ATOPIC DERMATITIS RESEARCH NETWORK (ADRN) CLINICAL RESEARCH CENTER

项目概要/摘要 特应性皮炎研究网络-临床研究中心（ADRN-CRC）提案旨在建立一个 临床和实验室基础设施，以支持ADRN领导中心（ADRN-LC）。当前 一项提案将评估三种AD表型的内在型：有湿疹倾向的AD患者 疱疹性湿疹（ADEH+）、无疱疹性湿疹病史的AD（ADEH-）和有食物过敏的AD（AD+FA+）。 我们认为这些不同的表型和内源性AD与不同的皮肤屏障有关， 可以通过基因组学、脂质组学、转录组学和蛋白质组学定义的谱。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，能够招募成年人， 儿童AD人群、临床研究机构、研究性药房服务、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联盟在AD的机制和治疗领域。在这里，我们提出了两个CRC特定的 本申请中概述的研究项目。项目1将侧重于传播病毒的机制， 疱疹性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， 来自ADEH+和ADEH-受试者和非特应性对照的皮肤活检的成纤维细胞系。我们打算 评价研究组确定的9种新型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，鞘脂代谢和S1 P在 将检查HSV复制。最后，ADEH+角质形成细胞的表皮分化程序影响 通过先前体内暴露于细胞因子环境和病毒暴露来评估。项目2将 评估皮肤屏障异常和氧化应激反应的AD患者的皮肤FA。项目 将通过临床和皮肤胶带条表征AD+FA+儿童和成人的皮肤屏障功能 脂质组学和蛋白质组学评估。AD+FA+皮肤样本中氧化应激反应的证据及其 将通过分析这些受试者中的 皮肤胶带剥离样品中的氧化应激反应酶、氧化蛋白质修饰和反应 AD+FA+受试者器官型皮肤培养物的氧化剂。这些项目将提供新的知识 关于AD内型、疾病评估的生物标志物和临床疾病的新分子靶点 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.