(MRC DTP) Defining the therapeutic role of particulate guanylate cyclases (pGC) in the pathophysiology of heart failure

Heart failure remains a leading cause of mortality and morbidity and is characterised by contractile dysfunction, reduced sensitivity to β-adrenergic stimulation and life-threatening ventricular arrhythmias. There remains a pressing need for novel and effective therapies to treat patients with heart failure as evidenced by survival following a diagnosis of heart failure being worse than many common cancers [1]. In this programme of work, you will investigate the potential of the particulate guanylate cyclase (pGC) pathway to act as a novel therapeutic target in heart failure.

Classically, β-adrenergic stimulation activates G-protein coupled receptors (β1, β2 & β3 receptors); of these β1 and β2 activate adenylyl cyclase leading to the production of cAMP and activation of protein kinase A (PKA) which then increases cardiac contractility, increases heart rate and also accelerates the rate of relaxation of the heart. Many of the steps in the β-adrenergic signalling cascade are perturbed in heart failure [2], thus underpinning much of the contractile dysfunction observed and the rationale for use of β-blockers as first line therapies in heart failure. Conversely, β3 adrenergic receptors activate nitric oxide synthase and soluble guanylate cyclase (sGC) and then signal through the cyclic guanosine monophosphate (cGMP) pathway and protein kinase G (PKG). Conventional wisdom holds that the cGMP/PKG pathway antagonises the cAMP/PKA pathway and activating of PKG is negatively inotropic. However, targeting this pathway to increase PKG signalling is an emerging, paradoxical yet seemingly effective therapy for some forms of heart failure [3]. In addition to via sGC, cGMP can also be produced by pGC which itself is activated by a different set of G-protein coupled receptors including the natriuretic peptide receptors (NPR) with recent data suggests that targeting the pGC pathway could also be beneficial in heart failure [4].

In this PhD you will apply in vivo, cellular and molecular approaches to elucidate the mechanisms by which the pGC pathway functions in the normal heart, how this is altered in heart failure and then if targeting this pathway is a potentially effective therapeutic approach in heart failure. The key objectives are to determine where the cGMP pool produced by pGC acts inside cardiac myocytes, which phosphodiesterases modulate this cGMP pool and how cGMP and PKG activated by pGC then modulate the activity of other cAMP/cGMP pools and cellular processes and how these inter-relationships are altered in heart failure [5].

https://www.research.manchester.ac.uk/portal/Andrew.W.Trafford.html

https://www.research.manchester.ac.uk/portal/katharine.dibb.html


Entry requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.