About the Project
Chronic pain is a major health problem worldwide and is especially prevalent in ageing populations. Pain is a complex phenotype as a consequence of the multiple pathways involved in initiating and propagating the pain response. However, the molecular mechanisms of these pathways are largely unclear. Further, one of the longest standing mysteries in defence is how some chemicals, especially riot control agents, interact with the human nervous system to cause irritation (including pain sensation). Understanding the molecular mechanisms behind these responses will give a clearer insight into how to accelerate the development of novel pain-relieving drugs, and how to protect humans from irritant chemicals.
A major mechanism of pain initiation is thought to involve stimulation of the promiscuous ion channel hTRPA1. Work to identify novel treatments countering hTRPA1 stimulation is currently hindered by the lack of mechanistic information on how chemicals (and indeed other stimulants) induce channel activation. Given that hTRPA1 can be activated by multiple stimulants, there are likely many mechanisms underpinning channel activation. Mechanisms of activation by electrophilic compounds (e.g. CS tear gas) likely involve reactions with nucleophilic residues on hTRPA1 (cysteine/lysine); however, it is unclear which residues are susceptible to modification (and indeed whether all reactive irritants react at the same sites), and also how these modifications facilitate ion influx. The proposed project aims to address these issues by characterising the structures of hTRPA1 electrophile adducts and the mechanisms by which such reactions activate the channel, using chemical, biochemical and biological techniques.
Throughout the project, the student will receive extensive supervision and support from researchers in the Department of Chemistry in Oxford and at the Defence Science and Technology Laboratory (Dstl), based at Porton Down. In Oxford, the student will undertake synthesis and characterisation of known/potential hTRPA1 stimulants (small molecule electrophiles), as well as (bio)chemical and structural analyses of their reactions with nucleophilic amino acids (proof of principle studies) and recombinantly expressed hTRPA1. During this work, the student will receive training in a variety of synthetic chemistry, biochemical and spectroscopic techniques (e.g. nuclear magnetic resonance spectroscopy, mass spectrometry, infra-red spectroscopy, small molecule and protein X-ray crystallography, circular dichroism, differential scanning fluorimetry, isothermal titration calorimetry), and recombinant protein expression and purification. At Dstl, the student will assess the ability of their synthesised compounds to stimulate hTRPA1 in human cells using fluorescent-based and patch-clamping approaches, for which the student will receive training and supervision, as well as help with interpreting structure-activity data using appropriate software and statistical packages. It is expected that the student will spend at least 6 months of their studies at Dstl.
This project is supported through the Oxford Interdisciplinary Bioscience Doctoral Training Partnership (DTP) BBSRC Industrial CASE (iCASE) studentship programme. The student recruited to this project will join a cohort of students enrolled in the DTP’s interdisciplinary training programme, and will be able to take full advantage of the training and networking opportunities available through the DTP. For further details please visit http://www.biodtp.ox.ac.uk.
Prospective applicants should contact the project supervisor Professor Chris Schofield ([Email Address Removed]) prior to submitting an application.
Applications for this project will be made via the Oxford Interdisciplinary Bioscience DTP. For further details please visit http://www.biodtp.ox.ac.uk.
Funding Notes
The student will not require prior research training but must have a keen interest in learning chemical, biochemical and biological research techniques and applying them to investigate biological questions.
Academic criteria: First/Upper Second Class honours degree, or equivalent. Applicants with a Lower Second Class degree will be considered if they have a Master’s degree or at least 3 years full-time equivalent relevant postgraduate work experience.
To be eligible for this studentship, you must either be a UK citizen or a European Union national who has been resident in the UK for at least 3 years prior to starting the degree.
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