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(MRC DTP) Investigate the therapeutic potential for the treatment of heart failure by targeting cardiac autophagy-regulated lipid homeostasis in diabetes


Faculty of Biology, Medicine and Health

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Dr E Cartwright , Dr Vicky Liu No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

The number of people with type 2 diabetes (T2D) will increase globally to 642 million by 2040. In clinics, diabetic cardiomyopathy (DCM) is a distinct heart disease, featuring cardiac pathological remodelling and diastolic/systolic dysfunction1. However, there is no specific treatment for DCM at present. At the cellular level, DCM is characterised by defects in organelle function and abnormal metabolic homeostasis, making the heart more susceptible to dysfunction in T2D populations2. The high energy demand to maintain cardiac contractility is mainly from fatty acid oxidation via mitochondria. Myocardial triglycerides (TG) stored intracellularly in the lipid droplets are an important storage pool of fatty acid. However, we and others have demonstrated that accumulated lipid droplets along with reduced mitochondrial fatty acid oxidation in the myocardium has been observed in DCM, indicating that the balance of lipid storage and utilization is impaired in the malfunctioning heart in T2D. Thus, maintaining cardiac lipid homeostasis is an emerging therapeutic option to prevent DCM and heart failure in diabetes.

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.

https://www.research.manchester.ac.uk/portal/wei.liu.html
https://www.research.manchester.ac.uk/portal/en/researchers/elizabeth-cartwright(0cc1bee3-9d44-4b80-98a0-c4456ac1770d).html

Entry Requirements:
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

Funding Notes

Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

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/

References

1. Bell DS. Diabetes care. 2003; 26:2949-2951.
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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