Racial Differences in Biomarkers and Therapeutic Targets for Chronic Itch

瘙痒是一种常见的症状，在美国每年有超过700万名临床医生就诊。 美国。事实上，世界卫生组织的全球疾病负担研究将瘙痒 在全球最流行的50种疾病中。瘙痒很难控制，因为治疗方法有限。 特应性皮炎(AD)和结节性瘙痒等皮肤病的瘙痒也存在种族差异。 (PN)，这对非裔美国人(AA)的影响不成比例。AD更有可能是丘疹，影响伸肌 在黑人中，与微丝蛋白功能丧失突变相关的可能性较小 高加索人。这项研究将研究人类AD和PN患者的新的瘙痒受体和细胞因子谱 关于RACE，为未来的治疗提供生物标记物和潜在靶点。 我们的第一个目标是关注最近发现的一组瘙痒受体，称为mas相关G蛋白- 偶联受体(MRGPR)。在人类中，有4个mrgpr基因(mrgprX1-4)。三位先生的角色 人类的基因已经被阐明：MRGPRX1介导氯喹诱导的瘙痒，这是不成比例的 影响AA，MRgprX2是假过敏反应的调节器，我们最近的研究证明了 MRgprX4作为胆红素受体介导胆汁淤积性瘙痒，但其功能尚不清楚。基座 根据初步数据显示，在皮损、瘙痒、PN皮肤中MRGPRX3显著上调，因为 MRGPRX3是角质形成细胞中表达最高的MRGPR，这一目的将决定细胞的定位， PN和AD患者MRgprX3基因表达的多态性和表型差异 刺激强度和赛跑。 我们的第二个目标是研究PN和AD患者IL-22细胞因子途径的上调 根据种族和瘙痒强度。我们的初步数据显示Th22相关的显著上调 皮损PN和AD皮肤中的基因与健康皮肤的比较。此外，我们还发现IL-22在 PN患者外周血单个核细胞与健康对照组的比较。因此，在这方面 目的测定血浆和外周血单核细胞中IL-22的循环水平。 PN和AD患者的样本与种族和不同的瘙痒强度有关。我们还将确定 IL-22和Th22相关基因在PN和AD皮损中的表达及细胞定位 最后，我们将检验这一假设，即Mr gprX3的表达受IL-22和Th22相关基因的调控。 这个项目将提供对MRpgrX3、IL-22的作用以及它们之间的相互作用的重要见解 这些介质参与了非裔美国人和高加索人AD和PN中瘙痒的发病机制。 重要的是，结果将与种族相关，以确定发病机制和新的治疗靶点。 在特定的患者群体中。从这些研究中获得的知识将确定可能受益的患者。 未来针对AD和PN中瘙痒的治疗。

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 will identify patients likely to benefit from future treatments aimed at targeting itch in AD and PN.