Structure-function studies of human FcRn

描述（由申请人提供）：本提案的目的是在分子和细胞水平上更好地了解人型MHC I类相关受体FcRn。最近的数据表明，除了作为将母体免疫球蛋白G（IgG）从母体转运至幼仔的受体之外，FcRn还调节IgG的血清水平。IgG稳态最有可能通过微血管内皮细胞中的FcRn表达来维持。FcRn还在不同身体部位（例如肠、肾和肺）的上皮细胞中表达。FcRn在细胞内（再循环）和跨细胞（转胞吞）转运IgG，并且是从溶酶体降解中挽救IgG的保护性受体。尽管人FcRn（hFcRn）和小鼠FcRn（mFcRn）共享约65%的氨基酸同一性，但最近的研究表明IgG结合特异性存在显著差异。hFcRn和大鼠FcRn（与mFcRn高度同源）的细胞内转运研究表明，在该水平也可能存在变异。因此，小鼠研究可能并不总是hFcRn功能的可靠指标。目前的研究旨在更好地了解人类和小鼠FcRn之间的相似性和差异。反过来，这将导致对hFcRn的了解得到改善。我们的具体目标是：1）理解hFcRn的不同结合特异性的分子基础。2)评估IgG突变对小鼠和人体系统功能活性的影响。3)分析hFcRn在内皮细胞中的胞内运输。因此，我们的研究旨在解决关于hFcRn如何发挥功能以维持血清IgG水平的基本问题，特别关注hFcRn-IgG相互作用和hFcRn在内皮细胞中的运输。这影响了治疗性和预防性IgG的成功应用，并且还与调节体液免疫的因子具有更广泛的相关性。

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.