Granulysin is a novel cytolytic molecule expressed by CTh and NK cells with activity against a variety of microbes and tumors. We first identified granulysin as part of a search for genes expressed by T lymphocytes """"""""late"""""""" (3-5 days) after T cell activation. Over the first three years of this grant we described the biosynthesis of granulysin, made granulysin specific monoclonal antibodies, and showed cytolytic and antimicrobial activity of granulysin. Perhaps most exciting is the considerable cytolytic activity against Mycobacterium tuberculosis. In this renewal application, we propose to further define the mechanism of action and in vivo function of granulysin. Specifically, we will use microarray technology to identify pathways of action, examine these pathways biochemically using a variety of techniques, express granulysin in transgenic mouse models, and evaluate therapeutic efficacy of recombinant human granulysin and synthetic granulysin derived peptides in vivo. These studies will examine granulysin activity against both microbial and tumor targets. The ultimate goal of these studies is to use granulysin, peptide components, and/or the information gained from the proposed mechanistic studies to develop new antibiotics and/or tumor chemotherapeutic agents.
