FDCR1 AND FOLLICULAR DENDRITIC CELL SIGNALING PATHWAYS

描述：（改编自申请人的摘要） 项目是“确定有助于形成的因素， 生长激素中心（GC）。“GC在淋巴滤泡中发育 在T细胞依赖性体液反应中， 记忆B细胞。克拉克博士和他的同事将研究分子 调节关键抗原呈递细胞（APC）的机制 生发中心：滤泡树突细胞（FDC）。他们隔离了 编码肿瘤坏死因子（TNF）新成员的cDNA FDC 1是肿瘤坏死因子受体（TNFR）家族的成员，他们称之为FDC受体1或FDCR 1。他们提出 确定FDCR 1在GC形成调节中的作用， 体液应答以及鉴定和表征FDC相关基因 调节GC B细胞。具体目的是：1）测试 FDCR 1在体内调节发育中起作用的假说 以及生发中心和抗原特异性B细胞的寿命。他们有 分离小鼠Fdcr 1基因，破坏ES细胞中的一个拷贝， 制备FDCR 1-/-小鼠。他们将检查FDCR 1-/-小鼠是否 与FDCR 1 +/+小鼠相比， 包括GC形成缺陷、IgG抗体应答和 长寿命的B细胞; 2）为了检验FDCR 1作为 改变TNFR/TNF家族成员表达的可溶性细胞因子， 细胞命运FDCR 1作为一种免疫调节剂从FDC-1细胞和其他细胞中释放出来。 可溶性蛋白因此，他们将测试可溶性FDCR 1是否可以调节 人GC相关B细胞、树突细胞（DC）和T细胞; 3） 检验FDCR 1的C末端区域对于以下方面至关重要的假设： 其受体功能和FDCR 1调节的mRNA表达; 4） 阐明新的滤泡树突状细胞（FDC）相关分子 调节B细胞。他们将测试FDC是否表达新型FDC- 特定受体通过强大的PCR选择方法， 已经确定了三个新的FDC相关基因;他们将分离出一个 或多个编码FDC限制性基因的cDNA，并基于严格的 标准，选择一个新基因进行进一步分析。这些研究将 有助于我们理解免疫学的分子基础， 记忆、抗体介导的自身免疫性疾病和GC相关 艾滋病和淋巴瘤等疾病。

DESCRIPTION: (Adapted from the applicant's abstract) The goal of this project is to "define factors contributing to the formation and regulation of germinal centers (GC)." GCs develop in lymphoid follicles during T cell-dependent humoral responses and are the birthplace of memory B cells. Dr. Clark and his colleagues will investigate molecular mechanisms regulating a key antigen presenting cell (APC) in the germinal center: the follicular dendritic cell (FDC). They have isolated a cDNA encoding a novel member of the tumor necrosis factor (TNF) receptor (TNFR) family, they call FDC receptor 1 or FDCR1. They propose to define the role of FDCR1 in the regulation of GC formation and humoral responses and to identify and characterize FDC-associated genes which regulate GC B cells. The Specific Aims are: 1) To test the hypothesis that FDCR1 plays a role in vivo in regulating the development and lifespan of germinal centers and antigen-specific B cells. They have isolated the mouse Fdcr1 gene, disrupted one copy in ES cells and begun preparing FDCR1-/- mice. They will examine whether FDCR1-/- mice compared to FDCR1+/+ mice have deficient T cell-dependent humoral responses including deficient GC formation, IgG antibody respones and long-lived B cells; 2) To test the hypothesis that FDCR1 functions as a soluble cytokine to alter expression of TNFR/TNF family members and cell fate. FDCR1 is released from FDC-1 cells and other cells as a soluble protein. Thus, they will test whether soluble FDCR1 can regulate human GC-associated B cells, dendritic cells (DCs) and T cells; 3) To test the hypothesis that the C-terminal region of FDCR1 is critical for its receptor functions and FDCR1-regulated mRNA expression; 4) To elucidate novel follicular dendritic cell (FDC)-associated molecules which regulate B cells. They will test if FDCs express novel FDC- specific receptors. Via the powerful PCR Select method, they have already identified three new FDC-associated genes; they will isolate one or more cDNAs encoding FDC-restricted genes, and based on stringent criteria, select one novel gene for further analysis. These studies will contribute to our understanding of the molecular basis of immunological memory, antibody-mediated autoimmune diseases, and GC-associated diseases such as AIDS and lymphomas.