PHOSPHOLIPASE B: A VIRULENCE FACTOR FOR CANDIDA GLABRATA

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DESCRIPTION (adapted from application abstract): In this K08 application, Cornelius Clancy requests 3 years of support to learn the skills necessary to achieve his career goal of becoming a successful clinician-scientist. The applicant's long-term research interest is in identifying and studying virulence factors for the yeast pathogen Candida glabrata, now a leading bloodstream fungal infection in the United States. C. glabrata is a model organism for studying molecular genetics because it has a haploid genome and is closely related to Saccharomyces cerevisiae. The applicant s laboratory has correlated levels of extracellular phospholipase B (PLB) activity with the severity of C. glabrata invasive infections in humans. He hypothesizes that the gene cgPLB2 is responsible for much of C. glabrata s PLB activity, and that disruption of cgPLB2 will significantly reduce the virulence of the organism. The applicant s short-term goal is to conclusively prove that cgPLB2 is important in virulence by fulfilling the molecular form of Koch's postulates. Specifically, he will finish cloning cgPLB2, demonstrate that the reduction of PLB activity caused by disruption of cgPLB2 attenuates virulence in a murine model of disseminated infection, and demonstrate that restoration of PLB activity by reinsertion of cgPLB2 restores virulence. In completing this project, he will learn a wide range of techniques in molecular biology, biochemistry, and animal models of disseminated infections. In addition he will learn to formulate hypotheses, design appropriate experiments, apply statistical tools, and interpret data. These skills will be complemented by an educational plan including courses and advanced seminars in basic sciences and statistics. He will receive this training in a multidisciplinary environment supported by the resources of the Dept of Medicine and the Dept of Molecular Genetics and Microbiology at the University of Florida, guided closely by his mentor, Alfred Lewin (a yeast geneticist) and his co-mentor, Frederick Southwick (Chief of Infectious Diseases and an expert in microbial pathogenesis and cell biology).