Biological definition of Fc receptor homologs

描述（由申请人提供）：本提案描述了一个为期五年的培训计划，在血液学的学术生涯的发展。该候选人是血液学/肿瘤学博士后研究员，拥有内科学委员会认证。建议在前两到三年在Max库珀博士的监督下进行免疫学研究培训，以扩展候选人在淋巴细胞和受体生物学方面的科学知识，以实现研究独立性。该研究项目的重点是表征由B淋巴细胞表达的Ig样受体的多基因家族中的一个成员，该成员是由候选人根据其与经典免疫球蛋白Fc受体的同源性共同发现的。由这些基因中的大多数编码的推定受体，暂时命名为Fc受体同源物（FcRH 1 -5），具有Ig样结构域序列，其表明Fc结合能力和具有基于酪氨酸的序列的胞质结构域，所述基于酪氨酸的序列具有共有激活或抑制基序。FcRH 1 -5在外周淋巴组织和不同类型的B系恶性肿瘤中的B细胞分化期间差异表达。FcRH 3是该提议的焦点，其家族成员被预测编码具有六个Ig样结构域、不带电荷的跨膜区段和含有基于激活和抑制性酪氨酸的共有基序的胞质结构域的I型糖蛋白。FcR和FcRH家族成员的Ig结构域比较分析表明，FcRH 3可能具有Fc结合能力，初步研究支持这种可能性。为了用于确定哪些细胞表达FcRH 3及其生物化学性质，将产生针对重组FcRH 3蛋白的单克隆抗体。为了确认FcRH 3的Fc受体能力，将使用不同同种型的纯化人骨髓瘤Ig及其Fc片段进行Ig结合试验。天然FcRH 3表达细胞将用于在免疫沉淀分析中搜索相关分子。抗FcRH 3抗体和天然配体将用于受体连接研究，以检查基于胞质酪氨酸的共有基序的信号传导能力。这里提出的研究集中在一个家庭成员的表达和功能，并作为一个原型模型，为未来表征的其他7个Fc受体同系物家庭成员和他们的角色在正常和病理条件。

DESCRIPTION (provided by applicant): This proposal describes a five-year training program for development of an academic career in Hematology. The candidate, a postdoctoral fellow in Hematology/Oncology, is board certified in Internal Medicine. Research training in Immunology under the supervision of Dr. Max Cooper is proposed for the first two to three years to expand the candidate's scientific knowledge in lymphocyte and receptor biology in order to achieve research independence. The research project focuses on characterization of one of the members of a multi-gene family of Ig-like receptors expressed by B lymphocytes that were co-discovered by the candidate on the basis of their homology with classical immunoglobulin Fc receptors. The putative receptors encoded by most of these genes, provisionally named Fc receptor homologs (FcRH1-5), have Ig-like domain sequences that suggest Fc binding capacity and cytoplasmic domains with tyrosine-based sequences possessing consensus activating or inhibitory motifs. FcRH1-5 are differentially expressed during B cell differentiation in peripheral lymphoid tissues and in different types of B lineage malignancies. FcRH3, the family member that is the focus of this proposal, is predicted to encode a type-I glycoprotein with six Ig-like domains, an uncharged transmembrane segment, and a cytoplasmic domain containing both activation and inhibitory tyrosine-based consensus motifs. Comparative Ig-domain analysis of FcR and FcRH family members suggests that FcRH3 may have Fc binding capacity, and pilot studies support this possibility. For use in determining which cells express FcRH3 and its biochemical nature, monoclonal antibodies will be produced against recombinant FcRH3 protein. In order to confirm the Fc receptor capacity of FcRH3, Ig-binding assays will be performed utilizing purified human myeloma Igs of different isotypes and their Fc fragments. Native FcRH3 expressing cells will be used to search for associated molecules in immunoprecipitation analyses. The anti-FcRH3 antibodies and the native ligands will be used in receptor ligation studies to examine the signaling capacity of the cytoplasmic tyrosine-based consensus motifs. The studies proposed here focus on expression and function of one family member, and serve as a prototypic model for future characterization of the other seven Fc receptor homolog family members and their roles in normal and pathologic conditions.