REGULATION OF TAP-1 AND MHC-I IN RESPIRATORY PAPILLOMAS

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This application from a young trained otolaryngologist is intended as an initial step in preparation for a career as a academic clinician/scientist. The grant will provide formal training in study design and conduct of an extensive research project and academic course work relevant to the project. Long term goals for the applicant are to be a productive research scientist, competitive for grant funding, in a clinical environment. The training environment is a large teaching hospital that is a clinical campus for a medical school. The hospital offers graduate medical education programs in primary care and medical and surgical specialities. It has a large number of full-time faculty with research grants from both federal and non-federal sources. The applicant's mentors are in the Departments of Otolaryngology and Pediatric Allergy/Immunology, and are full professors at the medical school. The long term goal of the research project is to understand the mechanisms of immune recognition in recurrent respiratory papillomatosis, so that better management of this disease can be achieved. The specific aims will test the hypothesis that human papillomavirus expression results in reduced levels or function of TAP-1 (transporter of antigen-1) and subsequently Class I MHC assembly and expression on the cell surface. The aims are: 1) Determine whether TAP-1 and MHC mRNA and/or proteins are reduced in laryngeal papilloma tissues and cultured cells, compared to normal tissue and cells. 2) Determine whether the TAP-1/MHC-I/calcium binding protein complex functions normally in papilloma cells and whether calcium modulates the complex and TAP-1 and MHC-1 expression differently in normal and papilloma cells. 3) Determine which viral early proteins alter TAP-1 and MHC-1 expression. 4) Determine whether MHC-I levels are increased if TAP-1 levels are increased or its function is bypassed.