Cardiovascular disease (CVD) is the leading cause of morbidity and 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, cardiac MRI 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 macrophages will be developed so that their biodistribution can be monitored using a newly installed state-of-the-art imaging platform comprising computed tomography (CT), positron-emission-tomography (PET) and single-photon-emission-computed tomography (SPECT).
The studentship will provide comprehensive training in non-invasive in vivo imaging techniques, with particular focus on multispectral optoacoustic tomography (MSOT) and MRI for respective monitoring of renal and cardiac function; whole animal cardio-renal physiology and pathology; stem cells and regenerative medicine biology; and in vivo cell tracking. The project will primarily be based in the Centre for Preclinical Imaging at the University of Liverpool (https://www.liverpool.ac.uk/translational-medicine/research/centre-for-preclinical-imaging/
) under the supervision of Murray (primary supervisor), 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 (https://medhealth.leeds.ac.uk/info/557/division_of_biomedical_imaging/
) under the supervision of Schneider (second supervisor). In Leeds, the student will learn how to perform cardiac MRI. When the student has become competent in this technique, with the support of supervisors 2 and 3, 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: https://www.nanobiosols.com/
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/
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)
*Joint senior authors
Scarfe L et al…Poptani H, Park BK, Murray P, Wilm B (2018). Non-invasive imaging reveals conditions that impact distribution and persistence of cells after in vivo administration. Stem Cell Research & Therapy 9:332 https://doi.org/10.1186/s13287-018-1076-x