This proposal outlines a career development program with the goal of developing a successful academic career in Pathology. The principal investigator (PI) is an Assistant Professor with a tenuretrack appointment in Pathology at the University of Rochester School of Medicine (UR). He is a diplomat of the American Board of Pathology and possesses significant clinical and teaching experience. This Mentored Clinical Scientist Award (KO8) proposal will facilitate the acquisition of basic research expertise in the area of liver immuno- pathology through a 5 year educational and research program focusing on the mechanism of antigen-independent CD8 T cell -induced liver damage. The liver appears to play a unique role in the elimination of CD8 T lymphocytes undergoing activation-induced apoptosis. Our current understanding of this mechanism of T cell clearance is based largely on the work of Dr. Crispe, the PI's Mentor, using mouse models expressing transgenic T cell receptors (TCR). Binding of target peptide to these transgenic T cells causes a clonal expansion, resulting in their selective uptake by the liver and subsequent death. As a consequence of this ongoing lymphocyte apoptosis in the liver, serum transaminase levels increase, indicating hepatocyte injury in the absence of hepatocyte expression of target antigen. Recent work in the PI's laboratory has demonstrated hepatitis, consisting of cellular infiltrates containing both CD8 T celland Kupffer cells both in the transgenic TCR model as well as in influenza infection. These data suggest that this phenomenon may represent a general response to expanded CD8 T cell populations and a common pathway of liver injury, which may have significant clinical implications. This study will investigate the mechanism of this novel antigen-independent CD8 T cell-induced hepatitis. Dr. Crispe is one of the leaders in the emerging area of liver-specific immunobiology and has an excellent track record as a mentor. In addition, a career development advisory committee consisting of 3 additional senior scientists will provide advice and guidance to the PI. Overall, the UR provides an outstanding setting by providing both excellent facilities and by fostering an atmosphere of support and collaboration. This structured and mentored program will facilitate the PI's evolution to independence as an investigator, culminating in a future RO1 application in the area of liver immunopathology.
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