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Cellular protein quality control in diabetes-associated heart disease: The insight into mechanisms and therapeutic potentials


Project Description

Cardiovascular complications are the leading causes of diabetes mortality. With the exception of vascular and valvular injuries, diabetic cardiomyopathy (DCM) is a distinct myocardial disease, which is characterised by abnormal cellular metabolism and defects in organelles function, leading to impaired cardiac function. Epidemiological studies have revealed increasing incidence of DCM in diabetic patients, featured by hypertrophy and diastolic dysfunction with consequential heart failure. Thus, elucidating molecular pathogenesis of DCM is pivotal for the discovery of potential therapeutic approaches. Protein homeostasis plays an essential role in maintaining overall cell function and viability. To preserve protein fidelity in the face of pathological stresses, cells possess an interconnected set of protein quality control pathways, including the endoplasmic reticulum (ER) stress response, ER-associated degradation (ERAD), the ubiquitin proteasome system and autophagy, which function to eliminate misfolded proteins and restore homeostasis. In the absence of these protective processes, overwhelming protein misfolding and aggregation becomes toxic to the cell. Indeed, accumulation of misfolded proteins has been discovered as a pathologic trigger for the development of DCM and cardiac dysfunction. However, the molecular basis for managing protein fidelity in myocardium and the therapy targeting cardiac protein homeostasis in diabetes mellitus remain largely unexplored.
In the proposed project, we aim to advance our understanding of the protective role of maintaining cardiac protein homeostasis in diabetes; elucidate novel molecular basis underlying proteotoxicity-induced cardiac dysfuntion; provide new insights into the beneficial effects of preserved protein homeostasis against DCM, as a means of ameliorating the onset and progression of heart failure in diabetes populations.

Entry Requirements:
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.

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

Funding Notes

Applications are invited from self-funded students. This project has a Band 2 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. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation. 2007;115:3213-3223.
2. Michael I, Stevens SCW, Schaffer S, Jong CJ, Wold LE. Metabolic dysfunction in diabetic cardiomyopathy. Heart Fail Rev. 2014;19:35-48.
3. McLendon PM, Robbins J. Proteotoxicity and cardiac dysfunction. Circ Res. 2015;116(11):1863-8182.
4. Douglas PM, Cyr DM. Interplay between protein homeostasis networks in protein aggregation and proteotoxicity. Biopolymers. 2010;93(3):229-236.
5. Borghetti G, von Lewinski D, Eaton DM, Sourij H, Houser SR, Wallner M. Diabetic Cardiomyopathy: Current and Future Therapies. Beyond Glycemic Control. Front Physiol. 2018;9:1514.

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