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Investigation of aortic remodelling in obesity and role of mitochondrial dysfunction


Project Description

Obesity is a global healthcare and economic burden with currently more than 650 million adults classified as obese (WHO, 2017). Obesity is a common precursor to type 2 diabetes (T2DM), and both are risk factors for developing cardiovascular disease. Obesity triggers a myriad pathophysiological pathways, many of which are yet to be fully understood, that lead to cardiac remodelling with hypertrophy of the left ventricle and development of diastolic dysfunction. Aortic stiffening is also a feature of obesity, with a correlation between aortic stiffening and mortality rates in T2DM patients1. Since the aorta is a regulator of central hemodynamics then structural changes to the aorta will have potential detrimental effects on heart/organ function. Patients with aortic stiffening have been shown to develop diastolic dysfunction with progression to HFpEF; although there is a limited understanding of the mechanisms involved or whether aortic stiffening precedes and is a predictor of left ventricular remodelling. Stiffening of large elastic arteries such as the aorta has been linked to impaired mitochondrial function in ageing2. However, while cardiac mitochondrial dysfunction is known to occur in the early stages of disease in the obese and diabetic myocardium3 much less is known about changes to mitochondrial function in the aorta. We have extensive expertise in a range of techniques for investigating mitochondrial function, dynamics and structural remodelling in the myocardium4,5, with recent studies extending to the aorta. This studentship will build upon our current studies taking a multi-disciplinary approach to investigate key mitochondrial signalling pathways in the aorta employing a model of obesity with mild left ventricular dysfunction. Delineation of the mechanisms leading to aortic mitochondrial remodelling as a consequence of diet-induced obesity may lead to the identification of novel pharmacological targets to attenuate disease progression.

Entry Requirements:
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with a Bioscience background (e.g. physiology, biochemistry, pharmacology, biomedical sciences etc), or those with a background in Medicine wishing to do a laboratory based PhD are encouraged to apply.

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. For more information please visit http://www.internationalphd.manchester.ac.uk

The project will involve a range of biochemical methods such as Western blotting, RT-qPCR, subcellular fractionation for mitochondrial isolation with functional analysis of mitochondrial function by measuring respiration rates (OCR) and Complex activity. Advanced 3-D electron microscopy imaging methods4,5 will be used to relate molecular and functional changes to mitochondrial remodelling. Proteomics and bioinformatic analyses coupled with biophysical techniques including microscale thermophoresis and isothermal titration calorimetry will be employed to delineate molecular mechanistic pathways to understand functional changes. The project will also employ cell culture, molecular biology methods including mammalian cell transfection techniques. Depending upon the interests and background of the student there may also be opportunities to undertake in-vivo studies.

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1.Ferreira, M.T. et al. Correlates of aortic stiffness progression in patients with type 2 diabetes; importance of glycemic control. Diabetes Care 2015; 38(5) : 897-904
2. Yu, E., Foote, K. and Bennett, M. Mitochondrial function in thoracic aortic aneurysms. Cardiovascular Research 2018; 114: 1696-1698
3. Jia, G, Hill, M.A. and Sowers, J.R. Diabetic Cardiomyopathy. Circulation Research 2018; 122:624-638
4. Pinali C. and Kitmitto A. Serial block face scanning electron microscopy for the study of cardiac muscle ultrastructure at nanoscale resolutions. Journal of Molecular and Cellular Cardiology 2014;76:1-11.
5. Pinali C. et al. Three-dimensional reconstruction of cardiac sarcoplasmic reticulum reveals a continuous network linking transverse-tubules: this organisation is perturbed in heart failure. Circulation Research 2013; 113: 1219-30

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