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MRC DiMeN Doctoral Training Partnership: Investigating the potential of a regenerative medicine therapy to treat cardiorenal disease


Project Description

Cardiovascular disease (CVD) is the leading cause of mortality in patients with chronic kidney disease (CKD). The strong association between CKD and CVD has been recognised for many years, but the mechanisms by which CKD causes CVD are largely unknown. A barrier to addressing this question has been our inability to monitor renal and cardiac function longitudinally in an appropriate rodent model. The overall goal of this project is to explore the relationship between CKD and CVD in mice, and investigate whether a cell-based regenerative medicine therapy (RMT) capable of ameliorating kidney injury, also has potential to improve cardiac health. A further goal will be to establish whether any improvement in renal and/or cardiac health is associated with homing of the cell-based RMT to the sites of tissue damage in the kidneys and heart.

The project comprises the following key aims:

The first aim is to investigate how CKD affects cardiac function. To this end, after CKD has been established in mice, magnetic resonance imaging (MRI) of the heart will be undertaken in the same animals to determine the relationship between CKD and CVD. Key objectives will be to determine whether there is a linear relationship between declining renal function and deteriorating cardiovascular health, or whether deterioration in cardiovascular health only becomes manifest when renal function declines by a specific amount (e.g., 50%).

The second aim is to administer a cell-based regenerative medicine therapy (RMT) that is known to ameliorate renal injury, and see whether this can improve or prevent further decline in cardiovascular health.

The third aim is to establish the biodistribution of the administered cells using non-invasive imaging techniques to determine whether they home to the kidneys and/or the heart. This work will be undertaken in collaboration with the SME Nano Biosols. In brief, a nanoprobe for labelling the administered cells will be developed so that their biodistribution can be monitored using a newly installed state-of-the-art imaging platform comprising positron-emission-tomography (PET).

The studentship will provide comprehensive training in (i) non-invasive in vivo imaging techniques, with particular focus on multispectral optoacoustic tomography (MSOT) and MRI for respective monitoring of renal and cardiac function; (ii) whole animal cardio-renal physiology and pathology; (iii) stem cells and regenerative medicine biology; and (iv) in vivo cell tracking. The project will primarily be under the supervision of Murray (primary supervisor) http://liverpoolmrcsdf.uk/SponsorProfiles/RegenerativeMedicine/PatriciaMurray.html, Poptani and Wilm (third and fourth supervisors). Secondments will be undertaken at the Leeds Institute of Cardiovasular and Metabolic Medicine at the University of Leeds under the supervision of Schneider (second supervisor) https://medicinehealth.leeds.ac.uk/medicine/staff/3054/professor-jurgen-e-schneider. In Leeds, the student will learn how to perform cardiac MRI. When the student has become competent in this technique, with the support of the Liverpool supervisors, s/he will set up the cardiac MRI protocols in Liverpool to monitor cardiac function in mice with CKD. Training in nanoparticle synthesis will be provided by Nano Biosols.

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Fully funded by the MRC for 3.5yrs, including a minimum of 3 months working within the industry partner. Enhanced stipend, tuition fees and budget for consumables, travel and subsistence.
Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website
Good luck.

References

Wech T, Seiberlich N, Schindele A, Grau V, Diffley L, Gyngell ML, Borzi A, Kostler H, Schneider JE (2016). Development of Real-Time Magnetic Resonance Imaging of Mouse Hearts at 9.4 Tesla- Simulations and First Application. IEEE Trans Med Imaging 35:912-920

Santeramo I, Herrera Perez Z, Illera A, Taylor A, Kenny S, Murray P*, Wilm B*, Gretz N* (2017). Human Kidney-Derived Cells Ameliorate Acute Kidney Injury Without Engrafting Into Renal Tissue. Stem Cells Transl Med 6(5):1373-1384. (DOI: 10.1002/sctm.16-0352)

Sharkey J, Ressel L, Brillant N, Scarfe L, Wilm B, Park BK, Murray P (2019) A Noninvasive Imaging Toolbox Indicates Limited Therapeutic Potential of Conditionally Activated Macrophages in a Mouse Model of Multiple Organ Dysfunction. Stem Cells International
https://doi.org/10.1155/2019/7386954

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