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Leaky Blood Vessels and Basement Membranes (Diabetes, Inflammation, Cancer)


   Department of Eye and Vision Science


About the Project

Aberrantly leaky blood vessels are a major problem in multiple disease situation including cancer progression, in stroke and Alzheimer’s disease, and diabetic retinopathy. However, a controlled ability for cells to extravasate from vessels into tissues is also an essential part of inflammatory responses. This PhD project will focus on one of the key aspects in the control of vascular leakiness; the basement membrane.

Basement membranes provide structural support for all endothelial cells, providing a physical barrier between the cells lining the blood vessels and the interstitial matrix. At core of every basement membrane are networks of laminins and type IV collagens. Recently, we discovered using a new transgenic animal model that increased expression of a laminin-related protein called LaNt alpha31 leads to increased vascular leakiness (1). Moreover, we have identified that LaNt alpha31 is upregulated in breast and some other cancer types (2). LaNt alpha31 is a comparatively unstudied protein but the effects it has are really dramatic. This means that there are lots of important questions that would be valuable to answer through research. For example, how, i.e. what mechanism, does LaNt alpha31 regulate vascular permeability, what is its contribution to  regulating normal and pathogenic vascular leakiness, and related questions such as whether targeting LaNt alpha31 or its function could have therapeutic potential.

As there is lots of scope with this project, a student you will be able to shape the direction of research depending on your interests and which skills you would like to develop. Your project could explore the genetic and/or protein regulation and dysregulation in normal, cancer, and diabetic conditions, it could investigate protein function at a biochemistry or cell biology level including advanced imaging approaches such as super-resolution microscopy and advanced 3D tissue models, and/or the studies could use transgenic mouse models to study the protein function in vivo mimicking disease or cancer states. There is even scope to do biomechanical analyses and to use in silico modelling approaches. In whichever direction you wish to develop, you will be supported by a supervisory team and local researchers who are experts in that area. This flexibility also means we can shape your project to fit your funder requirements. 

For enquiries about the opportunity or to enquire about applying please contact Dr Kevin Hamill on:


Funding Notes

This is a self funded opportunity.

References

1. Laminin N-terminus α31 expression during development is lethal and causes widespread tissue-specific defects in a transgenic mouse model. Conor J. Sugden, Valentina Iorio, Lee D. Troughton, Ke Liu, George Bou-Gharios, Kevin J. Hamill. bioRxiv 2020.07.26.221663; doi: https://doi.org/10.1101/2020.07.26.221663
2. Laminin N-terminus α31 is upregulated in invasive ductal breast cancer and changes the mode of tumour invasion Lee D. Troughton, Tobias Zech, Kevin J. Hamill. bioRxiv 2020.05.28.120964; doi: https://doi.org/10.1101/2020.05.28.120964

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