Novel Gene Control of Lymphoid Tissue Development

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DESCRIPTION (provided by applicant): The candidate: I am a veterinarian with a clinical background, completing a Ph.D. in biochemistry and molecular biology and a 4-year postdoctoral fellowship at The Jackson Laboratory. My primary interests are in genetics and immunology, with a long-term goal of becoming an independent research scientist. The unique opportunity offered by the K08 program to perform independent research of my own design with the guidance of experienced mentors at one of the world's premier biomedical institutions creates an ideal transition period in which to perform the valuable research described in this application and to gain the experience essential to scientific autonomy. The objective of this proposal is to identify the cellular and molecular basis of the chronic proliferative dermatitis (cpdm) mutation and to determine the role of the wildt ype allele in normal lymphoid development and function. Affected mice possess normal numbers of peripheral lymph nodes, but have multiple immunologic abnormalities including absent Peyer's patches, disorganized lymphoid architecture, diminished B cell maturation and class switching, and multi-organ inflamation. Peyer's patches are a key component of the gut-associated lymphoid tissue, which contributes to production of secretory IgA by B cells and provides the chief defense against oral pathogen invasion. IgA deficiency is a common form of immune deficiency in humans, and has also been implicated in autoimmunity. One of the goals of this research is to fill existing gaps in our current understanding of the developmental biology of Peyer's patches. Hypothesis: The gene containing the cpdm mutation is a stromal target downstream of the NF-KB transcription factor RelB/P52, and is critical for development of Peyer's patches and organization of lymphoid tissues. This gene also contributes to normal maturation and function of B cells. Specific aims: (1) Identify the gene containing the cpdm mutation, using quantitative RTPCR and direct sequencing of 21 remaining candidate genes in a 372-Kb interval, none of which has been previously implicated in lymphoid development, maintenance or function. (2) Evaluate mechanisms by which the cpdm locus contributes to Peyer's patch development, normal lymphoid organization and B cell immune responses. Significance: These studies will provide new insight into the unique developmental requirements for Peyer's patches and better understanding of the relationship between lymphoid organization and function.