There has been a recent explosion in the study of lipid mediated signal transduction and cell regulation. The over-riding paradigm has focused on modular signaling whereby one stimulus regulates one enzyme resulting in the generation of one active molecule. However, the complexity of lipid metabolism far exceeds a simple collection of individual signaling modules such that one agonist may regulate several enzymes, or the bioactive product of one enzyme (e.g. ceramide) may serve as a substrate for another enzyme generating a different bioactive molecule (such as diacyiglycerol or sphingosine). Thus, we hypothesize that this complexity of lipid metabolism serves primarily to provide a highly regulated and coordinated network of bioactive molecules with distinct and overlapping functions. These networks then serve to integrate and coordinate complex responses of cells to various agents and environmental stimuli. This hypothesis will be investigated in S. cerevisiae, focusing on gene expression responses (by microarray expression) as they relate to sphingolipid metabolism. We will develop and apply mathematical modeling of yeast responses and use a combination of biochemical and genetic approaches according to the following specific aims: 1) predicting the bioactive sphingolipid profile of S. cerevisiae in response to specific stimuli from analysis of transcription responses of yeast (expression of enzymes of sphingolipid metabolism) to these stimuli; 2) modeling trehalose metabolism and glycolysis in response to heat stress and relate it to sphingolipid metabolism; and 3) predicting specific cell responses to various stimuli from the profile of bioactive lipids. These studies will lay the groundwork for a global model in which we may be able to predict specific transcription pathways/modules that are regulated by sphingolipids, and predict the overall genetic response to a specific configuration of sphingolipid levels. This model system could then serve as a conceptual and practical platform to extend the hypothesis to other lipid classes, other aspects of regulated metabolism, and eventually to mammalian metabolism.
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