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How the Fat Flies – Understanding how whole body lipid metabolism is regulated using high throughput omics to provide mechanistic insight into obesity

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  • Full or part time
    Prof Griffin
    Prof Kathryn Lilley
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

This studentship represents a collaboration between the Griffin (metabolomics/lipidomics) and Lilley (proteomics) labs in the Department of Biochemistry, the Russell lab (Genetics and transcriptomics) in the Department of Genetics, the Cambridge Systems Biology Centre and the Steinbeck group at the European Bioinformatics Institute to investigate how the genome influences systemic lipid metabolism in flies, and in turn affects obesity and ageing at the whole organism level. Obesity is one of the major challenges affecting global health, and although associated with over-nutrition at a global level we know that an individual’s genotype also influences their body composition. Furthermore, nutritional status strongly influences ageing in a variety of organisms, in particular through the TOR-AKT-insulin receptor signalling pathway, although the exact mechanisms have not been defined.

The student will initially collect data from whole genome screens in yeast and C. elegans to identify genes involved in lipid metabolism, and in particular the accumulation of excess lipid species. Using the expertise of the Russell lab in fruit fly genetics, these genes will then be deleted in flies to examine how lipid metabolism is altered at the whole organism level and in fat bodies (the fly equivalent of adipose tissue). The deletion strains will be monitored for global phenotypic changes and in particular whole organism lipid content and rate of ageing. It is established across a range of model organisms including yeast, C. elegans, fruit flies and laboratory mice that there is an association between longevity and overall nutritional status, in part associated with AKT-TOR-insulin signalling. To further phenotype the fly models produced we will conduct a high throughput lipidomic and metabolomic screen within the Griffin group to identify changes in lipid metabolism, as well as core metabolic pathways including glycolysis, TCA cycle, amino acid metabolism and fatty acid oxidation/synthesis. These datasets will be used to cluster genes of similar function together, further defining the role a given gene plays in regulating core metabolism. We will also investigate how given perturbations in lipid metabolism influences the ageing process of the flies produced to have a better understanding how lipid metabolism interacts with the overall ageing process. Furthermore, to better understand the mechanisms associated with lipid accumulation in flies we will profile the proteome changes in the fat body of mutant flies using expertise in the Lilley lab in fly proteomics. Finally, data will be stored using databases developed at the EBI for poly-omic datasets. In addition the Steinbeck group at the EBI will provide expertise in data fusion to improve the interpretation of the datasets generated.

This studentship addresses the response mode priorities of the BBSRC of ‘data driven biology’, ‘food, nutrition and health’, ‘systems approaches to the biosciences’ and ‘healthy ageing across the life course.’ The project also addresses a vulnerable skills area by providing training in new ways of working in biological sciences (-omic sciences and bioinformatics), the project is interdisciplinary bringing together wet lab ‘-omic’ skills alongside the dry lab expertise of the EBI, and the project addresses the recent research highlight of ‘mechanistic research in nutrition.’

Applicants should have a strong background in analytical chemistry, with those with experience in LC-MS being particularly welcome.

Funding Notes

This studentship is funded by a combination of the University of Cambridge BBSRC DTP scheme and KAUST systems biology studentship fund.

References

Roberts LD, McCombie G, Titman CM, Griffin JL. A matter of fat: an introduction to lipidomic profiling methods. J Chromatogr B Analyt Technol Biomed Life Sci.; 871(2):174-81 (2008).
Roberts LD, Hassall DG, Winegar DA, Haselden JN, Nicholls AW, Griffin JL. Increased hepatic oxidative metabolism distinguishes the action of Peroxisome proliferator-activated receptor delta from Peroxisome proliferator-activated receptor gamma in the ob/ob mouse. Genome Med. 1(12):115 (2009).
Dunn WB, Broadhurst DI, Atherton HJ, Goodacre R, Griffin JL. Systems level studies of mammalian metabolomes: the roles of mass spectrometry and nuclear magnetic resonance spectroscopy. Chem Soc Rev.; 40(1):387-426 (2011).
Heather LC, Wang X, West JA, Griffin JL. A practical guide to metabolomic profiling as a discovery tool for human heart disease. J Mol Cell Cardiol. 2013 Feb;55:2-11.

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FTE Category A staff submitted: 189.63

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