The development of new drugs for the treatment of fungal diseases is of primary importance. Nevertheless, this will not be achieved until we have a more distinct picture of basic fungal physiology and biochemistry. The study of key enzymes involved in fungal dimorphism will help determine if these enzymes are useful targets for future antifungal drug development and to understand the mechanisms these organisms use to establish themselves in the human host. Even though dimorphism is an important characteristic of most pathogenic fungi, the information concerning the key enzymes involved in the control of this process is incomplete for most fungi. S. schenckii is a unique dimorphic pathogenic fungi. Phylogenetic analysis of S. schenckii genes studied in our laboratory groups this fungus closer to the filamentous fungi rather than to the customary human pathogens. But unlike most of the filamentous fungi, S. schenckii is unique in the sense that it is dimorphic and that at some point in evolution it acquired what was necessary to survive in the human host. Studies done by us revealed that the development of a particular morphology in S. schenckii, depends on transmembrane signaling pathways that respond to cell density, external pH, temperature, extracellular calcium concentration, cyclic nucleotides and protein kinase C (PKC) effectors, such as phorbol esters. Our working hypothesis is that the presence of heterotrimeric G proteins is fundamental in the expression of dimorphism in this fungus and ultimately in its pathogenicity. Heterotrimeric G proteins are important enzymes that transduce signals from the membrane into the cell in eukaryotic systems. The long term experimental objectives of this work are concerned with elucidating the role each G protein subunit plays on the development of alternate morphologies in this fungus. This includes the evaluation of the effects that specific heterotrimeric G protein gene knockouts have on the yeast to mycelium transition and the yeast cell cycle and the identification of the proteins that interact with the various forms of the G protein subunits in order to construct the signal tranduction pathways that are initiated at the cell membrane and ultimately result in differential gene expression and a visible change in morphology; This information will help to elucidate the chain of events that lead to a change in morphology in S. schenckii and the role G proteins have in the dimorphic process, and will ultimately contribute to determine if these enzymes are useful targets for future antifungal drug development.
Showing the most recent 10 out of 174 publications
