Discovery of altered binding and function in mutations in human apelin receptor identified from genomic sequencing of patients with rare diseases (360G-Wellcome-203814_Z_16_A)

Apelin and ELA peptides bind to the apelin receptor on the surface of cells in the cardiovascular system to mediate vascular effects and increase heart contractility. Apelin signalling is implicated in cardiovascular diseases such as pulmonary arterial hypertension (PAH) – a rare disorder that leads to heart failure and death, even when treated with current therapies. Apelin signalling has also been shown to regulate platelets, and may signal in red blood cells (RBCs), implicating apelin in blood disorders. In this project, apelin receptor mutations, identified in patients in the UK 10,000 Genomes BRIDGE project, will be assessed to determine the effect of these mutations on apelin receptor binding with apelin/ELA and cell signalling. In addition, human blood samples from healthy donors and apelin receptor mutant patients will be assessed for platelet and RBC function. Finally, mice that have been genetically engineered to express a selected apelin receptor mutant will be treated with SU 5416 in low oxygen conditions to evaluate the impact of the mutation on development and treatment of pulmonary hypertension. The work in this project will provide important insights into the role of apelin signalling in cardiovascular disease.