒河猴 (RM) 和人类抗体之间仍存在显着差异生物学表现在 Ab 同种型和亚类、FcR 表达的不同功能特征先天免疫细胞及其生物相互作用。该计划将扩展抗病毒地图抗 HIV-1 的活性是通过不同的效应机制来完成的，涉及不同的参与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人类和 RM 的整体结构和生物活性各不相同。仍然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技术中获得的见解临床保护和治疗研究，并促进有效的抗体免疫预防、治疗策略和疫苗设计。结构-功能分析核心将支持项目 1、2 和 3，并在实现计划目标是提供抗体特征的统一结构、生物物理、生化和数据分析 Fv 和 Fc 相互作用支撑有效的抗病毒活性。目标 1. 确定有效抗病毒抗体活性的生物物理基础。目标 2：确定有效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。