The aim of this proposal is to characterize the metabolic impact of the expression of key transcripts involved in fatty acid metabolism by using the model organism Caenorhabditis elegans. In particular, the main focus of the project will be on the systemic manipulation of the expression of genes for the fatty acid desaturases by an RNAi based intervention to understand their key role as regulatory control points in metabolism. To achieve this aim we will make use of state of the art metabolomic approaches including Nuclear Magnetic Resonance (NMR) spectroscopy, Gas Chromatography Mass Spectroscopy (GC-MS) and Liquid chromatography Mass Spectrometry (LC-MS) to provide a global, non-targeted description of systemic metabolism. Metabolomic analysis, conducted on different genetically modified animals, will result in a rich data-base of metabolomic profiles that, with the help of multivariate data analysis techniques, will permit the identification of specific biochemical markers that determine which pathways have been perturbed. In addition, we will also analyze flux changes directly using stable isotope labelled substrates experiments. The combination of steady state concentration data and flux changes will provide a description of the reorganization of the metabolism following the targeting of a given gene by our RNAi based intervention. Overall, the results will allow a global insight into consequences of altered genetic expression across the whole system of metabolism without any loss of intrinsic complexity - a so-called top-down systems biology approach. In addition understanding the metabolic roles the desaturases play in regulating global lipid metabolism will help us to increase our understanding of human metabolic diseases associated with lipid metabolism dysfunction including obesity, type II diabetes, dyslipidaemia and the metabolic syndrome.
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