INTESTINAL AND PLACENTAL FC-RECEPTORS FOR IMMUNOGLOBULIN

肠和胎盘免疫球蛋白 FC 受体

• 批准号: 6636856
• 负责人: NEIL E SIMISTER
• 金额: $ 27.31万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-02-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6636856
• 关键词: antibody receptor; biological signal transduction; biotransformation; confocal scanning microscopy; gastrointestinal epithelium; gene mutation; genetic transcription; human tissue; immunoelectron microscopy; immunoglobulin G; laboratory rabbit; laboratory rat; myotonic dystrophy; placenta; placental transfer; protein localization; protein sequence; protein transport; receptor binding; site directed mutagenesis; tissue /cell culture

DESCRIPTION (adapted from investigator's abstract): The neonatal Fc receptor, FcRn, transports IgG antibodies from mother to offspring. The acquisition of maternal antibodies is essential for immunologic defense, although autoantibodies and immune complexes of live pathogens are potentially harmful to the neonate. FcRn also protects circulating IgG from catabolism, controlling the level of serum IgG, and prolonging the time for which antibodies of a particular specificity are present at useful concentrations. FcRn serves both of these functions by transporting IgG across cells by a pathway that avoids lysosomal degradation. The long-term objective of this proposal is to describe in molecular terms how FcRn transports IgG across cells. The immediate goal is to identify and characterize amino acid sequences in the cytoplasmic domain of FcRn that direct uptake and targeting of the receptor. This will be done by making specific alterations in the receptor by site-directed mutagenesis, and analyzing the effects of the mutations in a cell culture model of IgG transport. The subcellular route of transport by FcRn will be determined by confocal and immunoelectron microscopy, and mutations that divert FcRn from this pathway will be identified. An FcRn-binding peptide will be used to study the effect of IgG on FcRn transport. Such a peptide will also be used to explore the possibility of blocking the interaction of IgG and FcRn. Related aims are to investigate the regulation of transcription of FcRn, and to determine whether decreased transcription causes the elevated IgG catabolism detected in some myotonic dystrophy patients. The clinical importance of maternal IgG for the defense of the neonate is well established. Another clinical area to which FcRn is relevant is that of monoclonal antibody therapeutics, where slow catabolism of IgG is generally desirable. Knowledge of the mechanism of FcRn function will contribute to a rational basis for clinical intervention in complications of maternofetal antibody transmission, and for manipulation of the half-lives of therapeutic antibodies.

描述（根据研究者的摘要改编）：新生儿FC受体， FCRN，将IgG抗体从母亲传输到后代。收购 孕产妇抗体对于免疫防御至关重要，尽管 活病原体的自身抗体和免疫复合物可能有害 到新生儿。 FCRN还保护循环IgG免受分解代谢，控制 血清IgG的水平，并延长了抗体的时间 特定的特异性以有用的浓度存在。 FCRN都服务 通过通过避免 溶酶体降解。 该提议的长期目标是用分子术语来描述 FCRN跨细胞运输IgG。直接目标是识别和 表征直接的FCRN细胞质结构域中的氨基酸序列 摄取和靶向受体。这将通过特定 通过位置定向诱变改变受体的改变，并分析 IgG转运细胞培养模型中突变的影响。这 FCRN的亚细胞运输途径将由共焦和 免疫电子显微镜和将FCRN从该途径转移的突变 将被确定。 FCRN结合肽将用于研究 IgG在FCRN运输上。这样的肽也将用于探索 阻止IgG和FCRN相互作用的可能性。相关目标是 调查FCRN转录的调节，并确定是否 转录减少会导致某些人检测到的升高的IgG分解代谢 肌营养不良患者。 母体IgG在防御新生儿的临床重要性很好 已确立的。 FCRN相关的另一个临床领域是 单克隆抗体疗法，IgG的缓慢分解代谢通常为 理想。了解FCRN功能机制的知识将有助于 临床干预的理性基础，含有植物并发症的并发症 抗体传播，以及用于治疗的半衰期 抗体。