Assessing Effects of Genetics and Environment on Metabolism in S cerevisiae

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DESCRIPTION (provided by applicant): Metabolism encompasses all the processes by which a cell generates energy and other essential molecules from nutrients. These pathways rely on hundreds of genes and involve thousands of small molecule intermediates, vitamins and cofactors. Small-scale analysis of metabolites is already a common practice for clinical diagnosis. Increased interest in small molecules has led to development of technologies that allow high-throughput profiling of metabolic intermediates. These methods have already led to new diagnostic techniques for kidney cancer. To further our understanding of the roles for small molecule metabolites, I have begun using capillary electrophoresis to profile metabolites in the yeast Saccharomyces cerevisiae. Yeast share all major metabolic pathways with humans and provide the advantages of a well-studied model organism. Based on the similarities, results in yeast can be easily translated to human biology. Preliminary studies demonstrate that this profiling method is simple, quantitative and easily amenable to automation. First, I will identify derivatization reagents that allow me to observe a wide variety of metabolites. Second, I will characterize yeast genes that affect the levels of cellular metabolites relevant to essential metabolic pathways. Third, I will profile metabolites during response to environmental stimuli and during cellular processes such as the cell cycle. Fourth, I will use yeast to determine how polymorphisms in human genes affect these pathways in human metabolism. These data will provide a clearer picture of the metabolic network in yeast and human, yielding insights into the biology of metabolic processes in human health and disease. PUBLIC HEALTH RELEVANCE: The basic processes of metabolism lie beneath every process of cell biology. By examining and understanding a cell's metabolic response to stimuli, we will gain insights into diverse biological processes. In addition, comparing normal cellular changes with the changes that occur during cells affected by cancer or diabetes provides a potentially novel mechanism for disease prevention and treatment.