4-year PhD Studentship: Endothelial glycocalyx damage as a therapeutic target in cardiopulmonary bypass associated acute kidney injury at University of Bristol on FindAPhD.com

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Dr R Ramnath, Prof Simon Satchell, Prof GD Angelini, Dr Rebecca Foster No more applications being accepted Self-Funded PhD Students Only

Bristol United Kingdom Biological Sciences

About the Project

Patients undergoing cardiopulmonary bypass (CPB) often develop acute kidney injury (AKI) caused by myocardial ischemia reperfusion injury (MIRI). This is associated with high mortality and post operative costs-of-care.(1) The exact mechanism by which CPB leads to AKI development is not fully understood, although evidence is starting to emerge that endothelial glycocalyx is damaged in CPB.

Endothelial glycocalyx (EGLX),(2-4) strategically situated at the interface between the bloodstream and the endothelium, is the frontline regulator of numerous physiological functions, including vascular permeability, inflammatory, coagulation and shear stress-mediated responses. EGLX damage has been implicated in a diverse range of diseases including atherosclerosis and kidney diseases.(3-6)

EGLX damage has been observed in patients undergoing CPB.(7-10) Its degradation reduces the production of nitric oxide(11) and is associated with reduced perfusion of the blood vessels. EGLX degradation also correlates with microcirculation perfusion disorders in patients during cardiac surgery.(8)

We have identified a novel mechanism, matrix metalloproteinases (MMP) 9 mediated EGLX damage, as a major contributor to glomerular endothelial cell injury and kidney damage in diabetes.(12, 13) MMP9-mediated EGLX damage could be the underlying mechanism of vascular endothelial cell injury in CPB associated AKI.

Aims and objectives

We hypothesise MMP9-mediated EGLX damage is critical in kidney injury and represents a potential novel therapeutic target in CPB-associated AKI.

We propose that MMP9 mediates EGLX damage, disrupting renal and systemic endothelium, resulting in increased vascular permeability and kidney dysfunction. Importantly this is amenable to therapeutic intervention.

Aims

Characterise EGLX damage, MMP activity and kidney injury in a mouse model of MIRI.
Determine whether EGLX protection will reduce the severity of kidney injury.
Confirm relevance of EGLX loss in human diseases.

This proposal will identify EGLX protection as a novel therapeutic target for patients with CPB-associated AKI.

Methodology

Aim 1 will be determined in a mouse model of MIRI.(1) EGLX damage on renal endothelium will be assessed by transmission electron microscopy, as shown previously.(12) Systemic GLX shedding will be quantified by measuring circulating GLX components, by ELISA.(12, 13) The activity of MMPs and its endogenous inhibitors, tissue inhibitor of MMPs (TIMPs), will be quantified by activity assay and ELISA respectively.(12) AKI will be confirmed by elevated serum creatinine and glomerular filtration rate.(14)

Aim 2 will use transgenic MMP9KO mice, deficient in MMP9, to confirm the specific role of MMP9 in MIRI. Furthermore, a recombinant TIMP will be injected intraperitoneally in MIRI mice to show that increasing the MMPs’ endogenous inhibitor is a clinically relevant approach.

Aim 3 will determine circulating EGLX components, MMPs and TIMPs in plasma from patients who have undergone CPB. The effects of the circulating components will be determined on renal endothelial cell lines (in vitro)13 and on isolated mouse glomeruli using our novel ex vivo glomerular albumin permeability assay.12 EGLX loss will be confirmed in human myocardial biopsy following CPB, by our novel peak to peak measurement, as shown previously.(12, 15)

How to apply for this project

This project will be based in Bristol Medical School - Translational Health Sciences in the Faculty of Health Sciences at the University of Bristol.

Please visit the Faculty of Health Sciences website for details of how to apply

Funding Notes

This project is open for University of Bristol PGR scholarship applications (closing date 25th February 2022)
The University of Bristol PGR scholarship pays tuition fees and a maintenance stipend (at the minimum UKRI rate) for the duration of a PhD (typically three years but can be up to four years).

References

1.Tang C, et al. Life Sci 2020; 257: 118004.
2.Reitsma S, et al. Pflugers Arch 2007; 454: 345.
3.Salmon AH, et al. J Pathol 2012; 226: 562.
4.Satchell S. Nat Rev Nephrol 2013; 9: 717.
5.Rabelink TJ, et al. Nat Rev Nephrol 2015; 11: 667.
6.Butler MJ, et al. Am J Pathol 2020; 190: 742.
7.Robich M, et al. J Surg Res 2020; 251: 287.
8.Wu Q, et al. Microvasc Res 2019; 124: 37.
9.Bruegger D, et al. J Thorac Cardiovasc Surg 2009; 138: 1445.
10.Rehm M, et al. Circulation 2007; 116: 1896.
11.Bartosch AMW, et al. Biophys J 2017; 113: 101.
12.Ramnath RD, et al. Kidney Int 2020; 97: 951.
13.Ramnath R, et al. FASEB J 2014; 28: 4686.
14.Oltean S, et al. J Am Soc Nephrol 2015; 26: 1889.
15.Butler MJ, et al. Kidney Int 2019; 95: 94.

Where will I study?

University of Bristol

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