A transgenic approach to the elucidation of the role of the orphan receptor GPR55 in cardiac remodelling induced by metabolic disease

A 4-year MRC Industrial CASE Award Studentship, in collaboration with Astra Zeneca (Sweden) is available to undertake training in advanced in vivo sciences.
Elevated blood glucose and high circulating cholesterol cause damage to the heart resulting in changes in the structure and function of the heart muscle (myocardial fibrosis), resulting in cardiac failure and increased morbidity. A key event in myocardial fibrosis is an imbalance between the synthesis and degradation of extracellular matrix material, in particular collagen. Moreover, the extent of collagen cross-linking determines the elasticity of the extracellular matrix material and is pivotal to determining the contractility of the heart. GPR55 is an orphan receptor activated by endogenous cannabinoid-like ligands. Previous work has demonstrated an influence of endocannabinoids in cardiac fibrosis, however the receptor(s) mediating this effect are unknown. This studentship aims to determine the role of GPR55 in hyperglycaemia and hyperlipidaemia-induced fibrosis using knockout mouse models for these metabolic disorders with an additional gene deletion for GPR55.

By using a double knockout transgenic approach in mice, the project will explore the role of the orphan receptor GPR55 in the development of cardiac dysfunction resulting from hyperlipidaemia and metabolic syndrome. Combined in vivo (non-invasive Doppler echocardiography and the measurement of pressure volume loops; PVL) and histopathological studies will be used to determine the functional and structural characteristics of these diseases in the presence and absence of GPR55. The concurrent use of primary isolated cardiac fibroblasts from these mice will explore alterations in the cellular mechanisms involved in fibrosis and will be used to develop a platform for drug discovery of anti-fibrotic drugs. Finally, complimentary studies using cardiac fibroblasts from patients with hyperlipidaemia and/or metabolic syndrome will be undertaken to establish the mouse model as an appropriate model for human disease.

Candidates should be highly motivated with a strong commitment to academic research. A First Class, or a 2.1 Honours Degree (or equivalent) or a Masters Qualification in a relevant biomedical science discipline is absolutely essential.