Wellcome Trust Clinical PhD Programme at the University of Oxford: 'The role of the G-protein subunit Galpha11, in the regulation of calcium homeostasis. (360G-Wellcome-097099_Z_11_Z)

G-protein coupled receptors (GPCRs) play a central role in facilitating cellular responses to diverse extracellular stimuli such as ions, metabolites and hormones. Moreover, GPCR mutations result in diseases that include tumour development and endocrine dysregulation. One such GPCR is the calcium-sensing receptor (CaSR), mutations of which cause familial benign hypocalciuric hypercalcaemia (FBHH) and parathyroid tumours. However, only approximately 65%of FBHH patients harbour CaSR mutations. GPCRs signal through association withheterotrimeric G-proteins that consist of alpha, beta and gamma subunits, and the CaSR specifically signals via Galphaq/11, Galphai and Galpha12/13. Professor Thakker's group therefore postulated that FBHH patients without CaSRmutations may have mutations in these downstream heterotrimeric G-proteins andidentified Galpha11 mutations in FBHH patients. My key goal is to determine the role of Galpha11 in the CaSR signalling pathway and in calcium homeostasisby: 1) Characterising the in vitro effects, by transient transfection assays, of the Galpha11 mutations in the CaSR signalling pathway. 2) Determining the in vivo role of Galpha11 and its mutants by investigating wild-type and established N-ethyl-N-nitrosurea (ENU) mutant Galpha11 mice. 3) Undertaking pharmacological studies using Galpha11 inhibitors and targeted peptides to determine their in vitro and in vivo modulatory effects.