The Biochemistry and Molecular Biology Department at St. Louis University School of Medicine is an ideal environment for the candidate to focus on a novel and potentially prolific research project identifying genes required for pathogenesis in the opportunistic fungal pathogen, Cryptococcus neoformans. The University offers a dynamic research environment including interactions with other mycologists, molecular geneticists and biochemists, and a generous allotment of space and equipment for the candidate to conduct a productive research program. The candidate has been committed to a carer in biological research and now has the opportunity to make a significant contribution to biomedical research and public health. The proposed research will identify new genes which are essential for pathogensis of the C. neoformans. C. neoformans causes cryptococcal meningitis in 6-10 percent of patients with AIDS. As a geneticlly manipulable haploid organism with several key molecular genetic tools already available, C. neoformans is an excellent model for other opportunistic fungal pathogens. To identify fungal genes that are essential for pathogenesis, """"""""signature-tagged"""""""" mutagenesis, a novel screen which has been highly successul in Salmonella, will be adapted for use in C. neoformans. Mutants strains of C. neoformans will be generated by insertion of a unique """"""""signature-tag"""""""" randomly throughout the genome. The mutant strains will be pooled and injected into a mouse. A strain that fails to proliferate in the animal host will be identified by the absence of its signature-tag in the genomic DNA of the recovered pooled organisms. Strains which are confirmed to be less virulent, will be analyzed thoroughly and the genes which have been disrupted by the signature tag will be cloned and characterized. Some of the genes identified in this screen could increase our understanding of which factors contribute to the ability of an organism to be an opportunistic pathogen. Other genes may prove to be promising new leads for novel antifungal targets.
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