4-year PhD Studentship: Investigating the regulation of MMP-dependent glycocalyx damage to refine therapeutic targets at University of Bristol on FindAPhD.com

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Dr S Satchell, Dr J Johnson, Dr RR Foster, Dr R Ramnath No more applications being accepted Self-Funded PhD Students Only

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Bristol United Kingdom Biological Sciences

About the Project

Each component of the glomerular filtration barrier (GFB) plays a crucial part. The endothelial glycocalyx (eGlx), a surface covering on the luminal surface of glomerular endothelial cells (GEnC), forms the first layer. The endothelial glycocalyx (eGlx) plays critical roles in health and disease in glomerular and systemic circulations. GEnC glycocalyx damage contributes to albuminuria and hence to progressive glomerular dysfunction.

The matrix metalloproteinases (MMPs) 2&9 cleave glycocalyx components from the surface of endothelial cells and are elevated in various diseases, including diabetes, where glycocalyx damage is a feature. Preventing MMP upregulation or inhibiting MMP activity is therefore an attractive therapeutic target. However, how MMPs are dysregulated to cause eGlx damage is not known. The objective of this project is to characterise the dysregulation of eGlx-damaging MMPs in glomerular endothelial cells (GEnC).

We have identified MMP14, heparanase and TIMPs as key candidate MMP-regulators. Activation of eGlx-damaging MMPs occurs in response to specific disease-related stimuli. We will use this fact, with human GEnC in vitro and a transcriptomic approach, to confirm expression changes in candidate regulators whilst discovering additional common upstream regulators of MMP2&9 activity.

Aims and objectives

The hypothesis is that defining the role and regulation of MMPs in eGlx shedding will identify potential targets for therapeutic intervention.

The purpose of the project is to characterise the dysregulation of eGlx-damaging MMPs in glomerular endothelial cells (GEnC).

The aims are as follows

Define the dysregulation of novel and pre-selected candidate regulators of eGlx-damaging MMPs.
Confirm that changes in identified regulators above are also present in vivo.
Demonstrate the functional importance of changes in candidate and novel MMP regulators

Methodology

1 Define the dysregulation of novel and pre-selected candidate regulators of eGlx-damaging MMPs.

By examining activation of MMPs in response to specific disease-related stimuli we will confirm the importance of candidate regulators (MMP14, heparanase and TIMPs) and discover novel regulators. We will use immortalised human GEnC which we have previously shown to provide a good model for study of eGlx damage. We will expose GEnC to specific disease stimuli (TNF, oxidative stress, RAAS activation) already known to lead to MMP 2&9 activation. We will use transcriptomics (RNAseq and bioinformatics) to investigate changes in candidate regulators and identify additional potential MMP regulators.

2 Confirm that changes in identified regulators above are also present in vivo.

We will confirm dysregulation of candidate and novel MMP regulators in GEnC in vivo using mouse models of renin angiotensin aldosterone (RAAS) activation and diabetes. We will confirm key findings in human samples.

3 Demonstrate the functional importance of changes in candidate and novel MMP regulators

We will demonstrate the functional importance of changes in expression of candidate and novel regulators in terms of MMP2&9 activity and eGlx integrity, using GEnC in vitro for mechanistic studies with chemical/genetic inhibition/stimulation.

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. Butler MJ, Down CJ, Foster RR, Satchell SC. The pathological relevance of increased endothelial glycocalyx permeability. Am J Pathol. 2020;190(4):742-751.
2. Ramnath RD, Butler MJ, Newman G, Desideri S, Russell A, Lay AC, Neal CR, Qiu Y, Fawaz S, Onions KL, Gamez M, Crompton M, Michie C, Finch N, Coward RJ, Welsh GI, Foster RR, Satchell SC. Blocking matrix metalloproteinase-mediated syndecan-4 shedding restores the endothelial glycocalyx and glomerular filtration barrier function in early diabetic kidney disease. Kidney Int. 2020;97(5):951-65.
3. Butler MJ, Ramnath R, Kadoya H, Desposito D, Riquier-Brison A, Ferguson JK, Onions KL, Ogier AS, ElHegni H, Coward RJ, Welsh GI, Foster RR, Peti-Peterdi J, Satchell SC. Aldosterone induces albuminuria via matrix metalloproteinase-dependent damage of the endothelial glycocalyx. Kidney Int. 2019;95(1):94-107.
4. Crompton M, Ferguson JK, Ramnath RD, Onions KL, Ogier AS, Down CJ, Skinner L, Dixon LK, Sutak J, Harper SJ, Pontrelli P, Gesualdo L, Welsh GI, Foster RR, Satchell SC, Butler MB. Early mineralocorticoid receptor antagonism in diabetic nephropathy limits albuminuria by preserving the glomerular endothelial glycocalyx. medRxiv. 2021. doi.org/10.1101/2021.05.13.21252519