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Targeting cardiac mitochondrial dynamics as a therapeutic strategy in obesity and diabetes

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  • Full or part time
    Dr A Kitmitto
    Dr E Cartwright
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Obesity is reaching pandemic proportions affecting over 650 million adults (WHO, 2017) and as such represents a global healthcare and economic burden. Obese patients have an associated 80-fold increased likelihood of developing Type 2 diabetes, T2DM (https://www.diabetes.co.uk/diabetes-and-obesity.html). Obesity is also an independent risk factor for developing cardiac complications1. The most common cause of obesity is the increased intake of high energy foods and the lack of physical activity 3. At the cellular level there is substantive evidence that cardiac mitochondrial dysfunction is a feature of obesity and T2DM2; but the mechanisms involved are complex and not fully understood. Our group is particularly interested in how mitochondrial dynamics are perturbed as a result of diet induced obesity. Mitochondrial dynamics are fundamental for regulating mitochondrial shape, size, cellular organisation as well as underpinning mitophagy as part of the cell’s mitochondrial quality control process. We have developed a model of obesity leading to the development of mild left ventricular dysfunction and impaired mitochondrial function. This project will build upon our current investigations to investigate the role of oxidative stress pathways in the ‘obese heart’ and links to mitochondrial remodelling. Since obesity is often a precursor to T2DM understanding how dysfunction develops prior to the onset of diabetes may also lead to the identification of novel pharmacological targets to attenuate disease progression.

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 will be used to relate molecular and functional changes to mitochondrial remodelling. 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 methods and siRNA technology. Depending upon the interests and background of the student there may also be opportunities to undertake in-vivo studies.

Funding Notes

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area. 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.

This project has a Band 3 fee. Details of our different fee bands can be found on our website (https://www.bmh.manchester.ac.uk/study/research/fees/). For information on how to apply for this project, please visit website (https://www.bmh.manchester.ac.uk/study/research/apply/).

Informal enquiries may be made directly to the primary supervisor.

References

1. Abel ED, Litwin SE and Sweeney G. Cardiac remodeling in obesity. Physiol Rev. 2008;88:389-419.
2. Bugger H and Abel ED. Molecular mechanisms for myocardial mitochondrial dysfunction in the metabolic syndrome. Clin Sci (Lond). 2008;114:195-210.
3. Lau DCW, Douketis JD, Morrison KM, Hramiak IM, Sharma AM, Ur E and Panel fmotOCCPGE. 2006 Canadian clinical practice guidelines on the management and prevention of obesity in adults and children [summary]. 2007.
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.



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