The Molecular and Neural Basis of Itch Sensation
Despite the clinical importance, the mechanisms underlying most chronic itchy conditions remain unknown due to a lack of information about principal pruritogens and itch receptors. Previously, we identified several novel itch receptors within a large family of G-protein‒coupled receptors called Mrgprs. We found that several Mrgprs recognize distinct pruritogens, and mediate acute itch evoked by these pruritogens. However, the function of these receptors in chronic itch remains to be determined. During the BRF funding period (2013-2014), we discovered that Mrgprs are required for both allergic and non-allergic chronic itch. This proposal will continue to uncover the underlying mechanisms by investigating the role of Mrgprs in mediating the interaction between sensory fibers and skin mast cells (allergic itch) / keratinocytes (non-allergic itch). Furthermore, the discovery of human MrgprX1 in acute and chronic itch prompts us to test whether antagonizing hMrgprX1 is a feasible therapeutic strategy for treating itchy conditions. These studies will not only advance our understanding of chronic itch at the molecular and cellular levels, but will also provide new targets for itch management.