Studies of Paired Immunoglobulin-Like Receptors

配对免疫球蛋白样受体的研究

• 批准号: 7074633
• 负责人: Hiromi Kubagawa
• 金额: $ 24.78万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7074633
• 关键词: SDS polyacrylamide gel electrophoresis; antibody receptor; binding proteins; biological signal transduction; gene deletion mutation; gene expression; genetic models; genetically modified animals; glycosylation; immunogenetics; laboratory mouse; ligands; polymerase chain reaction; protein isoforms; protein structure function; receptor expression

DESCRIPTION (provided by applicant): The overall goal of these ongoing studies is to define the structure/function relationships of a family of paired immunoglobulin-like receptors of activating (PIR-A) and inhibitory (PIR-B) isoforms in mice. PIR-A of approximately 85 kD and PIR-B of approximately 125 kD are cell surface glycoproteins having similar extracellular regions but with distinctive transmembrane and cytoplasmic regions. PIR-B is encoded by a single gene and contains three tyrosine-based inhibitory motifs in its cytoplasmic tail. In contrast, PIR-A receptors are encoded by multiple Pira genes and associate non-covalently with an adaptor protein, the Fc receptor common gamma chain (FcRgammac), to form a cell activation complex. In addition, the recently identified, heavily glycosylated PIR-A4 receptor of approximately 110 kD is expressed on the surface of FcRgammac-deficient cells. PIR-A and PIR-B are expressed by many hematopoietic cell types, including B cells, monocyte/macrophages, dendritic ceils, granulocytes, mast cells, and megakaryocyte/platelets, but not by T and NK cells. The cell surface levels of PIR increase as a function of cellular differentiation and activation. Based on our preliminary data, we propose the overall hypothesis that P/R-A and PIR-B play regulatory roles in inflammatory, coagulative, antigen-presenting, allergic, and humoral immune responses during host defense. This hypothesis will be tested in the following Specific Aims: 1) To identify the PIR ligands; 2) To determine the functional consequences of PIR-B deficiency in a gene-targeted mouse model; 3) To determine the molecular heterogeneity of PIR-A isoforms with respect to their glycosylation and association with adaptor proteins. The data generated in these mouse models show promise in establishing the foundation for the analysis of this type of regulatory mechanism in humans, and could suggest novel strategies for vaccine development, therapies for acute and chronic inflammatory responses, and treatments of allergic responses.

描述（由申请人提供）：这些正在进行的研究的总体目标是定义小鼠中激活（PIR-A）和抑制性的成对免疫球蛋白样受体的结构/功能关系。大约85 kD和PIR-B的PIR-A约为125 kD，是具有相似细胞外区域但具有独特跨膜和细胞质区域的细胞表面糖蛋白。 PIR-B由单个基因编码，并在其细胞质尾部包含三个基于酪氨酸的抑制基序。相比之下，PIR-A受体由多个PIRA基因编码，并与衔接蛋白FC受体普通伽马链（FCRGAMMAC）无共核心，以形成细胞活化复合物。此外，在FCRGAMMAC缺陷型细胞的表面上表达了最近鉴定出的大约110 kD的大量糖基化的PIR-A4受体。 PIR-A和PIR-B通过许多造血细胞类型表达，包括B细胞，单核细胞/巨噬细胞，树突状天花板，粒细胞，肥大细胞和巨核细胞/巨核细胞/血小板，但不受T和NK细胞的含量。 PIR的细胞表面水平随细胞分化和激活的作用而增加。基于我们的初步数据，我们提出了一个总体假设，即P/R-A和PIR-B在宿主防御过程中的炎症，凝结，抗原呈递，过敏和体液免疫反应中扮演调节作用。该假设将在以下特定目的中进行检验：1）确定PIR配体； 2）确定靶向基因的小鼠模型中PIR-B缺乏症的功能后果； 3）确定PIR-A同工型相对于它们的糖基化和与衔接蛋白的缔合的分子异质性。这些小鼠模型中产生的数据表明，有望建立对人类这种调节机制分析的基础，并且可以提出疫苗开发的新型策略，急性和慢性炎症反应的疗法以及过敏反应的治疗方法。