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Determining the structure and function of an endothelial-mesenchymal bridging complex


About This PhD Project

Project Description

Angiogenesis plays a critical role during development and in physiological processes such as wound healing, it is also critically involved in the pathogenesis of diseases including cancer and diabetic retinopathy. Angiogenesis is the formation of vessels from pre-existing vessels and it is mediated by endothelial cells, the cell type that lines all blood vessels. We have identified a cell surface protein, CLEC14A, that is expressed by endothelial cells in the vessels of many different solid tumour types, but is absent from the normal vasculature. This protein is being developed as a target in novel anti-cancer therapies designed to target tumour vessels. Further work by our laboratory has identified an extracellular matrix protein Multimerin 2 (MMRN2), also expressed by endothelial cells, as a ligand for CLEC14A. Interestingly, we have identified that CD93 and CD248, two cell surface proteins related to CLEC14A, are also able to bind MMRN2. CD93 is expressed by endothelial cells while CD248 is expressed by mesenchymal cells including pericytes and fibroblasts. We hypothesise that MMRN2 forms an intercellular bridge linking endothelial cells with pericytes and other stromal cells, and our data suggests that that this complex modulates the angiogenic process. The goals of this project are to characterise the structure and function of the CLEC14A-MMRN2-CD248 complex. Understanding the structure of this complex will facilitate efficient therapeutic targeting of CLEC14A and may uncover new strategies to modulate angiogenesis in a variety of pathologies.

A range of state-of-art methodologies in molecular and cellular biology and biophysics will be used to characterise this complex. The student will spend time at the Universities of Birmingham and Nottingham and the Medical Research Council funded Research Facility at Harwell to undertake this research, benefitting from the different expertise and specialist equipment in each site. The student will learn a range of molecular cloning and protein expression techniques which will enable them to engineer and produce protein. Endothelial cells will be cultured and manipulated to address how the CLEC14A-MMRN2-CD248 complex is regulating signalling and the angiogenic process. A range of biophysical techniques will be used to determine the structure of the CLEC14A-MMRN2-CD248 complex and measure the affinity between the different proteins in the complex.

We strongly encourage informal enquiries ahead of application. Please contact Dr Victoria Heath ().

Person Specification
Applicants should have a strong background in biology and/or biochemistry. They should have a commitment to research in the biomedical sciences and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a biological/ biochemical/ biophysical subject.

References

1 Potente M and Mäkinen T. Vascular heterogeneity and specialization in development and disease. Nat Rev Mol Cell Biol. 2017 18:477-494

2 Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov. 2011 10:417-27

3 Noy PJ, Lodhia P, Khan K, Zhuang X, Ward DG, Verissimo AR, Bacon A, Bicknell R. Blocking CLEC14A-MMRN2 binding inhibits sprouting angiogenesis and tumour growth. Oncogene. 2015 34:5821-31

4 Khan KA, Naylor AJ, Khan A, Noy PJ, Mambretti M, Lodhia P, Athwal J, Korzystka A, Buckley CD, Willcox BE, Mohammed F, Bicknell R. Multimerin-2 is a ligand for group 14 family C-type lectins CLEC14A, CD93 and CD248 spanning the endothelial pericyte interface. Oncogene. 2017 36:6097-6108

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