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Using luminescence and fluorescence techniques to characterise the molecular pharmacology of nanobodies targeting the vascular endothelial growth factor receptor 2 (VEGFR2)


School of Pharmacy

Dr Laura Kilpatrick , Prof B Kellam Tuesday, August 31, 2021 Funded PhD Project (UK Students Only)
Nottingham United Kingdom Biochemistry Biomedical Engineering Cancer Biology Pharmacology

About the Project

Applications are welcome for a fully funded 3 year PhD studentship based in the School of Pharmacy at the University of Nottingham co-supervised by Dr Laura Kilpatrick and Professor Barrie Kellam. In the 2014 Research Assessment Exercise, 97% of research undertaken at Nottingham was judged to be of ‘international standard’ with 80 per cent described as ‘world leading’. Additionally the School of Pharmacy was ranked 1st in the UK of all Pharmacy schools for research quality.

Vascular endothelial growth factor (VEGF) promotes the growth of new blood vessels (angiogenesis) by interacting with the vascular endothelial growth factor receptor 2 (VEGFR2) expressed on endothelial cells. Angiogenesis plays a critical role physiologically in wound healing, but also pathologically in conditions such as rheumatoid arthritis, macular degeneration and cancer growth and metastasis. The VEGF/VEGFR signalling axis is therefore a very attractive therapeutic target. A major class of therapeutics that target VEGF/VEGFR are monoclonal antibodies (eg. Avastin), however they often lack long term efficacy and are an expensive treatment option due to their complex production.

Nanobodies are single chain antibodies derived from camelid species such a llamas and alpacas that have huge therapeutic potential. Like conventional monoclonal antibodies, nanobodies can exhibit exquisite target selectivity, however a major advantage is that they are approximately 10 fold smaller (15KDa vs 150KDa for monoclonal antibodies). This makes them easier to produce and more amenable to modification for use as drug delivery devices, diagnostic tools or scientific tools to study endogenously expressed unmodified receptors. 

A panel of nanobodies targeting VEGFR2 have been developed and their sequences are openly available (Ma et al., 2016, Qasemi et al 2016). However their molecular pharmacology has not been fully characterised in respect to whether they bind VEGFR2 exclusively versus binding to other VEGFR subtypes (VEGFR1, VEGFR3), other RTKs (eg. EGFR, PDGFR) or to the co-receptor Neuropilin1. Additionally the mode of binding of these nanobodies has still not been fully determined (eg. are they competitive with VEGF? Do they change the conformation of VEGFR?) or whether they can induce activation of VEGFR2 and subsequent downstream signalling. This project will use medicinal chemistry to label these nanobodies with fluorescent tags. Alternatively luminescent tags will be genetically encoded within the nanobody sequence. Both of these approaches will allow the characterisation of the molecular pharmacology of these nanobodies firstly in model cell systems using overexpressed receptors, before moving into primary human cells (eg. endothelial cells, macrophages) where VEGFR is expressed at native levels. 

This project will provide experience of molecular pharmacology techniques, molecular biology, primary cell culture, confocal/advanced imaging, medicinal chemistry and nanobody purification.

Essential criteria

·        Minimum of 2:1 in first degree and/or a Master’s degree in a relevant subject such as biology/chemistry/pharmacology/biochemistry

Desirable

·        Excellent verbal and written communication skills

·        Some experience in the analysis of pharmacological data

·        Some experience in the molecular pharmacology of membrane bound receptors (eg. RTKs, G protein coupled receptors) 

How to apply

• Visit our how to apply page - https://www.nottingham.ac.uk/pharmacy/study/phd-vacancies/how-to-apply.aspx. Please upload your covering letter, CV, and academic transcripts as part of the online registration process. 

You must refer to the project title within the School of Pharmacy in addition to quoting the supervisor name ‘Laura Kilpatrick’

• Please note that the position will be filled as soon as a suitable person has been found, therefore you are encouraged to apply as soon as possible


References



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