Role of Skin Barrier and Immune Alterations in Allergic Sensitization

皮肤屏障和免疫改变在过敏性致敏中的作用

• 批准号: 10633370
• 负责人: Emma Guttman
• 金额: $ 28.39万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-07 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633370
• 关键词: Age; Allergens; Allergic; Allergic Disease; Allergic inflammation; Antibiotics; Atopic Dermatitis; Attenuated; Automobile Driving; Bathing; Biological; Biological Markers; Biopsy; Birth; Characteristics; Child; Childhood; Classification; Communities; Consumption; Cutaneous; Data; Developed Countries; Development; Disease; Environmental Exposure; Epithelium; Exposure to; Family; Farm; Farming Community; Food Hypersensitivity; Frequencies; Genes; Goals; Healthcare; Home; Hypersensitivity; Immune; Immunity; Immunologic Markers; Impairment; Infant; Inflammation; Inflammatory; Life; Life Style; Livestock; Longitudinal Studies; Measures; Mennonite; Methods; Milk; Molecular; Molecular Profiling; Pathway interactions; Permeability; Prevention; Prevention strategy; Primary Prevention; Production; Proteins; Proteomics; Public Health; Reverse Transcriptase Polymerase Chain Reaction; Ribosomal RNA; Risk; Role; Sampling; Severities; Skin; Skin Care; Skin colonization; Societies; Staphylococcus aureus; Swab; T-Lymphocyte; TSLP gene; Testing; Therapeutic; Water; atopy; cohort; comparison control; cytokine; early childhood; early detection biomarkers; early onset; high risk; microbial; microbiome; microbiome analysis; minimally invasive; novel; prevent; protective effect; respiratory; skin barrier; skin microbiome; socioeconomics; time interval; transcriptome sequencing; transcriptomics; unpasteurized

PROJECT SUMMARY/ABSTRACT – PROJECT 3 Atopic dermatitis (AD) often begins in the first year of life and is a precursor of allergic diseases. It is often followed by food allergy (FA), with subsequent development of respiratory allergies. While the frequency of AD and FA are increasing in industrialized countries, posing a large burden on healthcare, primary prevention strategies are not yet successful. There is growing evidence that a farming lifestyle in early life in infants is associated with a diverse microbiome and a reduced risk of atopy. We have recently shown that Old Order Mennonites (OOM), a traditional single-family farming community, are significantly protected against early childhood atopic disease (3.8% AD and 0% FA) as compared to a high-risk Rochester Children cohort (ROC), born to atopic families, that show increased rates of AD (30%) and FA (15%). Consumption of unpasteurized farm milk, exposure to farm animals, and greater microbial diversity were proposed to be associated with the protective effects in OOM children. However, the protective mechanisms responsible for the attenuated development of atopy in OOM children are unknown. Understanding these factors is key for development of preventive strategies against AD and atopic conditions. Recent data suggest that epicutaneous allergen sensitization occurs more readily through a disturbed skin barrier, as in AD. Further, development of FA is highly associated with early, more severe AD, and skin colonization with S. aureus increases the risk to develop FA. The effects of a farming lifestyle on promoting a healthy, homeostatic epidermal skin barrier, diverse microbiome, and normal skin immunity, that prevent development of AD and allergic sensitization, have not yet been evaluated. We hypothesize that lifestyle impacts the development of a healthy infant skin barrier, immunity, and microbiome that may protect from allergic inflammation in the OOM infants or predispose towards development of a perturbed skin barrier function and an aberrant skin immune millieu and microbiome that induce AD and allergic sensitization in the ROC infants. We will test our hypothesis in a new longitudinal birth cohort of high (ROC)- vs. low (OOM)-risk for development of atopy (n=80 in ROC and n=40 in OOM group), in which we will collect lifestyle, environmental exposure, allergic sensitization, trans-epidermal-water loss/TEWL), skin tape strips samples and skin swabs for microbiome, with the following specific aims: Specific aim 1: To determine gene, protein, and microbiome skin biomarkers that modify the risk to develop AD or promote a healthy skin barrier. Specific aim 2: To determine cutaneous biomarkers that promote or protect from development of FA (and other atopic conditions), both with and without concomitant AD. Identification of the skin mechanisms, including specific genes and pathways, and microbiome that predispose to allergic conditions, as compared to those that may be associated with prevention of AD and atopy, can lead to novel prevention as well as therapeutic strategies for AD and the atopic march. This project will have significant impact on public health.

项目摘要/摘要 - 项目3 特应性皮炎（AD）通常始于生命的第一年，并且是过敏性疾病的先兆。通常是 其次是食物过敏（FA），随后发展呼吸道过敏。而广告的频率 工业化国家的FA正在增加，对医疗保健，初级预防构成了巨大的燃烧 策略尚未成功。越来越多的证据表明，婴儿早期生活的生活方式是 与潜水员微生物组和特应性风险降低相关。我们最近显示了旧订单 门诺派（OOM）是一个传统的单户农业社区，受到了极大的保护 与高风险的罗切斯特儿童队列（ROC）相比 出生于特应家庭，这表明AD（30％）和FA（15％）的比率增加。消耗未经省剂 提议农业牛奶，暴露于农场动物以及更大的微生物多样性与 OOM儿童的保护作用。但是，受保护的受保护机制 OOM儿童的特应发展是未知的。了解这些因素是开发的关键 针对AD和特应条件的预防策略。最近的数据表明表皮过敏原 如AD中的敏感性，通过受干扰的皮肤屏障更容易发生敏化。此外，FA的开发很高 与早期，更严重的AD和带有金黄色葡萄球菌的皮肤定植相关的会增加发展的风险 fa。农业生活方式对促进健康，稳态表皮皮肤屏障的影响，潜水员 微生物组和正常的皮肤免疫力，可防止AD发展和过敏性敏感性的发展 尚未评估。我们假设生活方式会影响健康的婴儿皮肤屏障的发展， 免疫力和微生物组，可防止OOM婴儿过敏感染或倾向于 发育的皮肤屏障功能以及影响的异常皮肤免疫和微生物组 ROC婴儿的AD和过敏敏感性。我们将在新的纵向出生队列中检验我们的假设 高（ROC） - 与低（OOM） - 用于开发Atopy的风险（ROC中的n = 80，OOM组为n = 40），其中我们在其中 将收集生活方式，环境暴露，过敏感，跨性皮肤 - 水损失/TEWL），皮肤胶带 带有微生物组的样品和皮肤拭子，具有以下特定目的：特定目的1：确定 基因，蛋白质和微生物组皮肤生物标志物可改变发展AD或促进健康皮肤的风险 障碍。特定目的2：确定促进或保护FA发展的皮肤生物标志物 （以及其他特定条件），无论有没有伴随的AD。识别皮肤机制， 包括特定的基因和途径，以及与过敏性条件相比的微生物组 那些可能与预防AD和特应性有关的人可以导致新的预防以及 AD和特应特征游行的治疗策略。该项目将对公共卫生产生重大影响。