Project Summary: The human fungal pathogen Candida albicans causes a range of diseases including severe morbidity from mucosal infections and life-threatening systemic infections. There is an urgent need to improve the therapeutic management of C. albicans since the pool of susceptible individuals is increasing due to factors that include new medical treatments, an aging population, and the emergence of drug resistant strains. Central to the pathogenesis of C. albicans is its ability to grow in different morphologies that promote dissemination in the host. Small budding cells more readily colonize the G.I. tract and disseminate in the bloodstream, whereas elongated hyphal cells mediate invasion into tissues and promote biofilm formation. However, the current models for the regulation of hyphal growth that were developed ~20 years ago now have limitations. Therefore, we propose innovative new experiments to overcome the major barriers to progress. Aim 1 is to define the mechanisms of a novel cAMP-independent pathway for hyphal growth that we discovered recently. These results are expected to identify important new mediators of hyphal growth that move the field past the narrow focus on adenylyl cyclase and cAMP signaling. Aim 2 is to determine how phosphorylation regulates the signaling and morphogenesis proteins that promote hyphal formation. These studies are expected to fill a gap in our understanding of the mechanisms that stimulate hyphal growth that can’t be explained by previous studies that have focused on the role of hyphal-induced genes. Aim 3 is to determine which genes influence hyphal growth in the host by studying unusual clinical isolates that are defective in forming hyphae. These hyphal defective clinical strains are thought to arise during commensal growth, since budding cells are better able to colonize the GI tract (whereas hyphae are better invading into tissues). Defining the mechanisms that regulate the switch to hyphal morphogenesis will provide new insights into C. albicans pathogenesis and new opportunities for developing antifungal therapy.