The G protein-coupled receptor GPR35 in cardiovascular disease: downstream signalling, functional selectivity and potential as a therapeutic target (360G-Wellcome-099787_Z_12_A)

G protein-coupled receptors transduce extracellular signals to cytoplasmic G proteins and other adapters. G protein-coupled receptor 35 (GPR35) has been associated with various diseases, including cardiovascular disorders such as hypertension, coronary artery disease and heart failure; however GPR35 is still poorly characterised and its precise role in disease remains unclear. The project will investigate the role of GPR35 in cardiovascular disease by addressing four key goals: Develop tools for the study of GPR35 activation. GPR35 and phospho GPR35 antibodies and G protein and arrestin selective GPR35 mutants will be generated. Determine the pathophysiological effects of GPR35 on the cardiovascular system. In vitro models of various cellular cardiovascular components will be used to assess migration, proliferation and hypertrophy in response to GPR35 modulation. The pathophysiological consequences of GPR35 modulation will be studied in vivo in a rat model of hypertension. Characterise a GPR35 knockout mouse. Blood pressure, vascular resistance andend-organ damage will be assessed in GPR35-deficient mice under basal conditions and following challenge with a range of pathological stimuli. Assess the role of G protein and arrestin dependent signalling pathways. Signalling downstream of GPR35 activation will be studied in cells expressing wild type receptor or G protein and arrestin-selective mutants.