Diabetic cardiomyopathy is a complication of type 2 diabetes, and is associated with impaired metabolism and function of the diabetic heart . Metabolically, the healthy heart has the ability to switch between lipids and carbohydrates in response to hormonal stimulation, substrate availability, oxygenation and workload. This ability to switch substrates is impaired in T2DM, with the diabetic heart exhibiting metabolic inflexibility, relying more on β-oxidation of fatty acids. In addition, lipid accumulation has been associated with the accumulation of reactive lipid intermediates such as saturated acyl-CoA species, long chain acylcarnitine species, diacylglycerols and ceramides, resulting in lipotoxity.
In this PhD proposal we will investigate the metabolic events associated with the development and consequences of diabetic cardiomyopathy using a novel mass spectrometry (MS) imaging technique called matrix assisted laser desorption ionization (MALDI-) MS . In this approach tissue slices are examined by rastering a laser across the surface of the tissue at 40-50 um steps. Each pixel of the resultant image represents a mass spectrum and using current approaches measures over 300 lipid species. For this PhD the student will experiment with different chemical matrices to maximize the ionization of different classes of metabolites (e.g signaling molecules such as cAMP, high energy phosphates such as PCr and ATP) to allow us to build up an image of how metabolism varies across the diabetic heart. We hypothesize that metabolic changes are more pronounced in more metabolic stressed regions, with the ventricles accumulating lipotoxic species such as ceramides. Initially we will perform this in hearts taken from leptin deficient ob/ob and wildtype mice across the life course on either a normal chow or high fat diet to induce different levels of steatosis and cardiac dysfunction . In addition we will also investigate the effect of induced myocardial infarction and hypoxia in the diabetic heart.
Applicants should have a strong background in analytical chemistry, with those with experience in LC-MS being particularly welcome.
The PI is part of the MRC., BBSRC, BHF and Wellcome Trust funded PhD Departmental Training Programmes. Students eligable for these schemes (UK and EU nationals) are encouraged to apply to these programmes. For overseas students they are encouraged to apply through the Cambridge Overseas Trust and related funding schemes through the University of Cambridge.
1. Wang X, West JA, Murray AJ, Griffin JL. Comprehensive Metabolic Profiling of Age-Related Mitochondrial Dysfunction in the High-Fat-Fed ob/ob Mouse Heart. J Proteome Res. 2015;14(7):2849-62.
2. Hall Z, Bond NJ, Ashmore T, Sanders F, Ament Z, Wang X, Murray AJ, Bellafante E, Virtue S, Vidal-Puig A, Allison M, Davies SE, Koulman A, Vacca M, Griffin JL. Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease. Hepatology. 2017 Apr;65(4):1165-1180.
Heather LC, Wang X, West JA, Griffin JL. A practical guide to metabolomic profiling as a discovery tool for human heart disease. J Mol Cell Cardiol. 2013 Feb;55:2-11.
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