Regulation of non-canonical NF-kb signaling

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DESCRIPTION (provided by applicant): This proposal aims to provide an environment for the scientific and medical training of a young physician- scientist. As part of the training the student will complete both MD and PhD degrees, with a specific scientific emphasis during his PhD on the development of autoimmune and proliferative immune cell disorders. Training as part of the PhD will be focused on investigating the basic biochemical and molecular regulation of the non-canonical NF-kB pathway. This signaling pathway appears to be hyperactive in autoimmune diseases such as lupus and rheumatoid arthritis as well as proliferative immune cell disorders such as multiple myeloma and lymphoma. Although dysregulation of this pathway seems to contribute to several important blood disorders, how the pathway is normally regulated is poorly understood. The student has identified a previously unappreciated interaction between components of this pathway which may play an important role in the pathway's regulation. This proposal aims to fully understand the biochemical basis and functional significance of this novel interaction. Enhanced knowledge of how non-canonical NF-kB signaling is regulated will allow for an improved understanding of the pathologies, such as lupus and multiple myeloma, in which this pathway plays a role. Indeed, defects in new aspects of non-canonical NF-kB regulation may ultimately be found to be the source of disease development in certain patients. Furthermore, nuanced understanding of how non-canonical signaling is regulated may allow for novel targets for pharmaceutical manipulation of the pathway in disease treatment. Although the experiments described here are highly biochemical they will provide an intellectual and technical foundation to be used in the student's later career in translational medicine. Indeed, as part of the final aim of the proposal, the student will be trained for the clinical aspect of his career as a physician scientist. This will be achieved through participation in the clinical years of the medical school curriculum. This proposal, then, aims to prepare a young student for a career as a physician scientist, and as part of the training addresses important scientific questions in the area of blood pathology.