Biased ligands and allosteric modulators of G protein-coupled receptors: novel approaches for treating inflammatory diseases

Phagocyte activation are critical determinants of effective host defense, but their activation has to be tightlyregulated to reduce collateral tissue damage during inflammation.

Recent research has uncovered importantroles of the formyl peptide receptors and free fatty acid receptors (the FPRs and the FFARs; belonging to the GPCR family) in immune regulation and inflammation resolution.

The planned research to indepth elucidate the regulatory roles in innate immunity and inflammation of and to explore the emerging novel concepts of receptor functional selectivity and allosteric modulation that have opened new avenue in GPCR-based drug discovery.

The specific aims of this project are to identify novel drug-like molecules and to elucidate the molecular basis of FPR and FFAR signaling and activation, and to define the role of FPRs and FFARs in regulation of phagocyte functions and pathological inflammatory resolution.

The role of the FPRs and FFARs will be determined through studies of isolated human blood and tissue-derived neutrophils and in murine models of inflammation and inflammatory diseases.

The new results generated in the project will hopefully help in elucidating the pathogenesis of inflammatory disease and a detailed understanding of the structure-function relationships of FPRs and FFARs should facilitate our knowledge-based drug design of pharmaceuticals that can be used for treatment of inflammatory diseases.