ATOPIC DERMATITIS RESEARCH NETWORK LEADERSHIP CENTER

项目摘要/摘要 特应性皮炎(AD)是普通人群中最常见的慢性炎症性皮肤病。广告是 与皮肤屏障功能缺陷、微生物失调以及各种皮肤免疫有关 异常包括II型炎症和皮肤宿主防御能力降低。这些异常现象 翻译成多个未完全定义的表型和内型，因此，有效地有针对性 除了2型免疫阻断外，还缺乏逆转AD这些不同亚型的治疗方法。超越它的 对皮肤防御的影响，阿尔茨海默病与全身炎症有关，似乎是 其他特应性疾病的发展，包括食物过敏和哮喘。 此拨款申请是根据RFA-AI-19-014《特应性皮炎研究》提交的 网络领导中心(ADRN-LC)。这项提议的目标是创建一个ADRN-LC，它将 向ADRN提供总体科学战略和组织结构，并将与 ADRN临床研究中心(ADRN-CRCs)，以支持进行多站点临床研究和 将阐明皮肤屏障功能障碍和皮肤免疫反应机制的试验 特应性皮炎(AD)。 这个应用中的中心假设是AD的不同表型和内型是 与他们的皮肤屏障、微生物群和皮肤免疫反应的明显缺陷有关，这可能 以新颖的皮肤采样方法为特征，为范式转换开辟道路 严重持续性阿尔茨海默病患者的治疗干预。我们将实现我们的目标 目标如下： ·具体目标1：建立行政和临床研究业务领导 该中心将负责实施、协调和资助临床试验和 ADRN-LC在AD研究领域的研究进展、评价机制及治疗。 ·具体目标2：开发全网多中心ADRN临床试验，以评估长期和长期的 靶向微生物组移植对阿尔茨海默病和上皮性痴呆患者临床结局的远期影响 屏障功能、微生物失调和皮肤免疫。 ·具体目标3：设计一项全网ADRN一年观察性研究，以评估 用转录组学网络相关分析研究AD表型/内型的稳定性 (常规和单细胞RNA测序)、皮肤胶带蛋白质组学、类脂组学和微生物组学 持续性轻度阿尔茨海默病与持续性重度阿尔茨海默病患者随时间的变化及疗效评估 对外用皮质类固醇和Dupilumab的反应。 ·具体目标4：开展全网多中心ADRN临床试验，检查疗效 靶向IL-1阻断对临床结果、皮肤微生物群、皮肤上皮屏障和 对IL-4/IL-13阻断反应不足的AD患者的皮肤免疫反应 使用Dupilumab疗法。 这些具体目标的实现将有助于在我们的 了解AD的宿主皮肤防御机制和范式转换治疗。这个 该ADRN-LC的建立还将为该系统提供预算和科学资源 食物过敏联盟正在进行的早期特应性出生的生物学队列研究 研究(Cofar)。

PROJECT SUMMARY/ABSTRACT Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in the general population. AD is associated with defective skin barrier function, microbial dysbiosis, as well as various cutaneous immune abnormalities including type 2 inflammation and decreased cutaneous host defense. These abnormalities translate into multiple phenotypes and endotypes that are not fully defined and therefore, effective targeted therapies, beyond type 2 immune blockade, to reverse these various subsets of AD are lacking. Beyond its effects on cutaneous defense, AD is associated with systemic inflammation and appears to be the first step in the development of other atopic conditions including food allergy and asthma. This grant application is being submitted in response to RFA-AI-19-014, Atopic Dermatitis Research Network-Leadership Center (ADRN-LC). The goal of this proposal is to create an ADRN-LC which will provide the overall scientific strategy and organizational structure to the ADRN and will interact closely with the ADRN Clinical Research Centers (ADRN-CRCs), to support the conduct of multi-site clinical studies and trials that will elucidate mechanisms of skin barrier dysfunction and cutaneous immune responses in atopic dermatitis (AD). The central hypothesis in this application is that different phenotypes and endotypes of AD are associated with distinct defects in their skin barrier, microbiome, and skin immune responses which can be characterized by novel approaches to skin sampling and open up avenues for paradigm shifting therapeutic interventions to benefit patients with severe persistent AD. We will achieve our objectives with the following Aims: · Specific Aim 1: To establish an Administrative and Clinical Research Operations Leadership Center that will be responsible for implementation, coordination, and funding of clinical trials and studies for the ADRN-LC in research areas evaluating mechanism and treatment of AD. · Specific Aim 2: To develop a Network-wide multi-center ADRN clinical trial to evaluate the long- term effects of targeted microbiome transplantation on clinical outcomes in AD as well as epithelial barrier function, microbial dysbiosis, and cutaneous immunity. · Specific Aim 3: To design a Network-wide ADRN one-year observational study to assess the stability of AD phenotypes/endotypes using a Network correlation analysis of transcriptomics (conventional and single cell RNA sequencing), skin tape proteomics, lipidomics, and microbiome over time in subjects with persistent mild vs. persistent severe AD and assessment of therapeutic responses to topical corticosteroids and Dupilumab. · Specific Aim 4: To carry out a Network-wide multi-center ADRN clinical trial to examine the effects of targeted IL-1 blockade on the clinical outcome, skin microbiome, epithelial skin barrier, and cutaneous immune response in AD patients who have an inadequate response to IL-4/IL-13 blockade using Dupilumab therapy. Accomplishment of these Specific Aims will contribute to novel and important advances in our understanding of mechanisms of host skin defense and paradigm-shifting treatments of AD. The establishment of this ADRN-LC will also provide budgetary and scientific resources for the Systems Biology of Early Atopy Birth Cohort study that is under development by the Consortium for Food Allergy Research (CoFAR).