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Transgenic mouse core

转基因小鼠核心

基本信息

批准号：
9884719
负责人：
Stylianos Bournazos
金额：
$ 23.53万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9884719
关键词：
Animal Disease Models Animal Model Antibodies Antibody-Dependent Enhancement Antibody-mediated protection Antiviral Agents Binding Biological Biological Assay Biological Models Biology Cell Line Cells Characteristics Dengue Dengue Infection Dimensions Disease Effector Cell Engineering Epitopes Evaluation Exhibits Fab domain Fc domain Flavivirus Flavivirus Infections Genetic Engineering Genetically Engineered Mouse Genotype HIV Hepatitis B Virus Hepatitis Viruses Hepatocyte Human Human Activities Immune Immune Sera Immune response Immune signaling Immunity Immunocompetent Immunoglobulin G In Vitro Infection Influenza Interferons Leukocytes Mediating Molecular Monoclonal Antibodies Mouse Strains Mus Nature Pathogenesis Pathogenicity Pathway interactions Phenotype Predisposition Rag1 Mouse Research Personnel Role Series Severity of illness Signal Pathway Signal Transduction Surface System Transgenic Mice Vaccination Viral Viral Pathogenesis Viral Physiology Viral hepatitis Virus Virus Diseases anti-hepatitis B cell type cross reactivity defined contribution epidemiologic data experimental study humanized mouse immunoregulation in vitro Assay in vivo in vivo Model in vivo evaluation innovation neutralizing antibody novel particle pathogen pathogenic virus receptor reconstitution stem vaccine response virus core

项目摘要

ABSTRACT – Core A, Bournazos The ability of an IgG antibody to mediate biological effects in vivo, such as protection from viral infection, results from its bispecific nature. The Fab region of an antibody recognizes epitopes on the viral spike and may interfere with virus binding to target cells, while the Fc domain mediates diverse immunomodulatory activities through specific interactions with Fcγ receptors (FcγRs) expressed by effector leukocytes. Studies on several infectious pathogens have shown that Fc-FcγR interactions have the capacity to mediate a wide spectrum of opposing functions – from viral opsonization and clearance of infected cells (protective) to enhanced viral infection and disease severity (pathogenic). Understanding the precise mechanisms by which IgG antibodies mediate protective or pathogenic functions necessitates the use of well-defined in vivo experimental systems that reflect the unique complexity of effector leukocytes that participate in an immune response. Indeed, although in vitro assays using cell lines or primary effector cells represent well-established approaches for characterizing the function of IgG antibodies, such assays provide limited information on the precise molecular mechanisms that drive human immunity during infection or upon vaccination. We will provide a Core that will maintain, characterize, and distribute a series of genetically-engineered humanized mouse strains to the Center investigators in support of the proposed studies on the characterization of the pathogenic activity of anti-flavivirus antibodies that confer susceptibility to dengue disease, as well as on the evaluation of the protective antiviral function of neutralizing antibodies against hepatitis B viruses. Through specific deletions of key immune signaling pathways or reconstitution with human primary cells that represent the natural viral host cell type, these engineered mouse strains support the infection and replication of flaviviruses and hepatitis viruses in vivo, thereby facilitating the study of viral disease pathogenesis, as well as the characterization of the molecular mechanisms that contribute to the IgG antibody activity during viral infection.

摘要-核心A，Bournazos IgG抗体在体内介导生物学效应的能力，例如保护免受病毒感染，导致从它的双特异性的性质。抗体的Fab区识别病毒刺突上的表位，并且可以干扰病毒刺突上的抗原表位。与病毒结合靶细胞，而Fc结构域介导不同的免疫调节活性，与效应白细胞表达的Fcγ受体（FcγRs）的特异性相互作用。几种传染病的研究病原体已经表明，Fc-FcγR相互作用具有介导广谱的对抗性免疫应答的能力，功能-从病毒调理作用和感染细胞的清除（保护性）到增强病毒感染，疾病严重程度（致病性）。了解IgG抗体介导的精确机制保护性或致病性功能需要使用明确的体内实验系统，参与免疫反应的效应白细胞的独特复杂性。事实上，尽管在体外使用细胞系或原代效应细胞的测定代表了用于表征 IgG抗体的功能，这种测定提供了有限的信息，精确的分子机制，在感染期间或接种疫苗时驱动人体免疫力。我们将提供一个核心，鉴定并向中心分发一系列基因工程人源化小鼠品系研究者支持拟定的抗黄病毒致病活性表征研究对登革热易感性的抗体，以及对保护性抗病毒药物的评价抗B型肝炎病毒中和抗体的功能。通过特异性删除关键免疫信号途径或用代表天然病毒宿主细胞类型的人原代细胞重建，这些工程小鼠品系支持体内黄病毒和肝炎病毒的感染和复制，从而促进病毒性疾病发病机理的研究，以及病毒性疾病的分子表征，在病毒感染期间有助于IgG抗体活性的机制。