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Glucocorticoid regulation of NAD+ and energy metabolism in skeletal muscle ageing


Project Description

Glucocorticoid hormones are critical regulators of muscle energy homeostasis, and influence metabolic muscle disease contributing to age-related frailty and cardiovascular disease. Nicotinamide adenine dinucleotide (NAD+) is an important metabolic cofactor in redox reactions and signalling molecule, and impaired NAD+ synthesis or increased consumption is proposed to drive aspects of age-related muscle deficits. We have shown that using NAD+ precursors to augment the NAD+ metabolome can positively impact on mitochondrial function and inflammation. Glucocorticoids interact with the NAD+ synthetic metabolome pathways in muscle but the nature and impact of this interaction on age-related metabolic dysregulation requires mechanistic definition. We believe that glucocorticoid hormones and NAD+ synthesis and consumption pathways interact to modulate energy metabolism in ageing muscle through metabolic and transcriptional control of networks important to health. The aim of this studentship is to investigate this novel axis of metabolic regulation to illuminate new muscle biology and therapies in age-related disease processes. Work to be conducted will employ a range of mouse genetics and human physiology studies with additional training at the University of Copenhagen with world leading collaborators.

This studentship is full-time and will begin on 1st of October 2019.

Person Specification
Applicants should have a strong background in physiology and metabolism. They should have a commitment to research in metabolic physiology within a dynamic team environment, and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

How to apply:

Informal enquiries should be directed to Prof Gareth G Lavery () https://www.birmingham.ac.uk/staff/profiles/metabolism-systems/Lavery-Gareth.aspx)

Applications should be directed to Lisa Fuller (email – ). To apply, please send:

• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.

Funding Notes

To be eligible for a full award, a student must have no restrictions on how long they can stay in the UK and have been ordinarily resident in the UK for at least 3 years prior to the start of the studentship. Students from EU countries other than the UK are generally eligible for a fees-only award. To be eligible for a fees-only award, a student must be ordinarily resident in a member state of the EU; in the same way as UK students must be ordinarily resident in the UK. Further information on eligibility is available online - View Website


References

Morgan SA, McCabe EL, Gathercole , Hassan-Smith ZK, Larner DP, Bujalska IJ, Stewart PM, Tomlinson JW*, Lavery GG*. 11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess. PNAS. 2014, Jun 17;111(24):E2482-91. *Joint senior Authors.

Fletcher RS, Ratajczak J, Doig CL, Oakey LA, Callingham R, da Silva Xavier G, Garten A, Elhassan YS, Redpath P, Migaud ME, Philp AA, Brenner C, Canto C, Lavery GG. Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells. Mol Metab. 29 May, 2017.

Oakey LA, Fletcher RS, Elhassan YS, Cartwright DM, Doig CL, Garten A, Thakker A, Maddocks ODK, Zhang T, Tennant DA, Ludwig C, Lavery GG. Metabolic tracing reveals novel adaptations to skeletal muscle cell energy production pathways in response to NAD + depletion. Wellcome Open Res. 2018 Nov 15;3:147

Stephens FB, Chee C, Wall BT, Murton AJ, Shannon CE, van Loon LJ, Tsintzas K. Lipid-induced insulin resistance is associated with an impaired skeletal muscle protein synthetic response to amino acid ingestion in healthy young men. Diabetes. 2015 May;64(5):1615-20.

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