Filaggrin Expression in Atopic Dermatitis: Regulation and Impact on Disease Progression

摘要 特应性皮炎（AD）影响全世界高达20%的儿童，是一个日益严重的公共卫生问题。 虽然婴儿和幼儿的AD可以消退，但从AD进展为其他疾病的风险很大。 特应性疾病，包括食物过敏（FA）、过敏性鼻炎和哮喘，即特应性疾病。的机制 潜在的特应性进行曲是不完全理解的，这是一个关键的知识差距，因为这 信息是必要的，以便设计预防战略，可以劫持或中止特应性游行。的 细丝聚集蛋白（或丝聚蛋白，FLG）在AD和特应性进行中的重要作用 已经被证明和广泛的审查。特应性皮炎的发病机制 儿童哮喘（MPAACH）队列是一个AD儿童的早期队列，具有广泛的纵向临床特征， 健康结果数据和纵向生物样本。使用MPAACH，我们最近发现，低非病变， 而非病变，皮肤FLG表达与共致敏和中度- 严重AD，这两个关键的风险因素，为未来发展的过敏性共病的AD。项目2将测试 核心假设是包括CARD 14在内的遗传因素与环境因素协同作用， 炎症以确定AD皮肤中的FLG表达，驱动短暂或持续的皮肤屏障功能障碍， 这可能会对长期AD结果产生不同影响。项目2是在前几个非洲发展与合作中心供资周期的基础上开展的 并利用MPAACH提供的广泛的纵向临床和分子数据以及生物标本， 项目1。在目标1中，我们将鉴定调节皮肤FLG表达的遗传变异，并将其整合到皮肤中。 与来自MPAACH的临床、暴露和分子数据相结合，以确定决定性因素的组合， 皮肤FLG表达。我们发现CARD 14中的rs 11652075导致CARD 14表达增加， 导致FLG表达减弱。在目标2中，我们将建立在这些数据的基础上，并确定将 rs 11652075和增强的CARD 14信号传导至FLG稳态。虽然LoF FLG突变在 特应性进行曲，FLG表达的轨迹在生命早期和随着时间的推移， 纵向AD结果尚不清楚。在目标3中，我们将确定低皮肤FLG表达的影响， （持续或短暂）随着时间的推移和目标1中确定的遗传基因座对AD结局的影响。据报道， 早期皮肤使用润肤剂可以预防AD、过敏性致敏和食物过敏的发生。 过敏，这项研究是临床上重要的，因为它可能有助于确定个人的规模和持续时间 屏障功能失调，可能受益于预防和干预策略，旨在提高 皮肤屏障功能。此外，我们的研究将有助于确定提供这些干预措施的最佳时机。 最后，该项目充分代表了黑人和白色儿童，并将与项目1和项目3产生协同作用。 这一及时的项目将产生重大的公共卫生影响。

Abstract Atopic dermatitis (AD) affects up to 20% of children worldwide and is an increasing public health problem. Although AD in infants and young children can resolve, there is a substantial risk of progression from AD to other atopic diseases, including food allergy (FA), allergic rhinitis, and asthma, i.e. the atopic march. The mechanisms underlying the atopic march are incompletely understood and this is a critical gap in knowledge as this information is necessary in order to design preventive strategies that can hijack or abort the atopic march. The crucial role of Filament aggregating protein (or filaggrin, FLG) in the development of AD and the atopic march has been demonstrated and extensively reviewed. The Mechanisms of Progression of Atopic Dermatitis to Asthma in CHildren (MPAACH) cohort is an early life cohort of children with AD with extensive longitudinal clinical health outcomes data and longitudinal biospecimens. Using MPAACH, we recently found that low non-lesional, but not lesional, skin FLG expression is associated with the development of co-sensitization and moderate- severe AD, both key risk factors for the future development of allergic co-morbidities of AD. Project 2 will test the central hypothesis that genetic factors including CARD14 act in concert with environmental factors and inflammation to determine FLG expression in AD skin, driving transient or persistent skin barrier dysfunction, which may differentially impact long-term AD outcomes. Project 2 builds upon prior cycles of AADCRC funding and leverages the extensive longitudinal clinical and molecular data and biospecimens available from MPAACH and Project 1. In Aim 1, we will identify genetic variants that modulate skin FLG expression and integrate this with clinical, exposure, and molecular data from MPAACH to identify the combination of factors that determine skin FLG expression. We found that rs11652075 in CARD14 results in increased expression of CARD14 and leads to attenuated FLG expression. In Aim 2, we will build on this data and determine the mechanisms that link rs11652075 and enhanced CARD14 signaling to FLG homeostasis. While LoF FLG mutations are important in the atopic march, the relationship between the trajectory of FLG expression in early life and over time with longitudinal AD outcomes is unclear. In Aim 3, we will determine the impact of low skin FLG expression (persistent or transient) over time and the genetic loci identified in Aim 1 on AD outcomes. Based on reports that early application of emollients to the skin may prevent the development of AD, allergic sensitization, and food allergy, this study is clinically important because it may help identify individuals with the magnitude and duration of dysregulated barrier function that may benefit from prevention and intervention strategies designed to enhance skin barrier function. Moreover, our study will help determine the optimal timing to deliver these interventions. Finally, this project adequately represents Black and White children and will synergize with Projects 1 and 3. This timely project will have significant public health impact.