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Purinergic transmission in the carotid body: a potential novel strategy to control high blood pressure

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  • Full or part time
    Prof Paton
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

High blood pressure or hypertension is the world’s biggest killer, it affects 1 in 4 humans and continues to rise. Treating patients with hypertension costs the NHS in excess of £2billion per year. Despite the armoury of anti-hypertensive medications, there remains a huge unmet clinical need based on: (i) resistance and intolerance to present medication; (ii) non-compliance with current drugs due to their side-effects. The latter is compounded by the fact that hypertension is asymptomatic. Recently, in a pre-clinical animal model we discovered that a driver of both the hypertension and elevated vasomotor sympathetic nervous activity was the carotid body (McBryde et al. 2003; Paton et al. 2013). Based on this, we have performed a clinical trial in humans (e.g. Niewinski et al. 2013) with drug-resistant hypertension and found that removal of one carotid body lowers blood pressure. We are now searching for novel druggable targets within the carotid body that may allow us to control blood pressure in humans using novel pharmacological agents. To this end, we are using RNA sequencing to understand the changes that occur within both the carotid body and sensory neurones mediating peripheral chemosensitivity. We are particularly interested in ligand gated ion channels and G-protein coupled receptors. From these studies, we are exploring novel targets (e.g. purinergic antagonists to block P2X receptor sub-types within the carotid body; Ford et al. 2015) in pre-clinical animal models. Regarding the P2X receptors, some subtypes overexpress on primary sensory neurones during pathological conditions (Abdulqawi et al. 2015). This work is being translated to humans where we are using FDA approved and re-purposed drugs allowing us to perform first into man proof of principle trials in patients with high blood pressure. Numerous PhD projects are available based on the pre-clinical studies with animal models as well as our first-into-man clinical trials.

Funding Notes

This project is a self-funded project so you will to obtain your own funding. Although it states 'Applications accepted all year round' we do encourage that the course commences either in January, April, July or September

To apply you need to choose: Faculty of Biomedical Sciences under the ’Faculty’ section, School of Physiology and Pharmacolgy (PhD) under the ’programme choice’ section. Additionally under the ’Research Details’ section, please indicate that you are applying for a self funded project and give the project title and names of supervisors.

References

Abdulqawi R, Dockry R, Holt K, Layton G, McCarthy BG, Ford AP, Smith JA. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2015 385, 1198-205.

Ford AP, Undem BJ, Birder LA, Grundy D, Pijacka W, Paton JF. P2X3 receptors and sensitization of autonomic reflexes. Auton Neurosci. 2015; 191, 16-24.

McBryde FD, Abdala AP, Hendy EB, Pijacka W, Marvar P, Moraes DJ, Sobotka PA, PatonJF. The carotid body as a putative therapeutic target for the treatment of neurogenic hypertension. Nat Commun. 2013; 4, 2395. doi: 10.1038/ncomms3395.

Niewiński P, Janczak D, Rucinski A, Jazwiec P, Sobotka PA, Engelman ZJ, Fudim M, Tubek S, Jankowska EA, Banasiak W, Hart EC, Paton JF, Ponikowski P. Carotid body removal for treatment of chronic systolic heart failure. Int J Cardiol. 2013;168, 2506-9.

Paton JF, Sobotka PA, Fudim M, Engelman ZJ, Hart EC, McBryde FD, Abdala AP, Marina N, Gourine AV, Lobo M, Patel N, Burchell A, Ratcliffe L, Nightingale A. The carotid body as a therapeutic target for the treatment of sympathetically mediated diseases. Hypertension, 2013; 61, 5-13.

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