This program project for a medical mycology unit is focused on an interdisciplinary research approach to increase our understanding of the pathobiology of medically important fungi through the model pathogen, Cryptococcus neoformans. In this proposal we will use interrelated molecular biological approaches to identify and validate targets for the development of diagnostics, vaccines and therapeutics. To achieve these goals, the proposal has been divided into four distinct but interconnected projects which focus on Cryptococcus neoformans as a model system for pathogenic fungi. Project 1 is the genotype and phenotypic evolution of C. neoformans. In these population studies, the general importance and validity of drug targets can be determined; identification of yeast strain drift can be assessed which may affect vaccine development and help molecular diagnostics to interface with prognostic factors. Project 2 will study signal transduction pathways regulating virulence in C. neoformans. In this proposal, both conserved and unique features will be dissected to allow these central pathways for gene expression to be exploited for antifungal drug targets. Project 3 concerns genetic identification of antifungal drug targets in C. neoformans. With the use of saccharomyces cerevisiae as a surrogate, exploration into essential genes for temperature growth and requirements for amino acids and vitamins in C. neoformans will be performed. Project 4 is the genetic controls for host temperature growth in C. neoformans. In many respects the most simple but important virulence phenotype of C. neoformans (growth at 37 degrees Celsius) will be explored. In this project, a direct analysis of genes necessary of genes necessary or essential for growth at 37 degrees Celsius will be identified. A virulent mutants created from experiments in Projects 2-4 can be used either for live vaccines or tools for screening combinatorial libraries made on-campus for leads to antifungal compounds. This program emphasizes a focus on a single pathogen with a basic but broad-spectrum and highly interactive genomic approach to scientific investigations which can be extrapolated to other fungi.
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