This proposal is based on recent findings from our laboratories showing the existence in three pathogenic fungi of high affinity, steroid-specific, binding proteins which recognize vertebrate steroid hormones. Additionally, we have provided evidence for endogenous ligands in the fungi. We hypothesize these molecules represent fungal hormone-receptor systems. Furthermore, in each of the three fungi with a binding protein, we have demonstrated a functional response of the organism to treatment with the appropriate vertebrate steroid: Candida albicans possesses a corticosteroid binding protein and corticosteroids induce a change in protein pattern which can be detected by polyacrylamide gel electrophoresis; Paracoccidiodes brasiliensis possesses an estrogen binding protein and estradiol inhibits mycelial, i.e., yeast transformation; Trichophyton mentagrophytes possesses a progesterone binding protein, and progesterone inhibits fungal growth.
Our specific aims are: (1) to further characterize these fungal binding proteins and ascertain whether they function as hormone receptors; (2) to isolate and identify the endogenous ligand in Candida; and (3) to investigate the functional responses in the fungi and elucidate the hormonal mechanisms of action. The long range goals of the project include expanding our understanding of fungal biology, providing information on hormone-receptor evolution, and developing a simple and convenient model system for the study of the mechanism of action of steroid hormones. The health relatedness of the proposed research falls into several spheres: establishing the biochemical basis for observed epidemiological differences in host resistance to fungal infection based on the hormonal milieu of the host, understanding how the interactions between host hormones and fungi affect fungal pathogenesis, developing a better understanding of the mechanism of action of anti-fungal drugs and their side-effects, and identifying potential new sites of attack for anti-fungal therapeutic agents. 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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