About the Project
Autophagy exhibits a key role in maintaining cellular homeostasis through turnover of protein, nutrients, and energy source. Dysregulation of cardiac autophagy contributes to the onset and development of heart failure in response to pathological stresses: excessive autophagy is detrimental to the cell, while insufficient autophagy is unable to efficiently provide cellular energy recycling. Lipid droplets have been also identified as a substrate of autophagy, and the lipids in these droplets are hydrolysed to meet cellular energy demands3. It has been demonstrated that cardiac autophagic abnormalities in the heart in diabetes4; however, whether and how inappropriate cardiac autophagy contributes to the impaired lipid homeostasis and DCM progression in T2D is largely unknown. AMP-activated protein kinase (AMPK) is well-known as a nutrient sensor in cells, playing an essential role in cellular energy homeostasis. Activated AMPK promotes cellular energy supply through glucose, lipid and mitochondrial metabolism pathways, thus increasing ATP levels. In addition, AMPK activates autophagy by inhibition of mechanistic target of rapamycin (mTOR), a key negative regulator of autophagy5. We have reported that activation of AMPK is diminished in the failing heart from the diet-induced diabetic mouse. Therefore, it is crucial to gain molecular and functional evidence that cardiac AMPK regulation of autophagy participates in maintaining lipid metabolism in the myocardium in T2D, which will provide new insights into therapeutic potential for DCM by modulating autophagy-associated lipid homeostasis.
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
UK applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).
If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.
Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.
To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC Doctoral Training Partnership (DTP) website www.manchester.ac.uk/mrcdtpstudentships
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
2. Michael I, et al. Heart Fail Rev. 2014; 19:35-48.
3. Singh R, et al. Nature. 2009; 458:1131-1135.
4. Mellor KM, et al. Autophagy. 2011; 10:1263-7.
5. Garcia D & Shaw RJ. Mol Cell. 2017; 66:789-800.
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