Structure-function studies of human FcRn

人FcRn的结构-功能研究

• 批准号: 6817984
• 负责人: ELIZABETH SALLY WARD
• 金额: $ 39万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6817984
• 关键词: antibody receptor; binding sites; clone cells; gene mutation; human tissue; immunoglobulin G; intracellular transport; laboratory mouse; placental transfer; pregnancy immunology; protein protein interaction; protein structure function; protein transport; receptor binding; receptor expression; surface plasmon resonance; transcytosis

DESCRIPTION (provided by applicant): The goal of this proposal is to gain an improved understanding at the molecular and cellular level of the human form of the MHC Class I-related receptor, FcRn. Recent data suggest that in addition to being the receptor that transports maternal immunoglobulin G (IgG) from mother to young, FcRn regulates the serum levels of IgG. IgG homeostasis is most likely maintained by FcRn expression in endothelial cells of the microvasculature. FcRn is also expressed in epithelial cells at diverse body sites (e.g. intestine, kidney and lung). FcRn transports IgG within (recycling) and across (transcytosis) cells, and is a protective receptor which salvages IgG from lysosomal degradation. Although human FcRn (hFcRn) and mouse FcRn (mFcRn) share about 65% amino acid identity, recent studies indicate that there are significant differences in IgG binding specificity. Intracellular trafficking studies of hFcRn and rat FcRn (highly homologous to mFcRn) suggest that there may also be variations at this level. As a result, studies in mice may not always be reliable indicators of hFcRn function. The current study is directed towards better understanding the similarities and differences between human and mouse FcRn. In turn, this should lead to improved knowledge of hFcRn. Our specific aims are: 1)To understand the molecular basis of the distinct binding specificity of hFcRn. 2) To assess the effects of IgG mutations on functional activity in mouse and human systems. 3) To analyze the intracellular trafficking of hFcRn in endothelial cells. Our studies are therefore directed towards addressing the fundamental question as to how hFcRn functions to maintain serum IgG levels, with a particular focus on hFcRn-lgG interactions and hFcRn trafficking in endothelial cells. This impacts the successful application of therapeutic and prophylactic IgGs, and also has broader relevance to the factors that regulate humoral immunity.

描述（由申请人提供）：该提案的目的是在MHC I类相关受体FCRN的人类形式的分子和细胞水平上获得改进的理解。最近的数据表明，除了是将母体免疫球蛋白G（IgG）从母亲转移到年轻的受体外，FCRN还调节了IgG的血清水平。 IgG体内平衡很可能是通过微脉管系统内皮细胞中的FCRN表达来维持的。 FCRN在多种体位（例如肠，肾脏和肺）的上皮细胞中也表达。 FCRN在（回收）和（跨胞菌症）细胞内运输IgG，是一种保护性受体，可从溶酶体降解中挽救IgG。尽管人FCRN（HFCRN）和小鼠FCRN（MFCRN）具有约65％的氨基酸身份，但最近的研究表明，IgG结合特异性存在显着差异。 HFCRN和大鼠FCRN（与MFCRN高度同源）的细胞内运输研究表明，在此水平上也可能存在差异。结果，对小鼠的研究可能并不总是是HFCRN功能的可靠指标。当前的研究旨在更好地理解人和小鼠FCRN之间的相似性和差异。反过来，这应该导致对HFCRN的知识的提高。我们的具体目的是：1）了解HFCRN独特结合特异性的分子基础。 2）评估IgG突变对小鼠和人类系统功能活性的影响。 3）分析内皮细胞中HFCRN的细胞内运输。因此，我们的研究旨在解决HFCRN如何保持血清IgG水平的功能，特别关注内皮细胞中HFCRN-LGG相互作用和HFCRN运输。这影响了治疗和预防性IgG的成功应用，并且与调节体液免疫的因素具有更广泛的相关性。