Activated phosphoinositide 3-kinase, short PI3K, phosphorylates the membrane lipid phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) to generate the lipid second messenger, PI-3,4,5-P3 (PIP3). Regulating multiple important processes (survival, metabolism, migration etc) in health and disease, PI3K is one of the major regulators of all cells, and is frequently mutated in cancer. Major insights into PI3K function and regulation were gained in the last 30 years or so due to concerted efforts by many labs, e.g. using genetic models or isotype specific inhibitors. Despite this, detecting PIP3 remains challenging. Only few labs are able to measure PIP3 directly in a quantitative fashion. Detecting the site of PIP3 production can be achieved using genetically encoded fluorescent reporters which consist of a fluorescent protein fused to a PIP3 binding domain. These reporters are typically cytosolic and their translocation to the plasma membrane is being detected upon PI3K stimulation; signal analysis is hampered by the fluorescent background and reporter use is restricted to cells that are amenable to genetic modification. Alternatively, PIP3-specific antibodies are used to label PIP3 in fixed cells. The latter approach has suggested the existence of pools of PIP3 that do not localise to the plasma membrane. These may not be detected, or are not easily noticed due to background when using fluorescent PIP3 reporters.
This PhD project aims to generate a collection of fluorescent smartprobes for direct detection of PIP3 in live cells. We will prepare collections of peptides that will include activatable fluorophores to identify new cell-permeable PIP3-specific peptides that will only emit a fluorescent signal once it interacts with PIP3. The resulting smartprobes will have improved signal-to-noise-ratios over existing genetically encoded PIP3 reporters. By joining an interdisciplinary collaboration of chemists, biochemists and biologists, this project will combine cutting edge probe design involving organic and peptide chemistry with the design of biological assays to validate the specificity of candidate probes, ensuring target specificity in vitro and in vivo. The supervisory team reflects the interdisciplinary nature of the project, with 50:50 supervision by Dr Vermeren, expert in PI3K biology and Professor Vendrell, expert in the generation of fluorescent probes. The student will join both labs and effectively become a member of both teams. The project would suit a student with a background in chemistry, biochemistry or biotechnology who is keen to undertake an exciting interdisciplinary project at the cutting edge of science.
Funding information and Application Process:
This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership (DTP)
This opportunity is open to UK and international students and provides funding to cover stipend and UK level tuition fees. The University of Edinburgh will cover the difference between home and international fees meaning that the EASTBIO DTP will offer fully-funded studentships to all appointees. However there is a cap on the number of international students the DTP can recruit. It is therefore important for us to know from the outset which fees status category applicants will fall under when formally applying for entry to our university.
Please refer to UKRI and Annex B of the UKRI Training Grant Terms and Conditions for full eligibility criteria.
Informal enquiries should be addressed to Dr Vermeren. To apply, please send a cover letter outlining your previous research experience and reasons for applying, alongside an up-to-date CV to [Email Address Removed]
Download and complete our Equality,Diversity and Inclusion survey and then fill in the EASTBIO Application Form and submit it to [Email Address Removed]
Send the EASTBIOReference Form to your two academic/professional referees, and ask them to submit it to [Email Address Removed] before the application deadline.
We anticipate that our first set of interviews will be held 7th – 11th February 2022 with awards made in the following week.
If you have further queries about the application/recruitment process please contact [Email Address Removed]
The research group is located in the University of Edinburgh Centre for Inflammation Research; a world-class research environment at the interface between biological and medical science, with multidisciplinary groupings focused on inflammation, infection, disease and repair. The Centre is based within the Edinburgh Medical School in the outstanding facilities of the Queen’s Medical Research Institute at the site of the Royal Infirmary of Edinburgh hospital, maximising future translational opportunities.
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