This research project investigates the regulation of invasive growth in fungal organisms. In mammals, the ability to invade normal tissue barriers is an important attribute of metastatic cancer cells and of cells in the developing embryo. In contrast, in the adult regulatory interactions with the substratum control cell proliferation and apoptosis. This regulation by substratum is commonly lost upon malignant transformation. The goal of this research is to understand regulatory interactions with substratum. The fungi Candida albicans and Saccharomyces cerevisiae will be used as model systems because fungal cells also interact with substratum. In the opportunistic pathogen, C. albicans, interactions with the substratum may be important in promoting invasive growth of the organism within the tissues of a host. Thus, studies of C. albicans invasive growth will also contribute to the understanding of a process that plays an important role in disease. C. albicans responds to the presence of substratum by producing invasive filamentous hyphae, which penetrate into the matrix. Culture of C. albicans cells within surrounding matrix promotes rapid production of hyphae. Genetic analysis of this process has led to the identification of two gene products that are needed for normal hyphal production in response to surrounding matrix. S. cerevisiae also responds to the presence of substratum by undergoing invasive growth, although, in this organism, invasion is not associated with a dramatic change in morphology. S. cerevisiae homologues of the C. albicans genes described above are needed for normal invasive growth. Therefore, studies in S. cerevisiae will be performed in order to develop detailed molecular hypotheses for the function of the genes. Studies in C. albicans will test the generality of the hypotheses developed in S. cerevisiae. Experiments are proposed to identify interactors that bind to the gene products of interest and to elucidate the pathways in which these gene products participate.
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