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

基本信息

批准号：
10063471
负责人：
Gurjit K. Khurana Hershey
金额：
$ 74.72万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-06 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063471
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

项目摘要

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.

项目概要最近召开的一次国际研讨会回顾了哮喘/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，他们得出的结论是，一个关键的研究优先需求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空缺理解上的严重差距。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 的背景下足以诱发 AD 和肺部气道炎症，表明皮肤源性 TSLP 足以推动 AD 进展为哮喘。 TSLP 单核苷酸多态性 (SNP) 与过敏和哮喘以及AD有关。 AD 中 TSLP 的表达增加 TSLP 中与疾病相关的 eQTL 与 TSLP 表达相关。这些研究共同表明 TSLP 促进生命早期的过敏性致敏和 AD，并可能是部分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，但在人类皮肤中诱导 TSLP 的机制仍不清楚。我们最近发现，在已知的 TSLP SNP，25%破坏或创建新的CpG位点，明显高于CpG-的频率整个基因组中的 SNP，并且 CpG-SNP 的流行率在已被研究的 TSLP SNP 中更高。与过敏性疾病有关。我们最近发现了 TSLP 基因座上游的候选增强子可能驱动 TSLP 表达，并发现与过敏性疾病相关的 TSLP SNP（包括 eQTL）存在或者与这些候选增强子存在强连锁不平衡。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：专用增强子并且 TSLP 位点的遗传变异放松了这种调节，从而导致增强 TSLP 表达和哮喘的临床进展。该应用将对公共健康产生重大影响。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为 TSLP 转录； (2) 描述已知风险的影响和本法规的保护性等位基因； (3)确定TSLP位点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； (4)为新产品的开发提供基础准确预测学龄前儿童哮喘发展的算法。