Atopic dermatitis: mechanisms of disease progression

特应性皮炎：疾病进展的机制

• 批准号: 10379962
• 负责人: Gurjit K. Khurana Hershey
• 金额: $ 53.91万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-20 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10379962
• 关键词: Address; Affect; Allergic; Allergic Disease; Allergic rhinitis; Asthma; Atopic Dermatitis; Birth; Child; Childhood; Childhood Asthma; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Collection; Complex; Coupled; Data; Deltastab; Development; Disease; Disease Progression; Educational workshop; Enrollment; Environmental Risk Factor; Epigenetic Process; Evaluation; Food Hypersensitivity; Functional disorder; Funding; Genetic; Genomics; Goals; Human; Hypersensitivity; Immunologics; Intervention; Leadership; Lesion; Life; Longitudinal cohort study; Medical center; National Institute of Allergy and Infectious Disease; Observational Study; Outcome; Pediatric Hospitals; Phenotype; Physiological; Positioning Attribute; Prospective cohort; Prospective cohort study; Regulatory Affairs; Reporting; Research; Research Infrastructure; Research Project Grants; Sampling; Skin; Subgroup; Systems Biology; Visit; atopy; base; chronic inflammatory skin; cohort; comorbidity; dysbiosis; experience; peripheral blood; prospective; recruit; respiratory; response; skin barrier; skin disorder; skin microbiome

PROJECT SUMMARY Atopic dermatitis (AD) is a chronic, inflammatory skin disorder that affects up to 20% of children worldwide. AD has been highlighted as the first step in the “atopic march”, whereby AD typically predates the development of other allergic disorders. Atopic sensitization and food allergy have been reported to be precursors of AD progression to respiratory allergy, however recent data indicate that the mechanisms are far more complex. The National Institute of Allergy and Infectious Diseases recently convened a workshop titled ``Atopic dermatitis and the atopic march: mechanisms and interventions''6 and they concluded that only about 3% of children follow what has been conventionally referred to as the atopic march. They stated that a new prospective cohort study that uses multiparameter approaches to define phenotypic/endotypic subgroups of AD and to predict AD outcomes is needed. As part of our U19 Asthma and Allergic Diseases Cooperative Research Center (AADCRC) funded by the National Institute of Allergy and Infectious Diseases, we have built the first mechanistic longitudinal cohort study of pediatric atopic dermatitis (AD), the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH). MPAACH is the first early life prospective cohort of children with AD in the US and incorporates extensive evaluations of skin, gut, airway and peripheral blood, as well as the use of multiparameter approaches to define phenotypic and endotypic subgroups of AD. Thus far, we have enrolled 537 children. The goals of the MPAACH cohort are to define AD phenotypes and endotypes, dissect the mechanisms that contribute to the progression of AD to other allergic disorders (food allergy, allergic rhinitis, asthma), and delineate the immunologic, skin, biome, genetic/epigenetic/genomic, physiologic, and environmental factors that promote the development of allergic comorbidities in children with AD. To enable mechanistic studies, extensive biospecimens are collected from lesional and non-lesional skin. We have 20 years of experience and expertise in conducting large cohort studies and are uniquely positioned to contribute to ADRN and SUNBEAM due to our current cohorts and clinical research infrastructure, as well as our experienced and diverse large staff, who are experts in recruitment, regulatory affairs, conducting visits, collection and processing of biospecimens, and execution and reporting of studies. Based on our strong preliminary data from MPAACH, we are proposing 3 CRC-specific research projects to address our overarching hypothesis is that visually normal skin may have skin barrier dysfunction that becomes clinically evident (lesional) or remains subclinical (no lesions), but in both cases the skin barrier dysfunction coupled with dysbiosis of skin microbiome triggers alarmins, which initiates an immunologic cascade that promotes the subsequent development of allergic disease including food allergy, asthma and allergic rhinitis.

项目摘要 特应性皮炎（AD）是一种慢性炎症性皮肤病，影响全球多达20％的儿童。广告 已被强调为“特征游行”的第一步，广告通常早于发展 其他过敏性疾病。据报道，当特应敏感性和食物过敏是AD的前体 向呼吸过敏的进展，但是最近的数据表明机制要复杂得多。 美国国家过敏和传染病研究所最近召集了一个名为“特应性皮炎和 特征游行：机制和干预'6，他们得出的结论是，只有大约3％的孩子遵循 通常，被称为特征游行。他们说，一项新的前瞻性队列研究 使用多参数方法定义AD的表型/内型亚组并预测AD结果 需要。作为我们U19哮喘和过敏性疾病合作研究中心（AADCRC）的一部分 由美国国家过敏和传染病研究所，我们建立了第一个机械纵向队列 小儿特应性皮炎（AD）的研究，特应性皮炎向哮喘进展的机制 儿童（mpaach）。 MPAACH是美国与广告中的第一个早期生命的前瞻性队列， 包括对皮肤，肠道，气道和外周血的广泛评估，以及使用多参数 定义AD的表型和内型亚组的方法。那远，我们已经招募了537个孩子。这 MPAACH队列的目标是定义AD​​表型和内型，剖析机制 有助于AD向其他过敏性疾病（食物过敏，过敏性鼻炎）和 描述免疫，皮肤，生物组，遗传/表观遗传/基因组，生理和环境因素 促进AD儿童过敏合并症的发展。为了实现机械研究，广泛 从病变和非静态皮肤收集生物源性。我们有20年的经验和专业知识 在进行大型队列研究时，由于我们的 当前的人群和临床研究基础设施以及我们的经验以及潜水员的大型员工 专家招聘，监管事务，进行访问，生物测量的收集和处理以及 执行和研究报告。根据我们从MPAACH的强大初步数据，我们提出了3 CRC特定的研究项目旨在解决我们的总体假设 障碍功能障碍是临床上的证据（病变）或保持亚临床（无病变），但在这两种情况下 皮肤屏障功能障碍以及皮肤微生物组的营养不良触发了警报蛋白，这引发了 免疫学级联促进了随后发展过敏性疾病，包括食物过敏， 哮喘和过敏性鼻炎。