Translational Medicine and Therapeutics Programme at the University of Cambridge: 'The apelin-ACE-2 axis in cardiopulmonary disease'. (360G-Wellcome-097114_Z_11_Z)

The objective of the project is to test the hypothesis that apelin signalling is altered in PAH and that apelin may be a new mediator and potential new drug target for this condition. Basic and translational research into the pharmacological actions of apelin has been hampered by a lack of selective agonists and antagonists. Two novel molecules have recently been discovered by the group: MM07 an agonist and MM54, a competitive antagonist at the apelin receptor (APJ). This project will focus on identifying the cellular expression of apelin and APJ and measuring APJ densities and pharmacological characteristics in lung and right ventricle from patients with PAH to determine changes in the apelin/APJ system in this disease. Parallel studies will be carried out in heart and lung of the monocrotaline-treated rat to discover if this model reflects the changes in the apelin system in human tissues. I will determine the effects of MM07 and MM54 on progression of PAH in this animal model to identify whether pathway stimulation or blockade improve outcome. In collaboration with Dr I Wilkinson, I plan to perform forearm plethysmography in healthy subjects. If successful, it would be possible, subject to ethics approval, to perform limited studies in PAH patients.