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: 10214851
• 负责人: Shawn Gaurav Kwatra
• 金额: $ 17.7万
• 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/10214851
• 关键词: Affect; African American; Antipruritics; Area; Atopic Dermatitis; Bilirubin; Biological Markers; Biopsy; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Caucasians; Chloroquine; 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; 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症状，每年有超过 700 万临床医生就诊。 美国。事实上，世界卫生组织的全球疾病负担研究将瘙痒归类为 全球最流行的 50 种疾病之一。由于治疗方法有限，瘙痒很难控制。 特应性皮炎（AD）和结节性痒疹等皮肤病的瘙痒也存在种族差异 (PN)，这对非裔美国人 (AA) 产生了不成比例的影响。 AD更容易出现丘疹，影响伸肌 区域，并且与黑人相比，与丝聚蛋白功能丧失突变相关的可能性较小 白种人。这项研究将调查人类 AD 和 PN 患者的新型瘙痒受体和细胞因子谱 关于竞赛，为未来的治疗提供生物标志物和潜在目标。 我们的第一个目标集中在最近发现的一组瘙痒受体，称为 Mas 相关 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 人类基因已被阐明：MrgprX1 介导氯喹引起的瘙痒，这不成比例 MrgprX2 影响 AA，是假过敏反应的调节因子，我们最近的研究证明了 MrgprX4 作为介导胆汁淤积性瘙痒的胆红素受体，但 MrgprX3 的功能尚不清楚。基于 初步数据显示 MrgprX3 在病变、瘙痒、PN 皮肤中显着上调，并且因为 MrgprX3 是角质形成细胞中表达最高的 Mrgpr，该目标将决定细胞定位， PN 和 AD 患者中 MrgprX3 表达的多态性和表型差异 瘙痒强度和比赛。 我们的第二个目标是表征 PN 和 AD 患者中 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 相关的显着上调 与健康皮肤相比，病变 PN 和 AD 皮肤中的基因。此外，我们发现IL-22的强表达 PN 患者与健康对照者的人血外周血单核细胞。因此，在这个 目的 我们将测定更大范围内血浆和外周血单核细胞中 IL-22 的循环水平 PN 和 AD 患者样本的种族和不同瘙痒强度。我们还将确定 PN 和 AD 皮损皮肤中 IL-22 和 Th22 相关基因的表达和细胞定位。 最后，我们将检验 MrgprX3 表达受 IL-22 和 Th22 相关基因调节的假设。 该项目将为 MrpgrX3、IL-22 的作用以及两者之间的相互作用提供重要见解。 这些介质参与非裔美国人和白种人患者 AD 和 PN 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 在特定的患者人群中。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 瘙痒的治疗。