This project is part of our exciting and challenging University of Dundee 4-year MRC DTP Programme in Quantitative and Interdisciplinary approaches to biomedical science. This PhD programme brings together leading experts from the School of Life Sciences (SLS), the School of Medicine (SoM) and the School of Science and Engineering (SSE) to train the next generation of scientists at the forefront of international science. Further information on the programme structure and training can be found at https://www.dundee.ac.uk/study/pg/phds/dtp/mrc-dtp/
Diabetes and chronic heart failure (CHF) often coexist such that each condition may affect the other in terms of causation and outcome. This bidirectional interrelationship between CHF and diabetes also extend to insulin resistance. Insulin resistance and associated reductions in cardiac insulin signalling is emerging as a major factor for the development of CHF. The pathogenesis of insulin resistance in CHF is not fully understood. A growing body of evidence suggests a link between extracellular matrix (ECM) remodelling and insulin resistance. Preliminary data from Dr Li Kang’s research show that cardiac insulin resistance may be associated with increased deposition of ECM components, such as collagen III and collagen IV. Importantly, reduction of the ECM components has the potential of improving insulin sensitivity in the heart of insulin resistant mouse models. This project aims to test the hypothesis that reduction of heart ECM protein could rescue cardiac insulin resistance, which has the potential of improving cardiac function. The ECM not only provides structural support for tissues, but are ligands for cell membrane receptors. It has previously been shown that ECM-receptor signalling and endothelial dysfunction are associated with the development of skeletal muscle insulin resistance. Therefore, it is also hypothesized that ECM-receptor signalling and endothelial dysfunction could also contribute to cardiac insulin resistance and CHF. In this research, we plan to utilize the high fat-fed insulin resistant mouse model in the combination of genetic and pharmacological approaches to modulate cardiac ECM and its receptors, to extensively characterize the ECM profile of the heart (such as collagen III, IV, hyaluronan, matrix metalloproteinases etc.). The relationship between ECM remodelling, ECM-receptor signalling, and endothelial dysfunction in the heart with cardiac insulin sensitivity will provide important and novel insights into the role of the ECM in cardiac insulin resistance and CHF and ECM may well become a target for therapy in diabetic cardiovascular disease. This research project takes an interdisciplinary approach, which will be facilitated by Dr Kang’s expertise in in vivo insulin resistance physiology and Professor Lang, a leading expert in cardiology and clinical pharmacology with an interest in pathophysiology of cardiac metabolic disease.
Wong AK, Struthers AD, Choy AM, Lang CC. Insulin sensitization therapy and the heart: focus on metformin and thiazolidinediones. Heart Fail Clin. 2012; 8(4):539-50
Kang L, Mokshagundam S, Reuter B, Lark DS, Sneddon CC, Hennayake C, Williams AS, Bracy DP, James FD, Pozzi A, Zent R, Wasserman DH. Integrin-Linked Kinase in Muscle is Necessary for the Development of Insulin Resistance in Diet-Induced Obese Mice. Diabetes. 2016; 65(6):1590-600
Kang L, Ayala JE, Lee-Young RS, Zhang Z, James FD, Neufer PD, Pozzi A, Zutter MM, Wasserman DH. Diet-induced muscle insulin resistance is associated with extracellular matrix remodeling and interaction with integrin α2β1 in mice. Diabetes. 2011; 60(2):416-26
Cameron AR, Morrison VL, Levin D, Mohan M, Forteath C, Beall C, McNeilly AD, Balfour DJ, Savinko T, Wong AK, Viollet B, Sakamoto K, Fagerholm SC, Foretz M, Lang CC, Rena G. Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status. Circ Res. 2016 Aug 19;119(5):652-65.