Role and Regulation of TSLP in Childhood Allergic Disease

TSLP在儿童过敏性疾病中的作用和调节

• 批准号: 10307538
• 负责人: Gurjit K. Khurana Hershey
• 金额: $ 73.07万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-06 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307538
• 关键词: Age; Algorithms; Allergic; Allergic Disease; Antigens; Asthma; Atopic Dermatitis; Automobile Driving; Binding Sites; Biological Markers; Birth; Breast Feeding; CRISPR/Cas technology; Child; Childhood; Childhood Asthma; Clinical; Data; Defect; Development; Disease; Disease Progression; Educational workshop; Enhancers; Epithelial; Epithelial Cells; Experimental Models; FAIRE sequencing; Family; Foundations; Frequencies; Functional disorder; Genetic; Genetic Enhancer Element; Genetic Transcription; Genetic Variation; Genetic study; Genome; Human; Hypersensitivity; Immune; Impairment; In Vitro; Infection; Injury; International; Knowledge; Laboratories; Life; Linkage Disequilibrium; Literature; Lung; Mechanical Stress; Methylation; Modeling; Mus; Nude Mice; Nursery Schools; Pathogenesis; Pathologic; Patients; Phenotype; Positioning Attribute; Predictive Value; Preschool Child; Prevalence; Pruritus; Public Health; Publishing; Race; Recording of previous events; Regulation; Regulatory Element; Research Personnel; Research Priority; Risk; Risk Factors; Role; Sampling; Scanning; Severities; Single Nucleotide Polymorphism; Site; Skin; Socioeconomic Status; Structure of mucous membrane of nose; TSLP gene; Translating; Up-Regulation; Upstream Enhancer; Virus Diseases; aged; airway inflammation; base; biobank; bronchial epithelium; cohort; cytokine; early childhood; environmental tobacco smoke; epigenetic regulation; epigenetic variation; epithelial injury; filaggrin; in silico; innovation; keratinocyte; overexpression; pet animal; promoter; prospective; protective allele; risk variant; sex; skin barrier; skin lesion; traffic-related air pollution; transcription factor

Project Summary A recent international workshop convened to review the findings from asthma/allergy birth cohorts and identify knowledge gaps and research priorities. In their summary, they conclude that a key research priority need is to better understand the mechanisms of progression to asthma in early childhood. This proposal will help to fill this critical gap in understanding. Thymic stromal lymphopoietin (TSLP) is a major epithelial cytokine that and is strongly implicated in the pathogenesis of AD, allergic sensitization, and asthma. Antigen exposure in the skin in the context of TSLP is sufficient to induce AD and airway inflammation in the lung, suggesting that skin-derived TSLP is sufficient to drive the progression of AD to asthma. TSLP single nucleotide polymorphisms (SNPs) have been associated with allergic sensitization and asthma, as well as AD. Expression of TSLP is increased in AD and disease-associated eQTL in TSLP correlate with TSLP expression. These studies collectively suggest TSLP promotes allergic sensitization and AD in early life and may be an important driver of progression of a subset of early allergic phenotypes to asthma. Despite the increasingly evident role of TSLP in allergic disease, the mechanisms by which TSLP is induced in human skin remain unclear. We recently found that among the known TSLP SNPs, 25% disrupt or create a new CpG site, which is significantly higher than the frequency of CpG- SNPs across the genome, and the prevalence of CpG-SNPs is even higher among TSLP SNPs that have been associated with allergic disorders. We have recently identified candidate enhancers upstream of the TSLP locus that may drive TSLP expression and found that allergic disease-associated TSLP SNPs, including eQTL, reside or are in strong linkage disequilibrium with these candidate enhancers. Based on our preliminary data, we hypothesize that mechanical stress and/or barrier dysfunction are translated to TSLP expression through dedicated enhancers and that genetic variation in the TSLP locus relaxes this regulation resulting in enhanced TSLP expression and clinical progression to asthma. This application will have significant public health impact. Through the proposed aims, we will (1) elucidate the mechanisms by which barrier defects in human epidermal keratinocytes are sensed and translated to TSLP transcription; (2) delineate the impact of known risk and protective alleles on this regulation; (3) determine the utility of genetic and epigenetic variation in the TSLP locus as biomarkers of disease progression to asthma; and (4) provide the foundation for development of new algorithms to accurately predict the development of asthma among preschool aged children.

项目摘要 最近的国际研讨会召集了，审查哮喘/过敏出生队列的发现，并确定 知识差距和研究重点。在总结中，他们得出结论，关键的研究优先需要是 更好地了解幼儿时期发展为哮喘的机制。该建议将有助于填补此事 理解的危险差距。胸腺基质淋巴细胞生成素（TSLP）是主要的上皮细胞因子，是 与AD的发病机理，过敏敏化和哮喘密切相关。皮肤中的抗原暴露 在TSLP的背景下，足以诱导肺中的AD和气道炎症，这表明皮肤衍生 TSLP足以驱动AD向哮喘的发展。 TSLP单核苷酸多态性（SNP）具有 与过敏敏化和哮喘以及AD有关。 TSLP的表达在AD中增加 TSLP中与疾病相关的EQTL与TSLP表达相关。这些研究共同提出了TSLP 在早期促进过敏反应和广告，可能是一部分进展的重要驱动力 早期对哮喘的过敏表型。尽管TSLP在过敏性疾病中的作用越来越明显，但 人体皮肤中诱导TSLP的机制尚不清楚。我们最近发现，在已知的 TSLP SNP，25％中断或创建新的CpG位点，该位点显着高于CpG-的频率 在TSLP SNP中 与过敏性疾病有关。我们最近确定了TSLP基因座上游的候选增强剂 这可能会驱动TSLP表达，并发现包括EQTL在内的与过敏性疾病相关的TSLP SNP居住 或与这些候选增强子的强烈连锁不平衡。根据我们的初步数据，我们 假设机械应力和/或屏障功能障碍通过 专用增强剂和TSLP基因座的遗传变异使该调节放松，从而增强 TSLP表达和临床向哮喘的进展。该申请将对公共卫生产生重大影响。 通过提出的目标，我们将（1）阐明人类表皮中屏障缺陷的机制 角质形成细胞被感测并翻译为TSLP转录。 （2）描述已知风险和 该法规的保护等位基因； （3）确定TSLP基因座遗传和表观遗传变异的效用 作为疾病发展为哮喘的生物标志物； （4）为开发新的基础 算法可以准确预测学龄前儿童哮喘的发展。

项目成果

Analysis of chromatin accessibility in human epidermis identifies putative barrier dysfunction-sensing enhancers.

• DOI: 10.1371/journal.pone.0184500
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Lander JM;Supp DM;He H;Martin LJ;Chen X;Weirauch MT;Boyce ST;Kopan R
• 通讯作者: Kopan R