Function of GPR35 in inflammation (360G-Wellcome-103077_Z_13_Z)

G-protein-coupled-receptors play a major role in inflammation. Pepducins, short peptides coupled with a lipid moiety consciously designed towards the intracellular loops of GPCRs, are a novel approach for modulating GPCRs. They have both, utility for probing GPCR function and for developing novel therapeutics. GPR35, a receptor of unknown function, is activated by kynurenic acid, an end-product of L-tryptophan catabolism and 2-acyl-lysophosphatidic acid. Polymorphisms in GPR35 confer risk for ulcerative colitis and primary sclerosing cholangitis as revealed by genome-wide-association-studies. This proposal intends to address the role of GPR35 in inflammation. It rests on four major pillars: (1) Elucidation of GPR35 signal transduction and downstream biological consequences of receptor ligation. This will include the development GPR35-specific pepducins for the functional study of the receptor, and as novel therapeutics. (2) Interrogation of the role of GPR35 in inflammatory conditi ons in vivo. (3) Investigating the mechanistic consequences of the UC/PSC-associated GPR35 risk variant, through engineered variants, and in cells obtained from individuals with known GPR35 risk allelic status. (4) Investigation whether the pepducin strategy can be extended to pharmacologically correct altered GPCR function arising from genetic variants of GPR35. This may reveal novel precision medicines that target specific genetic variants.