Racial Differences in Biomarkers and Therapeutic Targets for Chronic Itch

慢性瘙痒生物标志物和治疗靶点的种族差异

• 批准号: 10451531
• 负责人: Shawn Gaurav Kwatra
• 金额: $ 17.71万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451531
• 关键词: Affect; African American; African American population; Antipruritics; Area; Atopic Dermatitis; Bilirubin; Biological Markers; Biopsy; Black Populations; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Caucasians; Chloroquine; Cholestasis; Clinical; Cutaneous; Data; Dermatologist; Development; Disease; Extensor; FDA approved; Flow Cytometry; Functional disorder; Future; G-Protein-Coupled Receptors; Gene Expression; Gene Frequency; Genes; Genetic Polymorphism; Human; Immune system; Inflammatory; Knowledge; Lesion; Measures; Mediating; Mediator of activation protein; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Plasma; Prurigo; Pruritus; Quality of life; Race; Reaction; Reporting; Research; Role; Sampling; Severities; Single Nucleotide Polymorphism; Skin; Sleep; Symptoms; T-Lymphocyte; Testing; Therapeutic; United States; Up-Regulation; Variant; Visit; World Health Organization; base; burden of illness; chronic itch; cohort; cytokine; filaggrin; insight; interleukin-22; keratinocyte; loss of function mutation; nano-string; negative affect; new therapeutic target; novel; patient population; peripheral blood; racial difference; receptor; relating to nervous system; skin disorder; skin lesion; therapeutic target; tissue biomarkers; transcriptome sequencing; translational study

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.

瘙痒或瘙痒是一种常见的症状，每年有超过700万临床医生访问 美国。实际上，世界卫生组织的全球疾病负担研究对瘙痒进行了分类 在全球50种最普遍的疾病中。由于治疗疗法有限，因此很难管理瘙痒。 皮肤疾病（例如特应性皮炎（AD）和prurigo nodularis）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。广告更可能是丘疹，影响延伸器 区域，与黑人的功能丧失突变有关 高加索人。这项研究将研究人类AD和PN患者的新型瘙痒受体和细胞因子谱 关于种族，为将来的治疗剂提供生物标志物和潜在目标。 我们的第一个目的集中于最近发现的一组瘙痒受体，称为MAS相关的G蛋白 - 耦合受体（MRGPRS）。在人类中，有4个MRGPR基因（MRGPRX1-4）。三个MRGPRX的角色 人类中的基因已被阐明：MRGPRX1介导了氯喹引起的瘙痒，这不成比例 影响AA，MRGPRX2是伪过敏反应的调节剂，我们最近的研究证明了对 MRGPRX4作为胆红素受体介导胆固醇瘙痒，但MRGPRX3的功能尚不清楚。基于 关于病变，核，PN皮肤中MRGPRX3的急剧上调的初步数据，因为 MRGPRX3是角质形成细胞中最高表达的MRGPR，此目标将决定细胞定位， PN和AD患者MRGPRX3表达的多态性和表型差异 瘙痒强度和种族。 我们的第二个目标将表征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。我们的初步数据揭示了Th22相关的显着上调 与健康的皮肤相比，病变PN和AD皮肤中的基因。此外，我们从 与健康对照相比，PN患者的人血外周血单核细胞。因此，在此 目的，我们将确定较大的血浆和外周血单核细胞中IL-22的循环水平 PN和AD患者的样本相对于种族和瘙痒强度变化。我们还将确定 PN和AD病变皮肤中IL-22和Th22相关基因的表达和细胞定位。 最后，我们将检验以下假设：MRGPRX3表达受IL-22和TH22相关基因调节。 该项目将为MRPGRX3，IL-22的作用以及之间的相互作用提供重要见解 这些介体在非裔美国人和高加索患者中涉及AD和PN的发病机理。 重要的是，结果将与种族相关，以确定发病机理和新型治疗靶标 在特定的患者人群中。从这些研究中获得的知识将确定可能受益的患者 从旨在针对AD和PN的瘙痒的未来治疗方法。