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Investigating the regulation and role of AMPKy2 phosphorylation in vivo


   MRC London Institute of Medical Sciences (LMS)

  Prof D Carling  Tuesday, December 14, 2021  Funded PhD Project (Students Worldwide)

About the Project

AMP-activated protein kinase (AMPK) plays an important role in maintaining energy homeostasis in eukaryotic cells1,2. In multicellular organisms, the role of AMPK has been adapted to play a role in integrating energy metabolism at an organismal level. Dysregulated metabolism underlies many diseases including cardiovascular disease, obesity, type 2 diabetes and cancer. Given its key role in regulating metabolism, AMPK has attracted significant attention as an attractive therapeutic target for drugs aimed at preventing or reversing dysregulated energy metabolism2. AMPK is a heterotrimeric complex comprising a catalytic a subunit and two regulatory subunits (b and g). In mammals there are two isoforms of the a and b subunits and three isoforms of the g subunit (all isoforms encoded by distinct genes), which allow for the expression of 12 different AMPK complexes (a1b1g1, a2b1g1, etc.). An important and largely unresolved issue is that of the biological relevance of the different isoform complexes3. Some clues have emerged from the identification of naturally occurring mutations in human g2 (PRKAG2). A number of dominantly-inherited gain-of-function mutations have been identified in g2 that lead to a cluster of severe cardiac abnormalities including left ventricular hypertrophy, glycogen accumulation and ventricular pre-excitation (Wolff–Parkinson–White Syndrome), often leading to sudden cardiac death4. These findings suggest that AMPKg2-containing complexes play a unique role in the heart (and perhaps other tissues). How this specificity is conferred is not clear. Recently, we identified a phosphorylation site within the N-terminal region of the g2 subunit that mediates the interaction of AMPK with a specific binding protein. We are generating a knock-in mouse model that harbours a serine to alanine mutation of this residue, preventing interaction of AMPK with the binding protein. The aim of the PhD project will be to use this mouse model to explore the role of g2 phosphorylation in vivo. We will use a combination of mouse physiological approaches e.g. monitoring metabolic rate and heart function, together with cell-based studies e.g. isolating primary cells from the knock-in mouse to study AMPK activity and downstream signalling. During the project the student will develop skills in mouse phenotyping as well as biochemical, cellular and molecular biology skills. This will enable the student to acquire a broad range of techniques and expertise, providing a strong platform for their future scientific career.


Funding Notes

This funding covers tuition fees and also a stipend amounting to £21,000pa paid directly to the student, for 3.5 years in total.
Whilst there are no residency restriction for these studentships, there is more funding available for Home Fee students (including UK nationals and those with settled and pre-settled status until at least April 2026), which make the international studentships highly competitive

References

1. Lin S.C. & Hardie, D.G. (2018). AMPK: Sensing Glucose as well as Cellular Energy Status. Cell Metab. 27, 299-313.
2. Garcia, D. Shaw, R.J. (2017). AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance. Mol. Cell 66, 789-800.
3. Steinberg, G. R. & Carling, D. (2019). AMP-activated protein kinase: the current landscape for drug development. Nat. Rev. Drug Discov. 18, 527-551.
4. Carling, D. (2017). AMPK signalling in health and disease. Curr. Opin. Cell Biol. 45, 31-37.
5. Arad, M., Seidman, C.E. & Seidman, J.G. (2007). AMP-activated protein kinase in the heart: role during health and disease. Circ. Res. 100, 474-488.

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