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.
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