Itch, or pruritus, is a commonly reported symptom with over 7 million clinician visits annually in the United States. Indeed, the Global Burden of Disease Study by the World Health Organization categorized itch in the top 50 most prevalent diseases worldwide. Itch is difficult to manage, as there are limited therapeutics. There are also racial differences in itch in skin diseases such as atopic dermatitis (AD) and prurigo nodularis (PN), which disproportionately affect African Americans (AA). AD is more likely to be papular, affect extensor areas, and less likely to be associated with filaggrin loss-of-function mutations in blacks as compared to Caucasians. This study will investigate novel itch receptors and cytokine profiles in human AD and PN patients with respect to race to provide biomarkers and potential targets for future therapeutics. Our first aim focuses on a recently discovered group of itch receptors, known as Mas-related G protein- coupled receptors (Mrgprs). In humans, there are 4 Mrgpr genes (MrgprX1-4). A role for three of the MrgprX genes in humans has been elucidated: MrgprX1 mediates chloroquine-induced itch, which disproportionally affects AA, MrgprX2 is a regulator of pseudoallergic reactions, and our recent study demonstrated a role for MrgprX4 as a bilirubin receptor mediating cholestatic pruritus, but the function of MrgprX3 is unknown. Based on preliminary data showing dramatic upregulation of MrgprX3 in lesional, pruritic, PN skin and because MrgprX3 is the most highly expressed Mrgpr in keratinocytes, this aim will determine the cellular localization, polymorphisms, and phenotypic differences in the expression of MrgprX3 in PN and AD patients with respect to itch intensity and race. Our second aim will characterize upregulation of the IL-22 cytokine pathway in PN and AD patients according to race and itch intensity. Our preliminary data reveals significant upregulation of Th22-associated genes in lesional PN and AD skin as compared to healthy skin. Further, we found robust IL-22 expression from human blood peripheral blood mononuclear cells in PN patients as compared to healthy controls. Thus, in this aim we will determine circulating levels of IL-22 from plasma and peripheral blood mononuclear cells in a larger sample of PN and AD patients with respect to race and varying itch intensity. We will also determine the expression and cellular localization of IL-22 and Th22-associated related genes in PN and AD lesional skin. Finally, we will test the hypothesis that MrgprX3 expression is regulated by IL-22 and Th22 associated genes. This project will provide important insights into the role of MrpgrX3, IL-22, and the interplay between these mediators into the pathogenesis of itch in AD and PN in African American and Caucasian patients. Importantly, the results will be correlated with race to determine the pathogenesis and novel therapeutic targets in specific patient populations. The knowledge gained from these studies w...