This proposal is based on recent findings from our laboratories showing the existence in fungi of high affinity, steroid-specific binding proteins and endogenous ligands which we hypothesize represent primitive hormone-receptor systems. The relevance to health results from four additional critical findings we have made. I. Pathogenic fungi including Candida albicans and Paracoccidiodes brasiliensis possess hormone-receptor systems. 2. The fungal binding sites exhibit high specificity for mammalian hormones (corticosteroids for C. albicans, estrogens for P. brasiliensis) providing a mechanism by which the hormonal milieu in the host might affect fungal colonization and pathogenesis. 3. The Candida ligand binds with high affinity to mammalian glucocorticoid receptors providing a mechanism by which the invading pathogen can affect host defenses. 4. The imidazole antimycotic drugs interact with both fungal and host hormonal systems by both inhibiting steroidogenesis and binding to receptor sites. This complex set of interactions provides several unique and interesting avenues for research regarding the basic biology of fungi, evolution of hormone-receptor systems, host-pathogen interactions and the mechanism of action and side-effects of antimycotic drugs.
Our specific aims are: (1) To characterize the binding proteins and the endogenous hormones, and determine the functions of these fungal hormone systems, (2) to elucidate the actions of the Candida hormone on mammalian cells particularly the possibility that this factor might exhibit corticosteroid properties leading to immuno-suppression and thereby promote fungal pathogenesis, (3) to elucidate the results of corticosteroid actions on C. albicans and estrogen effects on P. brasiliensis to determine whether these host hormones directly promote or inhibit fungal pathogenesis, and (4) to ascertain whether ketoconazole and related imidazole antimycotics have antifungal efficacy via receptor-binding and/or steroidogenic inhibition in either host or fungal cells. Overall this program combines expertise in endocrinology, infectious disease and pharmacology to develop new and provocative approaches into the biology and endocrinology of fungi, hormonal factors that may influence fungal pathogens and the pharmacology of antimycotic drugs.
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