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

摘要 特应性皮炎(AD)影响着全世界高达20%的儿童，是一个日益严重的公共卫生问题。 尽管婴幼儿的阿尔茨海默病可以缓解，但从AD进展到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，即特应性进行曲。其作用机制 特应性进行曲的背后是不完全理解的，这是知识上的一个关键差距，因为 为了设计能够劫持或中止特应性行军的预防策略，信息是必要的。这个 微丝聚集蛋白在AD发病和特应性进行期中的重要作用 已经得到了证明并得到了广泛的审查。特应性皮炎进展为 儿童哮喘(MPAACH)队列是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检疫。使用MPAACH，我们最近发现低非皮损， 但不是皮损，皮肤Flg的表达与共敏化和中重度AD的发展相关，这两个因素都是未来AD过敏性共病发展的关键危险因素。项目2将测试 包括CARD14在内的遗传因素与环境因素和 炎症以确定阿尔茨海默病皮肤中Flg的表达，导致暂时性或持久性皮肤屏障功能障碍， 这可能会对AD的长期结果产生不同的影响。项目2建立在AADCRC以前的供资周期基础上 并利用MPAACH提供的广泛的纵向临床和分子数据以及生物图谱 和项目1。在目标1中，我们将识别调节皮肤Flg表达的基因变体，并将其 MPAACH的临床、暴露和分子数据，以确定决定 皮肤Flg的表达。我们发现在CARD14中rs11652075导致CARD14和CARD14的表达增加 导致Flg表达减弱。在目标2中，我们将以这些数据为基础，并确定链接的机制 Rs11652075和增强的CARD14信号转导FLG动态平衡。虽然LOF FLOG突变在 特应性进行曲，早期生命中Flg表达轨迹与随时间推移的关系 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 随着时间的推移(持久性或暂时性)和目标1中确定的关于阿尔茨海默病结果的遗传位点。根据报告， 早期在皮肤上使用润肤剂可能会防止AD的发展、过敏反应和食物 过敏，这项研究具有重要的临床意义，因为它可能有助于识别个体的程度和持续时间 调节失调的屏障功能，可能受益于旨在增强 皮肤屏障功能。此外，我们的研究将有助于确定实施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人儿童，并将与项目1和项目3协同工作。 这一及时的项目将对公共卫生产生重大影响。

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.