Role and Regulation of TSLP in Childhood Allergic Disease

项目摘要 最近召开了一次国际研讨会，审查哮喘/过敏出生队列的研究结果，并确定 知识差距和研究重点。在总结中，他们得出结论，一个关键的研究优先需要是 更好地了解儿童早期发展为哮喘的机制。这项提议将有助于填补这一空白 理解上的严重差距。胸腺基质淋巴生成素(TSLP)是一种主要的上皮细胞因子 与AD、过敏性过敏和哮喘的发病机制密切相关。皮肤中的抗原暴露 在TSLP的背景下，足以诱导AD和肺部的呼吸道炎症，提示皮肤来源 TSLP足以推动AD向哮喘的进展。TSLP单核苷酸多态性(SNPs)具有 与过敏反应、哮喘以及阿尔茨海默病有关。阿尔茨海默病患者TSLP表达增加 TSLP中与疾病相关的eQTL与TSLP的表达相关。这些研究共同提出了TSLP 促进早期生活中的过敏性敏感化和阿尔茨海默病，可能是一系列疾病进展的重要驱动因素 哮喘的早期过敏表型。尽管TSLP在过敏性疾病中的作用越来越明显，但 在人类皮肤中诱发TSLP的机制尚不清楚。我们最近发现，在已知的 TSLP SNP，25%扰乱或创建新的CpG站点，显著高于CpG- 基因组中的SNPs，CpG-SNPs的患病率在TSLP SNPs中甚至更高 与过敏性疾病有关。我们最近发现了TSLP基因上游的候选增强子 这可能会推动TSLP的表达，并发现与过敏性疾病相关的TSLP SNP，包括eQTL，驻留在 或者与这些候选增强子处于强烈的连锁不平衡。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以下途径转化为TSLP表达 专用增强子和TSLP基因座的遗传变异放松了这一调节，导致增强 TSLP表达与哮喘临床进展的关系。这项应用将对公共卫生产生重大影响。 通过提出的目标，我们将(1)阐明人类表皮屏障缺陷的机制 角质形成细胞被感知并翻译成TSLP转录；(2)描绘已知风险和 这种调节的保护性等位基因；(3)确定TSLP基因座的遗传和表观遗传变异的效用 作为疾病进展为哮喘的生物标志物；以及(4)为开发新的 准确预测学龄前儿童哮喘发展的算法。

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.