ATOPIC DERMATITIS RESEARCH NETWORK LEADERSHIP CENTER

特应性皮炎研究网络领导中心

• 批准号: 10662102
• 负责人: DONALD YM LEUNG
• 金额: $ 160万
• 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/10662102
• 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).

项目概要/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 2 型炎症和皮肤宿主防御能力下降。这些异常 转化为多种表型和内型，但尚未完全定义，因此，有效的靶向 除了 2 型免疫阻断之外，目前还缺乏逆转 AD 的各种亚型的疗法。超越其 AD 对皮肤防御的影响与全身炎症有关，并且似乎是 AD 的第一步 其他特应性疾病的发展，包括食物过敏和哮喘。 该拨款申请是为了回应 RFA-AI-19-014，特应性皮炎研究而提交的 网络领导中心 (ADRN-LC)。该提案的目标是创建一个 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-CRC)，支持多中心临床研究的开展和 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）。 本申请的中心假设是 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的明显缺陷有关，这些缺陷可以 以新颖的皮肤采样方法为特征，并开辟范式转变的途径 治疗干预措施使患有严重持续性 AD 的患者受益。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运营领导机构 该中心将负责临床试验的实施、协调和资助 ADRN-LC 在 AD 机制和治疗评估领域的研究。 · 具体目标 2：开发全网络多中心 ADRN 临床试验来评估长期 靶向微生物组移植对 AD 和上皮细胞临床结果的长期影响 屏障功能、微生物失调和皮肤免疫。 · 具体目标 3：设计一项全网络 ADRN 为期一年的观察性研究，以评估 使用转录组学网络相关性分析 AD 表型/内型的稳定性 （传统和单细胞 RNA 测序）、皮肤胶带蛋白质组学、脂质组学和微生物组 随着时间的推移，持续性轻度 AD 受试者与持续性重度 AD 受试者的比较以及治疗评估 对局部皮质类固醇和 Dupilumab 的反应。 · 具体目标4：开展全网多中心ADRN临床试验，检验效果 靶向 IL-1 阻断对临床结果、皮肤微生物组、上皮皮肤屏障和 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我们在 了解宿主皮肤防御机制和 AD 的范式转换治疗。这 该 ADRN-LC 的建立还将为该系统提供预算和科学资源 食物过敏联盟正在开发的早期特应性出生队列生物学研究 研究（CoFAR）。