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

这个学生代表了生物化学系的Griffin和Lilley实验室，遗传学系的Russell实验室，剑桥系统生物学中心和欧洲生物信息学研究所的Steinbeck小组之间的合作，研究基因组如何影响果蝇的全身脂质代谢，进而影响整个生物体水平的肥胖和衰老。肥胖是影响全球健康的主要挑战之一，尽管在全球范围内与营养过剩有关，但我们知道，个人的基因型也会影响他们的身体组成。此外，营养状况强烈影响各种生物体的衰老，特别是通过tor - akt -胰岛素受体信号通路，尽管确切的机制尚未确定。该学生将首先从酵母和秀丽隐杆线虫的全基因组筛选中收集数据，以确定参与脂质代谢的基因，特别是过量脂质物种的积累。利用罗素实验室在果蝇遗传学方面的专业知识，这些基因将在果蝇中被删除，以研究在整个生物体水平和脂肪体（相当于脂肪组织的果蝇）中脂质代谢是如何改变的。将监测缺失菌株的全球表型变化，特别是整个生物体的脂质含量和衰老率。包括酵母、秀丽隐杆线虫、果蝇和实验室小鼠在内的一系列模式生物已经证实，寿命与整体营养状况之间存在关联，这在一定程度上与AKT-TOR-胰岛素信号传导有关。为了进一步对产生的果蝇模型进行表型分析，我们将在Griffin组中进行高通量脂质组学和代谢组学筛选，以确定脂质代谢的变化，以及包括糖酵解、TCA循环、氨基酸代谢和脂肪酸氧化/合成在内的核心代谢途径。这些数据集将用于将功能相似的基因聚类在一起，进一步确定给定基因在调节核心代谢中的作用。我们还将研究脂质代谢的给定扰动如何影响果蝇的衰老过程，以便更好地了解脂质代谢如何与整个衰老过程相互作用。此外，为了更好地了解与果蝇脂质积累相关的机制，我们将利用Lilley实验室的苍蝇蛋白质组学专业知识来分析突变果蝇脂肪体中的蛋白质组变化。最后，数据将使用EBI为多基因组数据集开发的数据库进行存储。此外，EBI的Steinbeck小组将提供数据融合方面的专业知识，以改进对生成的数据集的解释。该项目旨在解决BBSRC的“数据驱动生物学”、“食品、营养和健康”、“生物科学的系统方法”和“整个生命过程中的健康老龄化”的响应模式优先事项。该项目还通过提供生物科学（基因组学和生物信息学）新工作方式的培训，解决了一个脆弱的技能领域，该项目是跨学科的，将湿实验室的“基因组学”技能与EBI的干实验室专业知识结合在一起，该项目解决了最近的研究亮点“营养机制研究”。

Theme: Bioscience for HealthThis 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.'