Itch is an unpleasant sensation that evokes the reflex to scratch. Itch is mediated initially by a group of small-diameter sensory neurons in the trigeminal and dorsal root ganglia (DRG), yet how these neurons transduce itch stimuli remains elusive. Dr. Liu’s previous studies identified several Mrgprs as itch receptors in the DRG. These receptors detect itch-inducing chemicals and evoke itch responses. Here Dr. Liu proposes to test whether Mrgprs constitute a family of receptors that enable DRG neurons to detect various itch mediators. Furthermore, she will investigate whether these receptors mediate the interaction between keratinocytes and primary sensory neurons, and are involved in chronic itch. Finally, using a novel genetic allele, Dr. Liu and her lab will define the function of human MrgprX1 in acute and chronic itch. This research proposal is of significant relevance to human health and will significantly facilitate the study of itch pathogenesis and the treatment of chronic itch. Human MrgprX1 may provide a promising neuronal target for the development of effective anti-itch drug therapies.