The mechanisms by which eukaryotic cells control the synthesis of membrane lipids in coordination with ongoing membrane biogenesis are not well understood. Yet phospholipids, particularly inositol-containing phospholipids, have been implicated in complex signalling processess which play a role in controlling cell growth and proliferation in higher eukaryotes. Yeast cells synthesize a typically eukaryotic mixture of phospholipids, using pathways which are similar to those in higher eukaryotes. This organism can be manipulated using powerful molecular genetics and analyzed using new genome-wide techniques. The proposed analysis will produce a detailed model of the relative inputs and interactions of multiple signalling pathways influencing phospholipid metabolism, an essential cellular process which itself produces signals that feedback to produce autoregulatory loops and influence other cellular pathways. A genetic assessment will be conducted of the combinatorial inputs and interactions of cellular processes influencing regulation of phospholipid metabolism in yeast including, membrane trafficking, and signalling. Methods which allow quantitative determination of 100 or more metabolites in a single experiment will be used to assess lipid metabolism in selected mutants and their suppressors in order to identify metabolic signals influencing this regulation. Microarray analysis will be used to explore the kinetics of gene expression, genome wide, in response to changes in lipid metabolism. This analysis is expected to shed light on regulation of fundamental aspects of eukaryotic metabolism and cell biology relevant to metabolic diseases such as diabetes, as well as cancer and heart disease.
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