This proposal describes a five year interdisciplinary career development program for a physician scientist in academic dermatology. The long-term objectives of the proposed program are to continue to develop and expand the principal investigator's research and clinical expertise, with special focus on the causes and treatment of autoimmune blistering diseases of the skin. The scientific program centers on mechanisms of pathogenesis in pemphigus, a potentially fatal blistering disorder in which autoantibodies against desmoglein (Dsg) 3 and 1, desmosomal adhesion molecules, cause loss of keratinocyte cell adhesion. The research plan proposes to clone and characterize human pemphigus vulgaris (PV) monoclonal antibodies (mAbs) in order to define the pathogenic antibody cohort in PV. Specifically, the proposed experiments aim to determine whether anti-Dsg mAbs from different PV patients demonstrate shared antibody gene usage and/or idiotypes, and to use these mAb reagents to determine mechanisms of acantholysis induced by PV mAbs. The principal investigator has 15 years experience in biomedical research and is currently enrolled in a dermatology residency and research training program at the University of Pennsylvania. John R. Stanley, M.D., chairman of the Department of Dermatology, and Don L. Siegel, Ph.D., M.D., vice-chairman of the Department of Pathology and Laboratory Medicine, will serve as co-mentors for the principal investigator's scientific and clinical development. Dr. Stanley has over 30 years experience in the clinical care of pemphigus patients, has identified and characterized antigens involved in multiple autoimmune blistering disorders, and has trained numerous postdoctoral fellows, many of whom have become leaders in academic dermatology both nationally and internationally. Dr. Siegel is an internationally renowned expert in phage display and directs the clinical apheresis unit, where he supervises the treatment of many patients with severe or refractory PV. The proposed interdisciplinary program offers a unique combination of research and clinical training from two established and highly regarded physician scientists. The studies outlined within this proposal represent the first detailed genetic and functional analysis of human PV monoclonal autoantibodies and may establish a general paradigm for the study of humorally mediated autoimmune disease. Specific to PV, the project will define how different human mAbs contribute to the pathology of disease, develop valuable human mAb reagents for the study of pemphigus as well as desmosomal cell adhesion, and potentially lead to novel targeted therapies for this life-threatening disorder.
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