African-Americans with Atopic Dermatitis: Skin Barrier and Immune

 描述(申请人提供)：特应性皮炎(AD)是一种高度瘙痒的慢性发作性炎症性皮肤病，通常表现在3至6个月大，但也可能出现在儿童后期或成年。在美国，所有种族和民族的儿童中，大约有10%-20%受到阿尔茨海默病的影响。美国AD患病率最高的是非裔美国人。阿尔茨海默病在全球范围内的患病率正在上升，它是一个主要的公共卫生负担。大多数患有AD的儿童还会患上哮喘和季节性过敏。根据最近的全球疾病负担研究，AD是世界上最常见的50种疾病之一，在所有非恶性皮肤病中，它的残疾排名第二。最近的研究证实了微丝蛋白(flaggrin，一种编码一种负责维持完整皮肤屏障的蛋白质的基因)功能丧失突变与 广告。我们已经证明，这些突变也与更持久的AD有关。然而，这些突变在非洲血统的儿童中很少被注意到。因此，我们对非裔美国人阿尔茨海默病的基本生物学知识存在差距。我们最近发现，微丝蛋白-2(flaggrin-2，Flg2)突变与非裔美国儿童AD的持久性有关。我们还表明，编码胸腺基质淋巴生成素的基因的遗传变异似乎改变了Flg与AD的关联。本研究的目的是全面探讨非裔美国人中FlG2与AD的关系，更好地了解胸腺基质淋巴生成素与AD持续性的关系，并探讨TSLP/FlG2如何相互作用创造持续性AD的表型。我们将继续关注以FLG为模型的皮肤屏障基因的功能丧失突变，这一概念最近被一份报告证实，LOF可能是适应环境刺激的首选途径。我们计划将我们的研究重点放在非裔美国人身上。这项提议有两个目标。第一个目标是更好地了解非裔美国人的Flg2功能丧失突变。第二个目标是更好地了解TSLP的变异，并最终了解TSLP和屏障功能障碍之间的相互作用。

 DESCRIPTION (provided by applicant): Atopic dermatitis (AD) is a highly pruritic chronic episodic inflammatory skin disease that often presents between 3 and 6 months of age but may also present during later childhood or in adulthood. In the US, AD affects roughly 10-20% of all children of all races and ethnic groups. The highest prevalence of AD in the US is among African-Americans. The prevalence of AD is increasing worldwide and it is a major public health burden. The majority of children with AD will also develop asthma and seasonal allergies. From the recent Global Burden of Disease study, AD was among the top 50 most prevalent diseases worldwide and it had the second highest disability rank of all non-malignant skin diseases. Recent studies have established a strong association between loss-of-function mutations in filaggrin (FLG), a gene coding for a protein responsible for maintaining an intact skin barrier and AD. We have already demonstrated that these mutations are also associated with more persistent AD. However, these mutations are rarely noted in children of African ancestry. As a result, there is a gap in our knowledge with respect to the basic biology of AD in African-Americans. We recently found that mutations in filaggrin-2 (FLG2) are associated with persistence of AD in African-American children. We have also shown that genetic variation of the gene that codes thymic stromal lymphopoietin appears to modify the association of FLG with AD. The goals of this proposal are to comprehensively explore the association of FLG2 with AD in African-Americans, to better understand the association of thymic stromal lymphopoietin with the persistence of AD, and to explore how TSLP/FLG2 interact to create the phenotype of persistent AD. We will continue to focus on loss-of- function mutations in skin barrier genes using FLG as a model, a concept that was recently justified by a report that LOF may be a preferred pathway for adaptation to environmental stimuli. We plan to focus our studies on African-Americans. This proposal has two goals. The first goal is to better understand FLG2 loss-of-function mutations in African Americans. The second goal is to better understand TSLP variation and ultimately the interaction between TSLP and barrier dysfunction.