ATOPIC DERMATITIS RESEARCH NETWORK (ADRN) CLINICAL RESEARCH CENTER

项目摘要/摘要 这项特应性皮炎研究网络-临床研究中心(ADRN-CRC)的提案旨在建立一个 支持ADRN领导中心(ADRN-LC)的临床和实验室基础设施。海流 提案将评估三种AD表型背后的内型：有湿疹倾向的AD患者 疱疹(ADEH)、无疱疹湿疹病史的AD(ADEH-)和有食物过敏的AD(AD FA)。 我们认为这些不同的AD表型和内型与不同的皮肤屏障有关 可由基因组学、类脂组学、转录组和蛋白质组学定义的图谱。该项目将建立 由训练有素的临床工作人员组成的临床和行政基础设施，有能力招聘成年人和 儿童AD人群、临床研究设施、研究药房服务、IRB人员以及 能够进行单中心ADRN-CRC和多中心临床研究的实验室设施 ADRN协会在阿尔茨海默病的机制和治疗领域。在这里，我们提出两个特定于CRC的 本申请表中概述的研究项目。项目1将侧重于传播病毒的机制 疱疹湿疹的感染。该项目将利用存档的和新建立的角质形成细胞和 来自ADEH和ADEH受试者和非特应性对照皮肤活检的成纤维细胞系。我们打算 评估研究小组确定的9个新的ADEH遗传风险突变在抗HSV-1中的作用 反应和角质形成细胞分化。此外，鞘磷脂代谢和S1P在脑缺血中的作用 将检查HSV复制。最后，ADEH角质形成细胞的表皮分化程序受到影响 通过事先在体内暴露于细胞因子环境和病毒暴露将被评估。项目2将 评估患有FA的AD患者皮肤的皮肤屏障异常和氧化应激反应。该项目 将通过临床和皮肤纸条表征AD FA儿童和成人的皮肤屏障功能 脂肪组学和蛋白质组学评估。AD-FA皮肤样本氧化应激反应的证据及其临床意义 这些受试者的皮肤屏障异常之间的联系将通过分析 皮肤胶带样本中的氧化应激反应酶、氧化蛋白修饰和反应 对AD-FA受试者器官型皮肤培养的氧化剂。这些项目将提供新的知识 关于AD内型、疾病评估的生物标记物和临床疾病的新分子靶标 干预措施。

PROJECT SUMMARY/ABSTRACT This Atopic Dermatitis Research Network-Clinical Research Center (ADRN-CRC) proposal aims to establish a clinical and laboratory infrastructure to support the ADRN-Leadership Center (ADRN-LC). The current proposal will evaluate the endotypes underlying three AD phenotypes: AD patients with propensity to eczema herpeticum (ADEH+), AD without a history of eczema herpeticum (ADEH-) and AD with food allergy (AD+FA+). We propose that these different phenotypes and endotypes of AD are associated with different skin barrier profiles that can be defined by genomics, lipidomics, transcriptome, and proteomics. The project will establish a clinical and administrative infrastructure of trained clinical staff with capabilities of recruiting adult and pediatric AD populations, clinical research facilities, investigational pharmacy services, IRB personnel, and laboratory facility capable of conducting single-center ADRN-CRC and multi-center clinical research for the ADRN Consortium in the areas of mechanisms and treatment of AD. Here, we propose two CRC-specific research projects as outlined in this application. Project 1 will focus on mechanisms of disseminated viral infections in eczema herpeticum. The project will utilize archived and newly established keratinocyte and fibroblast cell lines from skin biopsies of ADEH+ and ADEH- subjects and non-atopic controls. We intend to evaluate the role of nine novel ADEH+ genetic risk mutations identified by the study group in anti-HSV-1 responses and keratinocyte differentiation. In addition, the contribution of sphingolipid metabolism and S1P in HSV replication will be examined. Lastly, epidermal differentiation program of ADEH+ keratinocytes influenced by prior in vivo exposures to the cytokine environment and viral exposure will be evaluated. Project 2 will assess skin barrier abnormalities and oxidative stress response in the skin of AD patients with FA. The project will characterize skin barrier function of AD+FA+ children and adults through clinical and skin tape strip lipidomic and proteomic assessment. Evidence for oxidative stress responses in AD+FA+ skin samples and its link to skin barrier abnormalities in these subjects will be examined through the analysis of expression of oxidative stress response enzymes, oxidative protein modifications in skin tape strip samples, and responses to oxidants of the organotypic skin cultures from AD+FA+ subjects. The projects will provide new knowledge about AD endotypes, biomarkers for disease assessment, and novel molecular targets for clinical disease interventions.