Role and Regulation of TSLP in Childhood Allergic Disease

项目摘要 最近召开的一次国际研讨会审查了哮喘/过敏症出生队列的发现， 知识差距和研究重点。在他们的总结中，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哮喘进展的机制。该提案将有助于填补这一 理解上的巨大差距。胸腺基质淋巴细胞生成素（TSLP）是一种主要的上皮细胞因子， 与AD、过敏性致敏和哮喘的发病机制密切相关。皮肤中的抗原暴露 在TSLP的情况下，足以诱导AD和肺部气道炎症，这表明皮肤来源的 TSLP足以促使AD进展为哮喘。TSLP单核苷酸多态性（SNP）具有 与过敏性致敏和哮喘以及AD相关。AD患者TSLP表达增加 TSLP中的疾病相关eQTL与TSLP表达相关。这些研究共同表明TSLP 在生命早期促进过敏性致敏和AD，可能是一个重要的驱动因素， 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， 在人皮肤中诱导TSLP的机制仍不清楚。我们最近发现， TSLP SNPs，25%破坏或创建新的CpG位点，这显著高于CpG位点的频率。 在基因组中的SNP，CpG-SNP的流行率甚至更高的TSLP SNP中， 与过敏性疾病有关。我们最近已经确定了TSLP基因座上游的候选增强子 这可能驱动TSLP表达，并发现过敏性疾病相关的TSLP SNP，包括eQTL， 或者与这些候选增强子处于强连锁不平衡。根据初步数据，我们 假设机械应力和/或屏障功能障碍通过 TSLP基因座中的遗传变异放松了这种调节，导致增强的 TSLP表达与哮喘临床进展这一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）描述已知风险的影响， 保护等位基因的调节;（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;和（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.