ATOPIC DERMATITIS RESEARCH NETWORK LEADERSHIP CENTER

特应性皮炎研究网络领导中心

• 批准号: 10382408
• 负责人: DONALD YM LEUNG
• 金额: $ 372.44万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-09 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10382408
• 关键词: Applications Grants; Area; Asthma; Atopic Dermatitis; Bacterial Infections; Biological; Birth; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Collaborations; Cutaneous; Data Coordinating Center; Defect; Development; Ensure; Epithelial; Food Hypersensitivity; Functional disorder; Funding; General Population; Goals; Grant; Health; Hospitalization; Host Defense; Hypersensitivity; Immune; Immune response; Immunity; Impairment; Inflammation; Infrastructure; Interleukin-1; Interleukin-13; Interleukin-4; Intervention; Intervention Studies; Leadership; Long-Term Effects; Morbidity - disease rate; Multi-site clinical study; National Institute of Allergy and Infectious Disease; Observational Study; Operations Research; Outcome; Pathway interactions; Patients; Performance; Phenotype; Proteomics; Protocols documentation; Quality of life; Research; Research Personnel; Resources; Sampling; Skin; Structure; Study Subject; Systems Biology; Therapeutic Intervention; Time; Topical Corticosteroids; Translating; United States National Institutes of Health; Virus Diseases; Work; atopy; biobank; chronic inflammatory skin; data integrity; design; dysbiosis; evidence base; follower of religion Jewish; lipidomics; microbial; microbiome; microbiota transplantation; novel; novel strategies; operation; organizational structure; programs; response; rho; safety study; single-cell RNA sequencing; skin barrier; skin disorder; skin microbiome; systemic inflammatory response; targeted treatment; transcriptomics; treatment response

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).

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，微生物失调以及各种皮肤免疫有关 异常，包括2型炎症和改善皮肤宿主防御。这些异常 转化为未完全定义的多种表型和内型，因此有效的目标 缺乏以外的2型免疫阻滞剂的疗法，以扭转这些AD的各种亚集。超越它 对皮肤防御的影响，AD与全身感染有关，似乎是第一步 其他特应疾病的发展，包括食物过敏和哮喘。 该赠款申请是针对RFA-AI-19-014，特应性皮炎研究提交的 网络领导中心（ADRN-LC）。该建议的目的是创建一个ADRN-LC 向ADRN提供整体科学策略和组织结构，并将与 ADRN临床研究中心（ADRN-CRC），以支持多站点临床研究的进行 试验将阐明皮肤屏障功能障碍和皮肤免疫调查的机制 特应性皮炎（AD）。 该应用程序中的中心假设是AD的不同表型和内型是 与皮肤屏障，微生物组和皮肤免疫反应中的不同缺陷有关 以新颖的皮肤采样方法和开放范式转移的途径的特征 治疗性干预措施使患有严重持续AD的患者受益。我们将实现我们的目标 以以下目的： ·特定目的1：建立行政和临床研究运营领导 负责临床试验的实施，协调和资金的中心 ADRN-LC在评估AD机制和治疗的研究领域的研究。 ·具体目标2：开发全网络多中心ADRN临床试验以评估长期 靶向微生物组移植对AD临床结果以及上皮的术语影响 屏障功能，微生物营养不良和皮肤免疫学。 ·特定目的3：设计一个网络范围的ADRN一年的观察性研究以评估 使用转录组学网络相关分析的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，脂肪组学和微生物组 随着时间的流逝，与持续的轻度与持续严重广告和评估的受试者有关 对局部皮质类固醇和二脂蛋白的反应。 ·特定目的4：进行全网络多中心ADRN临床试验以检查效果 在临床结果，皮肤微生物组，上皮皮肤屏障和 对IL-4/IL-13封锁反应不足的AD患者的皮肤免疫响应 使用Dupilumab治疗。 完成这些特定目标将有助于我们的新颖而重要的进步 了解宿主皮肤防御和AD范式转移治疗的机制。这 建立此ADRN-LC还将为系统提供预算和科学资源 食物过敏联盟正在开发的早期特应特应分娩队列研究的生物学 研究（科法尔）。