African-Americans with Atopic Dermatitis: Skin Barrier and Immune

患有特应性皮炎的非裔美国人：皮肤屏障和免疫

• 批准号: 9868281
• 负责人: David Margolis
• 金额: $ 34.43万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-18 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9868281
• 关键词: Adult; Affect; African; African American; Age-Months; Allergens; Asians; Asthma; Atopic Dermatitis; Biocompatible Materials; Biology; Child; Childhood; Chronic; Chronic Disease; Code; Development; Disease; Eczema; Ethnic group; European; Filament; Frequencies; Functional disorder; Genes; Genetic; Genetic Epistasis; Genetic Variation; Goals; High Prevalence; Immune; Immune system; Individual; Inflammatory; Knowledge; Longitudinal cohort; Lupus; Mental Depression; Mental disorders; Modeling; Mutation; Non-Malignant; Pathway interactions; Phenotype; Population; Prevalence; Production; Productivity; Prognosis; Proteins; Pruritus; Public Health; Publishing; Quality of life; Race; Recurrence; Registries; Relapse; Reporting; Risk; Role; Schools; Science; Sleep disturbances; Stimulus; Structure; TSLP gene; Variant; Work; base; burden of illness; cohort; disability; early childhood; filaggrin; immunoregulation; infection risk; loss of function; loss of function mutation; novel; protein aggregation; protein function; psychological distress; public health relevance; seasonal allergies; skin barrier; skin disorder; social; targeted treatment

 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.

 描述（由申请人提供）：特应性皮炎（AD）是一种高度过敏性慢性偶发性炎症性皮肤病，通常在3至6个月大时出现，但也可能在儿童后期或成年期出现。在美国，AD影响所有种族和民族的所有儿童的大约10-20%。美国AD的最高患病率是在非洲裔美国人中。AD的患病率在全球范围内不断增加，并且是主要的公共卫生负担。大多数AD儿童也会发生哮喘和季节性过敏。根据最近的全球疾病负担研究，AD是全球最流行的50种疾病之一，在所有非恶性皮肤病中残疾排名第二。 最近的研究已经确定了丝聚蛋白（FLG）的功能丧失突变之间的强烈关联，FLG是一种编码负责维持完整皮肤屏障的蛋白质的基因， AD.我们已经证明，这些突变也与更持久的AD有关。然而，这些突变很少在非洲血统的儿童中发现。因此，我们对非裔美国人AD的基本生物学知识存在差距。我们最近发现聚丝蛋白-2（FLG 2）突变与非裔美国儿童AD的持续性相关。我们还表明，编码胸腺基质淋巴细胞生成素的基因的遗传变异似乎改变了FLG与AD的关联。该提案的目标是全面探索FLG 2与非裔美国人AD的关联，更好地了解胸腺基质淋巴细胞生成素与AD持续性的关联，并探索TSLP/FLG 2如何相互作用以产生持续性AD的表型。我们将继续关注使用FLG作为模型的皮肤屏障基因的功能丧失突变，最近有报道称LOF可能是适应环境刺激的首选途径。 我们计划把研究重点放在非洲裔美国人身上。这项建议有两个目标。第一个目标是更好地了解非裔美国人的FLG 2功能丧失突变。第二个目标是更好地了解TSLP的变化，并最终了解TSLP和屏障功能障碍之间的相互作用。

项目成果

Identification of HLA-DPA1*01:03:01:57 and HLA-DPA1*02:01:01:29 from a case-control study of atopic dermatitis.

从特应性皮炎病例对照研究中鉴定 HLA-DPA1*01:03:01:57 和 HLA-DPA1*02:01:01:29。

• DOI: 10.1111/tan.14900
• 发表时间: 2023
• 期刊: HLA
• 影响因子: 8
• 作者: Damianos,Georgios;Duke,JamieL;Pagkrati,Ioanna;Margolis,DavidJ;Monos,DimitriS
• 通讯作者: Monos,DimitriS

Uncommon variants in FLG2 and TCHHL1 are associated with remission of atopic dermatitis in a large longitudinal US cohort.

• DOI: 10.1007/s00403-021-02319-7
• 发表时间: 2022-12
• 期刊: Archives of dermatological research
• 影响因子: 3

Human leukocyte antigen class-I variation is associated with atopic dermatitis: A case-control study.

• DOI: 10.1016/j.humimm.2021.04.001
• 发表时间: 2021-08
• 期刊: Human immunology
• 影响因子: 2.7
• 作者: Margolis DJ;Mitra N;Duke JL;Berna R;Margolis JD;Hoffstad O;Kim BS;Yan AC;Zaenglein AL;Chiesa Fuxench Z;Dinou A;Wasserman J;Tairis N;Mosbruger TL;Ferriola D;Damianos G;Kotsopoulou I;Monos DS
• 通讯作者: Monos DS

HLA Class I Polymorphisms Influencing Both Peptide Binding and KIR Interactions Are Associated with Remission among Children with Atopic Dermatitis: A Longitudinal Study.

• DOI: 10.4049/jimmunol.2001252
• 发表时间: 2021-05-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Margolis DJ;Mitra N;Kim BS;Duke JL;Berna RA;Hoffstad OJ;Wasserman JR;Ferriola DA;Mosbruger TL;Wubbenhorst BS;Nathanson KL;Monos DS
• 通讯作者: Monos DS