In response to antigenic challenge, B lymphocytes reprogram the expression of genes that mediate clonal expansion, antibody production, and humoral immunity. The specificity, magnitude, duration, and tissue distribution profoundly influences whether a B cell response leads to efficient antigen clearance or chronic inflammation. For example, the production of self-reactive antibodies in autoimmune patients results in systemic inflammation that can irreversibly compromise vascular and renal function. Despite extensive research on the cellular aspects of humoral immunity, little is known regarding the precise genetic mechanisms that regulate B cell activation in response to antigens, cytokines, or co-receptor stimulation. The long-term goal of this research proposal is to identify and characterize novel genes that mediate B cell function during an inflammatory response. To capture these inflammatory response genes (IRGs), we will employ an embryonic stem cell library harboring mutagenic retroviral insertions together with DNA microarray analyses, which will allow us to rapidly assess expression patterns for each of the trapped genes. Mutant loci that display restricted expression in resting versus activated B cells will be selected for transmission into the murine germline. A comprehensive phenotypic analysis will be performed on these novel mouse strains to investigate the role of mutated IRGs in B cell differentiation, activation, and function in mouse models of inflammation. We expect to identify two distinct classes of IRG-defective mutants, exhibiting either heightened or attenuated responses to inflammatory stimuli. In conjunction with DNA microarray and bioinformatics, these animal models will be exploited to determine changes in gene expression profiles resulting from specific mutations . Together, our findings will not only yield novel insights into the genetic mechanisms that control B cell responses but also a panel of important in vivo reagents for in-depth molecular studies of inflammatory disease processes.
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