) The academic career of the applicant has focused on clinical research in large granular lymphocyte (LGL) leukemia. An immediate career goal is to further develop clinical investigations in LGL leukemia with the long term objective being to understand the pathogenesis of the disease. The scientific environment and institutional support at Moffitt, a NCI designated cancer center, serve as a catalyst for accomplishment of these goals. LGL leukemia is a clonal lymphoproliferative disorder associated with neutropenia and autoimmune disease. Altered expression of Fas receptor (Fas) and Fas ligand is associated with lymphoproliferative and autoimmune diseases in animal models. Preliminary data suggest that dysregulation of the Fas-Fas ligand apoptotic pathway underlies the pathogenesis of LGL leukemia. Leukemic LGL, like T cells from Fas ligand transgenic mice, constitutively express high levels of Fas, yet are resistant to Fas-dependant apoptosis. Sera from LGL leukemia patients contain high levels of Fas ligand and cause apoptosis of normal neutrophils in a Fas-dependant fashion. We propose to investigate LGL leukemia as a model of dysregulated apoptosis causing human malignancy and autoimmune disease. An important component of the application is the development of a mentoring plan for beginning clinical investigators. Trainees with an interest in clinical investigation of LGL leukemia will be selected from the Clinical/Translational research fellowship training program at Moffitt. This training program is a structured mentored program with two pathways for hematology/oncology fellows aiming for an academic career as a clinical investigator. The first pathway includes didactic work leading to a M.P.H. degree in biostatistical/epidemiology. The second pathway is designed for in-depth mentored laboratory training and includes didactic course work in molecular biology and immunology. The work proposed is important not only for further understanding the pathogenesis of malignancies and autoimmune diseases, but also for providing training for clinical investigators in hematologic malignancies.
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