EVALUATING THE THERAPEUTIC POTENTIAL OF ORPHAN G-PROTEIN COUPLED RECEPTORS: GPR19 AND GPR17

Abstract

The characterization of orphan GPCRs (oGPCRs), whose endogenous ligand is yet to be identified, offers a chance not only to identify new therapeutic targets but also to understand new signaling mechanisms. Main goal of this thesis was to validate the oGPCR, GPR19 as a candidate drug and to undertake its de-orphanization. Here, GPR19 was found to be dysregulated in breast carcinomas and therefore its role was studied in breast cancer models. In mesenchymal breast cancer cells it was shown to promote the expression of an epithelial phenotype as evinced by the upregulation in E-cadherin expression and changes in functional behavior of the tumor cells. This study validates, adropin as a ligand for GPR19 and also identifies the potential G-protein coupling of GPR19. The work done here also provides evidence for the activation of MAPK/ERK1/2 pathway upon stimulation of GPR19 by adropin. The translational aspect of this thesis looks into the design and generation of mAbs for a validated target, which is oGPCR GPR17.