The goal of this career development award is for the applicant to gain knowledge and technical expertise in lymphocyte biology in order to advance our understanding of how the interaction between BCL10 and MALT1, two critically important lymphocyte signaling proteins, influences lymphocyte function and dysfunction. Knowledge gained during this career development award will provide new insights into the mechanism of interaction between BCL10 and MALT1 as well as the molecular pathogenesis of immune disorders associated with MALT1 dysregulation, including psoriasis and colitis. Experiments are designed with the ultimate goal of determining the therapeutic potential of targeting the BCL10-MALT1 protein-protein interaction in these inflammatory disorders. Specifically, the proposed studies will investigate how manipulation of the BCL10- MALT1 interaction affects MALT1 activity, proinflammatory lymphocyte signaling, and progression of psoriasis and colitis. The proposed experimental aims utilize sophisticated protein biochemistry techniques, in-depth in vitro analyses of lymphocyte function, robust in vivo models of inflammatory disease, and detailed bioinformatic analyses. The applicant has selected a mentor and co-mentor who have strong track records of both research mentorship and scientific achievement and who are therefore well positioned to provide expert guidance. Additionally, the applicant has constructed a career mentoring committee with expertise in developing small molecule protein-protein interaction inhibitors, in lymphocyte biology, and in the analysis of animal models of inflammatory disease. The applicant has also identified key collaborators with needed expertise in immune dysfunction in psoriasis and in biostatistics. The University of Pittsburgh provides a fantastic environment in which to launch an independent career as a productive biomedical scientist. The primary mentor and co-mentor are committed to guiding the applicant towards a highly successful career as a physician scientist via a formal program of scientific and professional milestone assessments. Key milestones emphasize the mastery of specific scientific techniques, the development of research mentoring skills, the transition to senior/corresponding authorship of scientific manuscripts and the preparation of the applicant to initiate her own independent laboratory program. The applicant’s career development plan was carefully crafted to take full advantage of the outstanding environment at University of Pittsburgh including graduate level course work in immunology and biochemistry, workshops and formal coursework in bioinformatics, didactics in murine models of disease, face- to-face career development workshops offered through the Office of Academic Career Development, and workshops in Responsible Conduct of Research. The applicant has identified opportunities to present her work locally as well as at national meetings. With full support of her mentor and co-mentor, t...