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Developing new targeted approaches to study human metabolism across the life course

Principal Supervisor: Professor Warwick Dunn, School of Biosciences, University of Birmingham

Co-supervisor: Professor Mark Viant, School of Biosciences, University of Birmingham

PhD project title: Developing new targeted approaches to study human metabolism across the life course

University of Registration: University of Birmingham

Project outline:

Introduction and project rationale:Metabolism plays many important roles in humans including providing the precursors for the synthesis of other biochemical (proteins, RNA and DNA), in acute responses to changes in lifestyle and environment and in defining the dynamic phenotype of humans at the molecular level. The study of metabolism at a global level is defined as metabolomics and provides an untargeted study of endogenous and exogenous metabolites in human biofluids and tissues. The metabolic response to changes as humans age is currently not well studied but has major implications in relation to how exercise, diet and other lifestyle factors impact on humans at the molecular level. To be able to study the complex interactions between genome, diet and lifestyle in the human population requires many hundreds of samples to be collected in a cost-efficient strategy. The most cost-effective strategy is to allow human subjects to collect their own samples and subsequently post these to the research laboratory because all costs for trained staff and sample processing are removed. Dried blood spots (DBS) are the most common sample type collected in this area though collection of dried saliva, urine and fecal water samples is also possible depending on the research question being asked. Once samples are collected, the chemical identification of metabolites in human biofluids and tissues will maximise the metabolic information achieved. The proposed project will build on two BBSRC iCASE studentships awarded to Professor Dunn.

In this project, there are four major objectives:

  1. To identify all endogenous and exogenous metabolites routinely detected in human biofluids including blood, urine, saliva and fecal water. The use of software tools and open access data available in the data repositories MetaboLights and Metabolomics Workbench will be integrated with UPLC-MS untargeted metabolomics assays performed by the student to maximise information content.
  2. To develop targeted broad-spectrum UPLC-MS assays for collection of metabolite data in these sample types for small and large-scale human studies.
  3. To assess the applicability of the collection of dried saliva, urine and fecal water samples.
  4. Apply the targeted broad-spectrum UPLC-MS assays to study human ageing and metabolic changes during ageing across the life course in multiple dried sample types.

Research team:The supervisory team is built with experts in the areas of metabolism, metabolomics, analytical chemistry and statistical modelling (Professors Dunn and Viant, University of Birmingham).

Methods to be applied:During your PhD you will receive training in complementary and inter-disciplinary research skills including metabolomics, analytical chemistry, statistical analysis, network modelling, subject recruitment and human study design. The research will be primarily based at the University of Birmingham in the group of Professor Dunn.

References:

  1. Dunn, W.B., Broadhurst, D.I., Atherton, H.J., Goodacre, R. and Griffin, J.L., 2011. Systems level studies of mammalian metabolomes: the roles of mass spectrometry and nuclear magnetic resonance spectroscopy. Chemical Society Reviews, 40(1), pp.387-426.
  2. Dunn, W.B., Broadhurst, D., Begley, P., Zelena, E., Francis-McIntyre, S., Anderson, N., Brown, M., Knowles, J.D., Halsall, A., Haselden, J.N. and Nicholls, A.W., 2011. Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry. Nature protocols, 6(7), p.1060.
  3. Drogan, D., Dunn, W.B., Lin, W., Buijsse, B., Schulze, M.B., Langenberg, C., Brown, M., Floegel, A., Dietrich, S., Rolandsson, O. and Wedge, D.C., 2014. Untargeted metabolic profiling identifies altered serum metabolites of type 2 diabetes mellitus in a prospective, nested case-control study. Clinical Chemistry, pp.clinchem-2014.

BBSRC Strategic Research Priority: Molecules, Cells and Systems

Techniques that will be undertaken during the project:

  1. Metabolomics: use of liquid chromatography-mass spectrometry platforms for collection of data related to the concentration of tens to thousands of metabolites in human blood, urine and tissues (in Dunn research team)
  2. Statistical analysis and mathematical modelling: use of univariate and multivariate data analysis tools to dissect complex metabolic-phenotypic datasets and identify casual relationships (in Dunn research group)
  3. Design of projects involving humans: use of highly controlled circadian and sleep laboratory protocols to define the role of behaviour (feeding/fasting; sleep/wake), the environment (light/dark) and the circadian timing system on metabolic profiles (in Skene research team).
Contact: Professor Warwick Dunn, University of Birmingham