Project

Characterisation of novel clinical targets for treating pulmonary vascular disease

Supervisor(s)

Area

Cardiovascular, pulmonary arteries, vasoconstriction, signalling mechanisms

Description

Oxygen enters our bodies by passing from the lungs into blood vessels that carry blood to and from the lungs. In healthy people the pulmonary arteries that carry blood to the lungs are normally relaxed, with a wide diameter, which maximises delivery of blood to the lungs. This is not the case, however, in disorders such as pulmonary arterial hypertension and chronic obstructive pulmonary disease, where the arteries are chronically constricted and narrow. This lowers delivery of blood to the lungs, leading to less oxygen being absorbed from the air into the body. Unsurprisingly, patients have a reduced quality of life, suffering from symptoms such as tiredness, oedema and dyspnoea associated with exertion. Unfortunately, the therapeutic options available at present for treatment of pulmonary vascular disorders are limited and so the prognosis is poor, with patients suffering an early death.

It is a clear that we must identify new therapeutic targets before treatment of pulmonary vascular disorders can improve. In this project we will characterise novel clinical targets, such as P2X and P2Y receptors, which are implicated in the control of pulmonary arterial blood flow under physiological and pathophysiological conditions. We will study these targets in animal models of pulmonary vascular disease and also in human tissue, in collaboration with Dr. Colin Church, a consultant in the Scottish Pulmonary Vascular Unit at the Golden Jubilee National Hospital in Glasgow. The data generated will help identify will help in the development of new treatments for pulmonary disease and so ultimately improve human health.

Techniques

During the project you will be taught myography in order to measure muscle tone in isolated pulmonary arteries. Ca²⁺ imaging, patch clamp electrophysiology and western blotting techniques will be used to further characterise the action of drugs that act on the arteries. These are powerful experimental tools on which to build a career and using these cutting-edge techniques, you will advance the search for new, effective drugs for the treatment of pulmonary vascular disease.

References

Baliga, R.S., MacAllister, R.J., Hobbs, A.J. (2011). New perspectives for the treatment of pulmonary hypertension. Br. J. Pharmacol., 163, 125-140.

Chootip, K., Ness, K.F., Wang, Y., Gurney, A.M. & Kennedy, C. (2002). Regional variation in P2 receptor expression in the rat pulmonary arterial circulation. Br. J. Pharmacol., 137, 637-646.

Chootip, K., Gurney, A.M. & Kennedy, C. (2005). Multiple P2Y receptors couple to calcium-dependent, chloride channels in smooth muscle cells of rat pulmonary artery. Resp. Res., 6:124.

Kennedy, C. (2013). The importance of drug discovery for treatment of cardiovascular diseases. Future Med. Chem., 5, 355-357.

Kennedy, C., Chootip, K., Mitchell, C., Syed, N.H. and Tengah, A. (2013). P2X and P2Y nucleotide receptors as targets in cardiovascular disease. Future Med. Chem., 5, 431-439.

Mitchell, C., Syed, N.H., Gurney, A.M. & Kennedy. C. (2012). A Ca²⁺-dependent chloride current and Ca²⁺ influx via Ca_v1.2 ion channels play major roles in P2Y receptor-mediated pulmonary vasoconstriction. British J. Pharmacol., 166, 1503-1512.

Mitchell, C., Syed, N.H., Tengah, A., Gurney, A.M. & Kennedy. C. (2012). Identification of contractile P2Y₁, P2Y₆ and P2Y₁₂ receptors in rat intrapulmonary artery using selective ligands. J. Pharmacol. Exp. Therap., 343, 755-762.

Syed, N.H., Tengah, A., Paul, A. & Kennedy, C. (2010).Characterisation of P2X receptors expressed in rat pulmonary arteries. European J. Pharmacol., 649, 342-348.