STRUCTURE AND FUNCTION OF HUMAN SECRETORY COMPONENT

人体分泌成分的结构和功能

• 批准号: 3131511
• 负责人: Randall M Goldblum
• 金额: $ 17.21万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1991-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3131511
• 关键词: affinity chromatography; antibody receptor; autoradiography; chemical binding; chemical structure function; child (0-11); conformation; enzyme linked immunosorbent assay; epithelium; gel electrophoresis; gene expression; genetic library; glycoproteins; high performance liquid chromatography; human milk; human subject; immunoglobulin A; laboratory mouse; laboratory rabbit; monoclonal antibody; nucleic acid probes; phosphorylation; protease inhibitor; protein sequence; proteolysis; radiotracer; receptor mediated endocytosis; secretory immune system; steroid hormone; transposon /insertion element

The goal of this study is to evaluate the contribution of the epithelial cell to the formation of secretory immunoglobulins (Ig's), which protect the mucosal surfaces of the body. Our work is focused on the human polymeric Ig receptor (PIgR) pathway, which transports polymeric Ig's across epithelial cells and enchances their secretory function. Recent studies have defined the protein sequence and Ig-like domain structure of PIgR and its cleavage product, secretory component (SC), the primary molecules which mediate the conversion of polymeric Ig into secretory Ig. Using a unique panel of monoclonal antibodies which bind to human SC, secretory IgA and tryptic fragments of these molecules, we have developed a hypothetical model for the three dimensional structure of PIgR/SC and its molecular interactions with the polymeric Ig's. The model provides a useful conceptual structure for designing experiments with these antibodies and PIgR cDNA probes to examine the relationship between the structure and function of the various molecular forms of PIgR/SC. We will test the following research hypotheses: 1) The multiple functions of human PIgR and SC are mediated by the structure of specific Ig-like domains of these glycoproteins; and 2) Modulation occurs at several sites in the human PIg/SC pathway. We will biochemically characterize the structures of human PIgR and SC that are responsible for Ig binding, transcrytosis, and proteolytic protection. Our second hypothesis will explore potential sites for regulation or modulation of secretory immunoglobulin production in epithelial cells. The physiological significance in humans of these mechanisms will be explored. Human biological fluids, tissue extracts and thin sections, cultured cells and products of cloned DNA will provide complementatry model systems for examination of the human PIgR/SC pathway from several perspectives. By characterizing the structural and physiological requirements for SIg formation in humans, and identifying mechanisms which may modulate this system, these studies should help to elucidate the molecular and cellular basis for epithelial cell contributions to mucosal immunity. This information may be useful in identifying pathologic abnormalities in the system and designing therapeutic interventions for mucosal infections and/or diagnostic methods for early epithelial malignancies.

这项研究的目的是评估的贡献， 上皮细胞分泌免疫球蛋白的形成 (Ig的），其保护身体的粘膜表面。 我们的工作 集中于人聚合物IG受体（PIgR）途径， 它将多聚IG's转运穿过上皮细胞， 增强其分泌功能。 最近的研究表明， PIgR蛋白质序列和Ig样结构域结构及其 裂解产物，分泌成分，初级 介导聚合物IG转化为 分泌型IG。 使用一组独特的单克隆抗体， 人SC、分泌型伊加和这些的胰蛋白酶片段 分子，我们已经开发了一个假设的模型，为三个 PIgR/SC的空间结构及其分子间相互作用 与聚合物IG的。 该模型提供了一个有用的概念 用于设计这些抗体的实验的结构， PIgR cDNA探针，以检查 PIgR/SC的各种分子形式的结构和功能。 我们将测试以下研究假设：1）多重 人PIgR和SC的功能由以下结构介导： 这些糖蛋白的特异性Ig样结构域;和2）调节 发生在人Pig/SC途径的几个位点。 我们将 生物化学表征人PIgR和SC的结构 负责IG结合、转胞吞和蛋白水解 保护 我们的第二个假设将探索潜在的网站， 分泌性免疫球蛋白产生的调节或调节 在上皮细胞中。 这些机制在人类中的生理意义将 被探索。 人体生物体液、组织提取物和稀释液 切片、培养细胞和克隆DNA产物将提供 用于人体检查的互补模型系统 PIgR/SC通路从几个角度。 通过表征 免疫球蛋白形成的结构和生理要求， 人类，并确定可能调节这一机制 系统，这些研究应有助于阐明分子和 上皮细胞对粘膜上皮细胞增殖的细胞基础 免疫力 这些信息可能有助于识别 系统中的病理异常和设计治疗 粘膜感染的干预和/或诊断方法 用于早期上皮恶性肿瘤