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

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

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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.

Abstract_core 2 大量证据表明，包括FC受体（FCR）在内的各种抗体（AB）活性的作用 - 病毒负荷减少和阻断HIV-1采集的介导功能。虽然FCR效应器的作用抗病毒活性的功能在多个模型系统和ABS中保持，机械见解很复杂通过特定于物种的解决方案，可以平衡有效的AB效应活性与破坏性炎症，不同表位，效应和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。尽管进化接近，但恒河猴（RM）和人类AB之间的显着差异 FCR表达的生物学表现为AB同种型和亚类的不同功能特征关于先天免疫细胞及其生物学相互作用。该程序将扩大有关抗病毒如何的地图针对HIV-1的活动是通过各种效应子机制来完成的，涉及不同的参与可溶性因子和效应细胞群，以及免疫复合物中的独特免疫球蛋白类型在人类和RM中，它们的整体建筑和生物活动各不相同。持续需要在人类和动物模型中定义这种生物学，以便有效地翻译出从新兴中获得的见解对诊所的保护和治疗性研究，并燃料有影响力的AB免疫预防，治愈策略和疫苗设计。结构功能分析核心将支持项目1、2和3，并在实现方面发挥关键作用通过提供统一的AB特征的结构，生物物理，生化和数据分析来实现程序目标以及支撑有效抗病毒活性的FV和FC相互作用。目标1。定义有效抗病毒AB活性的生物物理基础。目标2：定义有效抗病毒AB活性的结构基础。目标3。建模免疫细胞和AB特征以定义最佳抗病毒活性。