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Endothelial glycocalyx as a novel therapeutic target in myocardial and renal ischemia reperfusion injuries


Bristol Medical School

About the Project

Rationale
All the endothelial cells in our body possess a surface glycocalyx (e-GLX)1 which plays a key role in maintaining vascular homeostasis. Although the microvascular endothelial dysfunction is recognised as a key player in the pathophysiology of both myocardial and renal ischaemia and reperfusion injuries (IRI), the e-GLX has been relatively overlooked.

Emerging evidence suggests that the GLX is degraded in the coronary2 and in peritubular vascular beds in response to IRI.3 Metalloproteinases (MMPs) are known to play a key role in the pathogenesis of both myocardial and renal IRI.4 Excitingly, we have identified a novel mechanism, MMP9 mediated e-GLX loss,5 demonstrating that this pathway leads to hyperpermeability in early diabetic kidney disease.6. Taken together, we hypothesise that MMP9-mediated e-GLX loss is critical in IRI and represents a potential novel therapeutic target. We propose that MMP9 mediates shedding of e-GLX, disrupting both the myocardial and renal endothelium. These will result in increased vascular permeability, increased neutrophil transmigration, hemodynamic changes and tissue oedema, all of which contribute to impaired cardiac and renal function. Importantly this is amenable to therapeutic intervention.

Aims & Objectives
1. Characterise MMP-mediated GLX shedding as a mechanism of myocardial and renal endothelial damage in IRI.
2. Determine whether strategies to protect or restore the e-GLX reduce the severity of IRI.
3. Confirm relevance of e-GLX loss in pig and human diseases.

Methods
Aim 1 will be determined in myocardial and renal IRI mouse models.
i) Cardiac and kidney dysfunction will be confirmed by echocardiography and elevated serum creatinine/urea respectively. Microvascular permeability, oedema and neutrophil infiltration will also be determined in those tissues.
ii) Changes in myocardial, renal including tubular morphology will be determined by light microscopy and e-GLX will be measured following transmission electron microscopy and by confocal. Circulating and urinary GLX components will be measured by ELISA to detect GLX shedding.
iii) Composition of GLX will be analysed by ion exchange chromatography to determine the proportions of GLX components.
v) The activity of MMP9, other MMPs and tissue inhibitor of MMPs will be quantified by ELISA activity assays and histology will localise their expressions.

Aim 2. The models and assays described in Aim 1 will be carried out in MMP9KO mice to confirm the specific role of MMP9 in IRI.
Furthermore, a potent MMP9 inhibitor will be given to IRI mice to show that blocking this enzyme is a clinically relevant approach.

Aim 3. E-GLX loss will be confirmed in human and pig biopsies from IRI by our novel peak to peak measurement.

This PhD project will define the role of the microvascular e-GLX in myocardial and renal IRI and so identify novel therapeutic opportunities. In addition, this very interesting project will provide fantastic training opportunities using cutting-edge technologies. These will be carried out in our state-of-the-art facilities. It will also provide opportunities to attend conferences and seminars to present the data. It is anticipated that the results obtained from this project will lead to high impact publications.

References

1.Satchell S. Nat Rev Nephrol. 2013;9:717-25.
2.Rehm M et al. Circulation. 2007;116:1896-906
3.Bongoni AK et al. Transplant Direct. 2019;5:e341.
4.Tan RJ and Liu Y. Am J Physiol Renal Physiol. 2012;302:F1351-61.
5.Ramnath R et al. FASEB J. 2014 Nov;28(11):4686-99
6.Ramnath RD et al. Kidney Int. 2020 May;97(5):951-965

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