Genetics of epithelial genes in childhood asthma

过敏性疾病是一个主要的全球健康负担，影响高达40%的世界人口。共同 生物学途径是过敏性疾病如哮喘、AD、FA和EE的基础， 链接.事实上，上皮细胞越来越多地被认为是过敏性疾病发病机制的关键参与者。 炎症因此，需要研究进一步阐明上皮基因和途径， 导致过敏性炎症这是强调的事实，目前没有哮喘治疗 专门针对上皮细胞在上一轮融资中，我们采用了一种新颖的无偏见策略， 结合哮喘患者鼻上皮细胞的表达谱， 哮喘患病率的差异和遗传关联研究，以确定上皮基因， 导致儿童哮喘。我们鉴定了几个上皮基因，这些基因以前没有被认识到在 哮喘对这些基因的进一步分析表明，这些基因中的一些是特定于一种上皮细胞的。 表面，并与一个过敏性疾病，而其他共同的多个上皮表面 和过敏性疾病。总的来说，我们的数据表明，根据靶器官/粘膜表面， 有共同的和不同的上皮基因和途径导致变应性炎症。的 识别上皮基因和途径，使个体易患特异性或共同的过敏性 疾病，将授权寻找专门针对上皮表面的新疗法， 开发针对单独和/或组合的变应性病症优化的治疗策略。在 在前一个周期，我们研究了患有哮喘和/或AR的儿童。在本申请中，我们建议扩展我们的 遗传学方法来检验这一假设，即过敏驱动的上皮基因在前一个周期中识别， 资金（SERPINB 3/4，KIF 3A，DNAH 5，SPRR 2B，ADCY 2，PDE 4 B，PLAU，EGFR）将证明独特的 与儿童哮喘、特应性皮炎和/或食物过敏的重叠关联， 这些基因的遗传贡献通过与上皮基因的上位性相互作用而改变， 维持粘膜屏障的完整性和/或促进Th 2应答。

Allergic disorders are a major global health burden affecting up to 40% of the world population. Common biologic pathways underlie allergic diseases such as asthma, AD, FA and EE with the epithelium being a link. Indeed, epithelial cells are increasingly recognized as critical participants in the pathogenesis of allergic inflammation. As such, studies are needed to further elucidate the epithelial genes and pathways that contribute to allergic inflammation. This is underscored by the fact that there is currently no asthma therapy that specifically targets the epithelium. In the last cycle of funding, we utilized a novel unbiased strategy, which combined expression profiling of nasal epithelial cells from patients with asthma, population differences in asthma prevalence, and genetic association studies, to identify epithelial genes that contributed to childhood asthma. We identified several epithelial genes with previously unrecognized roles in asthma. Further analyses of these genes suggest that some of these genes are specific to one epithelial surface and are associated with one allergic disease, while others are common to multiple epithelial surfaces and allergic disorders. Collectively, our data suggest that depending on the target organ/mucosal surface, there are common and distinct epithelial genes and pathways that contribute to allergic inflammation. The Identification of the epithelial genes and pathways, which predispose individuals to specific or shared allergic disorders, will empower the search for novel therapeutics aimed specifically at the epithelial surface, and the development of treatment strategies that are optimized for allergic disorders alone and/or in combination. In the prior cycle, we studied children with asthma and/or AR. In this application, we propose to extend our genetic approach to test the hypothesis that allergy-driven epithelial genes Identified in the prior cycle of funding (SERPINB3/4, KIF3A, DNAH5, SPRR2B, ADCY2, PDE4B, PLAU, EGFR) will demonstrate unique and overlapping associations with asthma, atopic dermatitis, and/or food allergy in children and that the genetic contribution of these genes is modified by epistatic interactions with epithelial genes critical in maintaining the integrity of the mucosal barrier and/or promoting Th2 responses.