Heart failure is the most common cause of mortality in diabetes patients, but current diabetes therapies have a limited impact on the incidence of heart failure in diabetic populations. Diabetic cardiomyopathy (DCM) is a distinct myocardial disease accelerating the progression of heart failure; however, there is a dearth of effective clinical therapies for treating DCM1. Thus, it is crucial to decipher the molecular pathogenesis of DCM and discover therapeutic approaches for heart failure in T2D.
Diabetes stress impairs metabolic flexibility in the heart, and subsequently induces DCM, characterised by supressed fatty acid and glucose utilization, lipid accumulation, oxidative stress accompanied with profound apoptosis in cardiomyocytes, which eventually leads to myocardial energy deprivation and a deterioration in contractility. Hypoxia-inducible factor (HIF) has emerged as a potential candidate for therapeutic manipulation in DCM, because it has a strong impact on cellular metabolism. Prolyl-hydroxylases (PHDs) catalyse the degradation of HIF. PHDs are upregulated by oxygen, abnormal metabolic status, and oxidative stress, which impairs lipid and glucose metabolism, resulting in decreased mitochondrial ATP synthesis. Interestingly, inhibition of PHDs in the myocardium is cardioprotective in hypoxia, therefore PHDs have become an attractive therapeutic target for treating ischemia. In addition, genetic and pharmacological inhibition of PHDs activate adaptive responses in various cells under pathological stresses. However, the function of cardiac PHDs in DCM and the molecular mechanisms underlying PHDs regulation of cardiac metabolism is largely unknown. Importantly, our pilot data has demonstrated that PHDs are increased in the failing heart in diet-induced diabetic mice. Thus, it is crucial to investigate whether inhibition of PHDs has therapeutic potential for treating heart failure in T2D. Given that PHDs inhibitors are in clinical trials for the treatment of anaemia, the path for translating these drugs into suitable T2D therapies has already begun.
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related subject. Candidates with experience in any molecular and cellular techniques or with an interest in diabetes and heart diseases are encouraged to apply.
How To Apply
For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the appropriate subject title.
For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences.
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