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MRC DTPiCASE: Investigating redox signalling regulating angiogenic endothelial function using multicellular 3D-cell models


   School of Life Sciences

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  Dr C Murdoch  No more applications being accepted  Competition Funded PhD Project (European/UK Students Only)

Dundee United Kingdom Biochemistry Bioinformatics Molecular Biology

About the Project

Endothelial dysfunction is the precursor to a variety of diverse diseases including peripheral artery disease, cardiac fibrosis and preeclampsia. Critical risk factors associated with endothelial dysfunction include ageing, obesity and diabetes. Oxidative stress, the cellular imbalance between oxidants and antioxidants is pivotal to endothelial dysfunction and common to these risk factors. In contrast, some oxidants at low levels are involved in physiological signalling, termed redox signalling, where proteins function is altered by oxidative post-translational modifications (oxPTM). We recently linked oxPTMs with regulation of angiogenic factors in ischemia(1). Advances using proteomic and bioinformatic approach have identified redox sensitive proteins involved in endothelial angiogenic pathways, whereby the ox-PTM can act as a redox switch(2). The interaction between endothelium and the extracellular matrix (ECM) is essential for endothelial function, with changes in ECM composition in disease contributes to arterial stiffness and endothelial dysfunction.

This iCASE will aim to investigate how the redox switch can change protein function altering angiogenic potential of endothelial cells in different disease settings. 

This studentship will benefit from secondment with Biogelx a biomaterial company that makes synthetic hydrogel. Biogelx cutting-edge hydrogel technology mimics the ECM by tuning each formulation to match the tissue stiffness in a disease setting, including being used at various stiffness to differentiate iPSC. In addition, incorporating synthetic biomimetic peptide sequences, using ECM components including laminin, collagen and fibronectin, to improve cell interactions. We intend to utilise the Biogelx hydrogel to assess endothelial migration and interaction with varying ECM stiffness and components. To assess endothelial cell migration and tip formation we will use organ-on a chip technology and Biogelx hydrogel to develop 3D-cell organoids. Redox signalling will be deciphered in molecular pathways involved in angiogenic factor release. The studentship will expose the candidate to a variety of cutting-edge multidisciplinary techniques including genetic engineering, organ-on-a-chip technology, stem cells, cardiovascular pathophysiology and proteomics. In addition, collaboration with an industry partner.   Combining these techniques will help improve our ability to model the complex disease in multicellular systems. Gaining a better understanding of redox signalling in endothelial cells related to pathophysiological setting providing a wide spanning expertise in translational research. 

PLEASE NOTE:

Applications for this round of recruitment are open to candidates who meet the following eligibility criteria –

·      Be a UK National (meeting residency requirements), or

·      Have settled status, or

·      Have pre-settled status (meeting residency requirements), or

·      Have indefinite leave to remain or enter

Further information on eligibility and residency requirements can be found in the UKRI Training Grant Terms & Conditions (found here: https://www.ukri.org/wp-content/uploads/2021/03/UKRI-150321-TrainingGrantsTermsConditions-Mar2021.pdf)

and accompanying guidance documentation (found here: https://www.ukri.org/wp-content/uploads/2020/10/UKRI-291020-guidance-to-training-grant-terms-and-conditions.pdf)

 


References

References

1. Watanabe Y, Murdoch CE, Sano S, Ido Y, Bachschmid MM, Cohen RA, et al. Glutathione adducts induced by ischemia and deletion of glutaredoxin-1 stabilize HIF-1α and improve limb revascularization. Proc Natl Acad Sci U S A. 2016;113(21).

2. Lermant, A.; Murdoch, C.E. Cysteine Glutathionylation Acts as a Redox Switch in Endothelial Cells. Antioxidants 2019, 8,
315. https://doi.org/10.3390/antiox8080315

3. Alakpa, E Jayawarna V, Lampel A, et al Tunable Supramolecular Hydrogels for Selection of Lineage-Guiding Metabolites in Stem Cell Cultures, Chem, Volume 1, Issue 2, 2016, Pages 298-319.