How the fat flies - understanding how whole body lipid metabolism is regulated using high throughput omics to provide mechanistic insight into obesity

Theme: Bioscience for Health

This studentship represents a collaboration between the Griffin and Lilley labs in the Department of Biochemistry, the Russell lab 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.'