The research performed in the context of the K08 follows work as a fellow and by combining pharmocodynamics (PD) and molecular biology will open the development of an entirely untapped field of study. C. albicans is the most common opportunistic pathogen in HIV infected patients. Azoles are frontline agents for treatment of Candida infections, however therapy remains suboptimal and several mechanisms of azole resistance have recently emerged. There is a need for improved therapy and an understanding of drug exposure factors that lead to and prevent of the emergence of resistance. The proposed research is divided into two phases. (l) In phase one, azole PDs will be studied in a murine model. The findings obtained in the PD studies will be used to optimize dosing of azoles and investigate the relationship between the emergence of specific resistance mechanisms and azole dosing using (a) reconstruction experiments with a susceptible parent strain, doped with a fixed level of the genetically related resistant mutant strain and (b) a strain which has demonstrated temporary phenotypic resistance. (2) In phase two, basic studies of gene expression in C. albicans will be undertaken and correlated with results of phase I PD studies. Serial analysis of gene expression (SAGE) will be used to study mRNA abundance in C. albicans on a genome-wide basis. The biologic variables will include: the adaptive response of C. albicans to azole antibiotics (a) during the initial exposure, (b) following exposure during period of inhibition and regrowth, or the postantifungal effect (PAFE), and (c) the effect of specific known resistance mutations on these responses. The candidate's goal is to integrate knowledge of antifungal PD and the acquisition of approaches and skills in molecular biology through the completion of this grant.
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