The goal of this proposal is to determine the molecular mechanisms of morphogenesis for Candida albicans. C. albicans is the most common fungal pathogen in humans and causes particularly severe life-threatening infections in immunocompromised individuals. The significance of C. albicans as a health risk is increasing as better medical techniques make long-term care of organ transplant, cancer, and HIV patients more common. A better understanding of the mechanisms of pathogenesis is needed to formulate new therapeutic strategies to combat Candidiasis because the drugs currently used against C. albicans are not very effective, especially after it has invaded into tissues. One virulence factor that has been strongly implicated in the pathogenesis of C. albicans is the ability of this yeast to undergo morphological transitions between round budding cells and filamentous hyphae. Therefore, the specific aims of this grant are designed to identify the proteins that regulate morphogenesis of C. albicans. In particular, the septin family of cytoskeletal proteins will be examined because the septins play important roles in morphological transitions in the yeast S. cerevisiae and other organisms. Genetic strategies will be used to determine which members of the septin family function in hyphal morphogenesis. Biochemical approaches will then be used to study the mechanisms that regulate C. albicans septin proteins, and targeted mutagenesis will be used to determine their role in controlling hyphal morphogenesis. Septins act by recruiting key regulatory proteins. Therefore, Septin function in C. albicans will be defined further by identifying septin-binding proteins and analyzing their function. The experimental procedures are designed to take full advantage of recently improved strategies for the genetic analysis of C. albicans and the data being made available from the C. albicans genome sequencing project. Altogether, these studies are expected to identify key regulators of morphological transitions that promote the pathogenesis of C. albicans.
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