Candida albicans is one of the most frequently isolated fungal pathogens of humans. It can undergo reversible morphogenetic transitions among budding yeast, pseudohyphal, and hyphal growth forms. Its unique ability to switch from yeast to hyphal growth in response to various environmental signals not only is inherent to its pathogenicity, but also provides an excellent paradigm to understand how signaling pathways coordinate growth and development. The objectives of this research are to understand how various signaling pathways are integrated to control the expression of a common set of hypha- specific genes, and the molecular connection between the signaling pathways and cell morphogenesis. There are three Aims: 1) Identification of downstream effectors of filamentation signaling pathways that are responsible for hyphal morphogenesis in C. albicans. Differential gene expression studies with C. albicans DNA arrays will be performed to identify changes in gene expression associated with morphological differentiation as well as regulated by filamentation signaling pathways. Functional studies of the genes identified from the array experiments will be carried out to address whether any newly identified genes are responsible for hyphal morphogenesis. 2) Mechanisms of transcriptional integration at the promoters of hypha-specific genes in C. albicans. A combination of DNA binding experiments and functional assays using site-specific mutations in the promoter of a selected hypha-specific gene will be used to address whether the terminal transcription factors of a MAP kinase pathway and the cAMP pathway act directly on the promoter, and whether they act cooperatively with each other, or with yet unidentified components on the promoter. In addition, upstream DNA sequences of hypha-specific genes from Aim 1 will be used to predict and identify novel cis-elements and their binding proteins. 3) Regulation and function of Ste12 in S. cerevisiae. Ste12 is the terminal transcription factor of the MAP kinase pathways required for mating, invasive growth and pseudohyphal growth in S. cerevisiae. Both biochemical and genetic experiments are proposed to identify novel regulators of Ste12. Additional DNA array experiments will be used to determine the molecular connections between Ste12 activation and cell elongation.
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