Physical Resources Core

物理资源核心

• 批准号: 10475276
• 负责人: Justin Joseph Pollara
• 金额: $ 82.27万
• 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/10475276
• 关键词: Active Immunization; Alleles; Animals; Antibodies; Antibody Diversity; Antibody Response; Antigen-Antibody Complex; Antigens; Bar Codes; Base Sequence; Biophysics; Cell Line; Cell Surface Proteins; Cells; Cellular biology; Clinical Trials; Collection; Computing Methodologies; Data; Data Reporting; Data Set; Development; Disease Progression; Effector Cell; Evaluation; Fc Immunoglobulins; Fc Receptor; Fc domain; Future; Generations; Genes; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Gold; HIV; HIV-1; HIV-1 vaccine; Haplotypes; Human; Immune; Immune response; Immunoglobulin Allotypes; Immunology; In Situ; In Vitro; Individual; Infection; Knowledge; Macaca mulatta; Mediating; Methods; Modeling; Monitor; Monoclonal Antibodies; Outcome; Outcome Study; Passive Immunization; Phenotype; Population; Production; Protein Isoforms; Reagent; Receptor Gene; Recombinants; Regulation; Reporting; Research Personnel; Research Project Grants; Research Support; Resources; Rhesus; Sampling; Sequence Analysis; Serology; Services; Signal Transduction; Single Nucleotide Polymorphism; Structure; Surveys; Testing; Therapeutic; Translations; Validation; Viral Antibodies; Viral Proteins; Viremia; Virus; Work; base; clinical trial participant; disorder risk; experience; experimental study; immunoprophylaxis; improved; in vivo; infection risk; innovation; neutralizing antibody; next generation sequencing; novel; outcome prediction; programs; prophylactic; prospective; response; simian human immunodeficiency virus; tool; transcriptome; transcriptome sequencing; vaccine candidate; vaccine strategy

ABSTRACT_Core 1 Fc receptors (FcRs) are cell surface proteins that interact with antibody Fc domains to mediate effector cell responses that contribute to the antiviral functionality of antibodies. The diversity of antibodies (isotypes, subclasses, allotypes) and FcRs (types, gene polymorphisms, isoforms) influences antiviral antibody effector functions by modulating the interactions between antigen–antibody immune complexes and FcRs. However, the relative combined contributions of these key variables to protective outcomes in human and rhesus macaque (RM) active and passive immunization studies are unknown. Thus, there is a critical need to characterize how different antibody isotypes, subclasses, allotypes, and FcR alleles impact species-specific FcR-dependent antibody effector functions in order to understand how immunoprophylaxis trials conducted in the RM model can predict outcomes in humans. The overall goal of the Physical Resources Core is to develop and provide this Program with the tools, reagents, samples, and nucleic acid sequence datasets and analyses needed for translation of FcR and antibody Fc genetic diversity among humans and RM to phenotypes, effector functions, and study outcomes. To achieve this, the Physical Resources Core brings together an innovative team of investigators with extensive experience and expertise in the generation, validation, and analysis of next-generation sequencing data; and in the development, production, validation, distribution, and application of novel immunology reagents and materials that are not commercially available. Guided by strong preliminary data, and using a combination of gold-standard and state-of-the art approaches, the Physical Resources Core will achieve the objective of supporting Research Projects 1, 2, 3 and the Overall Program through focus on completion of three Specific Aims: Aim 1. Quantify human FcR diversity in HIV-1 clinical trial participants. Aim 2. Define antibody Fc allotype diversity in humans and RM. Aim 3. Provide immunology reagents and services. Fulfillment of the aims of the Core will be significant and impactful because it will lead to identification of the combinations of nAb and nnAb and effector cell biology for improved understanding of in situ functions. This will provide a roadmap to improve testing accuracy and evaluations of both future active, and immunoprophylaxis, vaccine candidates in human clinical trials. The Physical Resources Core will help generate knowledge essential to accomplishing the Overall Goal of this Program: to determine the impact of antibody allotype and FcR genotype on antiviral outcomes in vitro and in vivo, thus informing how antibody Fc effector functions can be used to improve antibody-based vaccine strategies, increase the relative antiviral activity of HIV-1 specific antibody subclasses, and augment broad-neutralizing antibody-based prophylactic and therapeutic approaches.

摘要_核心1 Fc受体（FcRs）是与抗体Fc结构域相互作用以介导效应细胞增殖的细胞表面蛋白。 有助于抗体的抗病毒功能的应答。抗体的多样性（同种型， 亚类、同种异型）和FcR（类型、基因多态性、同种型）影响抗病毒抗体效应子 通过调节抗原抗体免疫复合物与FcR之间的相互作用来发挥作用。但是，在这方面， 这些关键变量对人类和恒河猴保护性结果的相对综合贡献 猕猴（RM）主动和被动免疫研究是未知的。因此，迫切需要 表征不同的抗体同种型、亚类、同种异型和FcR等位基因如何影响物种特异性 FcR依赖性抗体效应子的功能，以了解如何进行免疫预防试验， RM模型可以预测人类的结果。物理资源核心的总体目标是开发 并向本计划提供工具、试剂、样本和核酸序列数据集和分析 人类和RM中的FcR和抗体Fc遗传多样性转化为表型所需的， 效应器功能和研究结果。为了实现这一目标，物理资源核心汇集了 创新的研究团队，在生成、验证和 分析下一代测序数据;以及在开发、生产、验证、分销和 新的免疫学试剂和材料的应用是不可商购的。以强为导 初步数据，并使用金本位和最先进的方法相结合，物理 核心资源将实现支持研究项目1、2、3和整体计划的目标 通过重点完成三个具体目标： 目标1。量化HIV-1临床试验参与者中的人类FcR多样性。 目标2.定义人类和RM中抗体Fc同种异型多样性。 目标3.提供免疫学试剂和服务。 实现《核心文件》的目标将具有重要意义和影响力，因为它将导致确定 nAb和nnAb与效应细胞生物学的组合用于改善对原位功能的理解。这 将提供一个路线图，以提高测试的准确性和评估未来的活动， 免疫预防，人类临床试验中的候选疫苗。物理资源核心将帮助 产生实现本计划总体目标所必需的知识：确定 抗体同种异型和FcR基因型对体外和体内抗病毒结果的影响，从而告知抗体Fc 效应子功能可用于改进基于抗体的疫苗策略，增加相对抗病毒性， HIV-1特异性抗体亚类的活性，并增强基于广泛中和抗体的预防性 和治疗方法。