There has been a recent explosion in the study of lipid mediated signal transduction and cell regulation. The over-riding paradigm has evolved from a reductionist approach and 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 diacylglycerol or sphingosine). Thus, we hypothesize that the complexity of lipid metabolism serves 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 proposal will test the specific hypothesis that the sphingolipid sub-universe of cell regulation in S. cerevisiae constitutes a relatively discrete domain that allows the elucidation of biochemical regulation as well as integrative approaches. We also propose that mathematical modeling of these responses is feasible, provides for the integration of diverse data sets, allows specific predictions of experimental results, and will provide novel insights into the understanding of these pathways and their function. Thus, we aim to 1. develop a model that will predict and test the profiles of bioactive sphingolipids in S. cerevisiae in response to specific perturbations of sphingolipid metabolism; 2. Perform reverse modeling in which we analyze and predict what biochemical strategies the cell may employ to establish a specific total profile of sphingolipids; and 3. Determine and then predict specific transcriptional responses to specific profiles of bioactive lipids. These studies will lay the groundwork for a global model in which we hope to eventually be able to 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, and eventually to metabolomics. Lay Summary:
This research aims at defining mechanisms by which eukaryotic cells respond to stress, focusing on the role of an emerging group of fatty substances called sphingolipids. The proposal endeavors to use biochemical, molecular as well as mathematical approaches that allow a deeper understanding of the stress response at a semi-comprehensive level, commensurate with the post-genomic era of research. ? ? ?
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