: Granulysin is a cytolytic molecule expressed by CTL 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 four years of this grant, we described the biosynthesis of granulysin, generated granulysin specific monoclonal antibodies, and characterized the cytolytic and antimicrobial activities of granulysin. In this renewal application, we propose to further define the mechanism of action and in vivo function of granulysin. Specifically, we will further elucidate the molecular pathways involved in granulysin mediated apoptosis; express human granulysin in murine T cells using both transgenic and retroviral technologies, and evaluate the therapeutic efficacy of synthetic peptides corresponding to sub regions of granulysin in vivo. The effects of granulysin or granulysin peptides will be assessed 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 mechanistic studies to develop new antibiotics and/or tumor chemotherapeutic agents.
