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Investigating the interplay between oxygen and nutrients – how does oxygen keep us healthy?

Principal Supervisor: Dr. Daniel Tennant, Institute of Metabolism and Systems Research

Co-supervisor: Dr. Christian Ludwig, Institute of Metabolism and Systems Research

PhD project title: Investigating the interplay between oxygen and nutrients – how does oxygen keep us healthy?

University of Registration: University of Birmingham


Project outline:

General Background

When mammals move into lower oxygen environments an immediate physiological response is triggered by the carotid body sensing changes in arterial oxygen content. Amongst other phenotypes, this elicits an increased ventilatory rate and perfusion. However, every one of the cells within the body is capable of sensing changes in oxygen tension, and their metabolic response is critical for the ongoing survival of the animal when exposed to low oxygen (hypoxia). One major class of enzymes responsible for altering the cell phenotype in response to hypoxia is the 2-oxoglutarate-dependent dioxygenase superfamily.

The Tennant research group is investigating how loss of activity of these enzymes in hypoxia can influence the metabolic physiology of animals. Importantly, we are particularly interested in whether changes in oxygenation during our lives can lead to metabolic perturbations that interfere with normal tissue function. Our studies are improving our understanding of how the cells in our body link together the environment in which we live (i.e. oxygen level) with how we process different nutrients – such as during foetal development, exercise, or living at altitude. However, importantly, it also sheds light on how our metabolism may change if tissues are starved of oxygen, such as happens during surgery, or as part of a chronic disease process (e.g. cardiovascular disease, diabetes, obstructive sleep apnoea).

The EGLN family of enzymes within the superfamily of dioxygenases is of particular interest to us. They were originally identified as being responsible for the control of the hypoxia-inducible transcription factor, HIF1, but since then a number of additional functions have been identified. We recently found that members of this family can control both sugar and fat metabolism, providing a fascinating link between normal tissue oxygenation and maintenance of a ‘healthy’ metabolism.

The Overall Objective of this project will be to define how the function of the EGLN family of enzymes influences the way in which nutrients are used by mammalian cells.

Methods: To carry out our studies we will use stable isotope (13C and 15N) enriched metabolic tracing in both cells and the Egln knockout animals that we have in the research group. This means that we can follow how specific nutrients – such as glucose and fatty acids – are used by normal cells compared to those lacking EGLN enzymes. Both mass spectrometry and NMR spectroscopy will be used to trace the fate of each nutrient, allowing us to determine exactly how metabolism is altered.


References:

  • Wheaton and Chandel. Hypoxia 2: Hypoxia regulates cellular metabolism. Am J Physiol Cell Physiol (2011). 300(3):C385-393
  • Eales et al. Hypoxia and metabolic adaptation of cancer cells. Oncogenesis (2016). 5, e190
     

BBSRC Strategic Research Priority: Molecules, Cells and Systems


Techniques that will be undertaken during the project:
 

  • Mammalian cell culture
  • CRISPR/Cas9 generation of knockout cell lines
  • Work with GEM models
  • Stable isotope-enriched metabolic tracer studies
  • GC-MS
  • NMR spectroscopy
  • LC-MS analyses


Contact: Dr. Daniel Tennant, Institute of Metabolism and Systems Research