Investigation of the interplay between TRPV1 channels and the receptor tyrosine kinase Flt3 in living cells

About the Project

Transient Receptor Potential (TRP) channels are a large and conserved family of ion channels that sense touch, movement, pain and temperature1. Dysfunction of TRP channels has been implicated in numerous disease states, including pain, inflammation, central nervous system (CNS) dysfunction and pulmonary and metabolic disorders2. The importance of TRP channels is further highlighted by the award of the 2021 Nobel Prize in Physiology or Medicine for their discovery3, 4.

Currently unpublished work by Dr Sanchez has investigated an additional role of TRP channels and shown that TRPV1 activation by capsaicin (the pungent component of chilli peppers) modulates some membrane bound G protein-coupled receptors (GPCRs) by altering their ability to traffic throughout the cells. Such impact in the localisation and pharmacology of the largest drug target family is likely to have a profound impact in health and disease. In addition, TRPV1 channels have been shown to interact with intracellular kinases such as Src5, however evidence of a direct physical interaction with another family of membrane proteins, receptor tyrosine kinases (RTKs), is currently unclear.

This PhD project will investigate potential interactions or modulation of TRPV channels by FMS-like tyrosine kinase 3 (Flt-3), a RTK implicated in pain.

Previous observations have suggested potentiation of TRPVI responses to capsaicin by the FLT-3 ligand FL, alongside signalling convergence following independent ligand activation of TRPVI or FLT-3 at the level of downstream signalling mediators like PI3K.

This studentship will use a combination of NanoLuciferase bioluminescence resonance energy transfer (NanoBRET), downstream signalling assays, CRISPR/Cas9 gene editing and imaging initially in model cell systems to investigate the potential interactions of TRPV1 and Flt-3 in living cells using full length proteins. The potential pharmacological consequences of any interaction would then be investigated in a pain context using sensory neurons.

The student would supervised by Dr Julie Sanchez and Dr Laura Kilpatrick in the School of Pharmacy at the University of Nottingham (ranked 12th in the World QS Rankings). The student would also become a member of the Centre of Membrane Proteins and Receptors (COMPARE) a joint initiative between the Universities of Nottingham and Birmingham https://www.birmingham-nottingham.ac.uk/compare/. The University of Nottingham ranks ranked 97th in the 2026 QS world ranking and

7th in the UK for Research Power (Research Excellence Framework 2021) with 90% of our research classed as "world-leading" (4*) or "internationally excellent" (3*) with research collaborations both nationally and internationally.

This studentship is open to self-funded students only who have secured or intend to seek sponsorship or other independent means to cover fees, living and research expenses. Excellent written and oral English language skills are essential. Applicants should hold a BSc (minimum award of 2:1 honours degree (or equivalent)) in a molecular cell biology related discipline (biology, biochemistry, pharmacology or similar).

Informal enquiries may be directed to laura.kilpatrick@nottingham.ac.uk

References

1. Vangeel, L. and T. Voets Cold Spring Harb Perspect Biol (2019) 11(6).

2. Yue, L. and H. Xu J Cell Sci (2021) 134(13).

3. Cheng, Y. IUCrJ (2022) 9(Pt 1): p. 4-5.

4. Earley, S., L.F. Santana, and W.J. Lederer Physiol Rev (2022) 102(2): p. 1153-1158.

5. Alessandri-Haber, N., et al. J Neurosci (2008) 28(5): p. 1046-57.