Genetics of epithelial genes in childhood asthma

过敏性疾病是一个主要的全球健康负担，影响着多达40%的世界人口。普普通通 过敏性疾病如哮喘、AD、FA和EE的基础是生物途径，上皮是一种 链接。事实上，上皮细胞越来越多地被认为是过敏症发病机制中的关键参与者。 发炎。因此，需要研究进一步阐明上皮性基因和通路 会导致过敏性炎症。目前没有哮喘治疗方法的事实突显了这一点 它专门针对上皮细胞。在上一轮融资中，我们采用了一种新颖的、不偏不倚的策略 结合哮喘患者鼻黏膜上皮细胞的表达谱 哮喘患病率的差异，以及遗传关联研究，以确定 导致儿童哮喘。我们确定了几个以前未被认识的上皮基因在 哮喘。对这些基因的进一步分析表明，其中一些基因是一种上皮细胞所特有的 与一种过敏性疾病有关，而另一些则常见于多个上皮表面 和过敏性疾病。总的来说，我们的数据表明，根据目标器官/粘膜表面的不同， 有共同和独特的上皮基因和途径，有助于过敏性炎症。这个 识别使个人易患特定或共同过敏的上皮基因和途径 疾病，将使寻找专门针对上皮表面的新疗法，以及 制定针对过敏性疾病单独和/或组合优化的治疗策略。在……里面 在前一个周期中，我们研究了患有哮喘和/或AR的儿童。在此应用程序中，我们建议扩展我们的 用遗传学方法检验在前一个周期中发现的过敏驱动的上皮细胞基因的假设 资助(SERPINB3/4、KIF3A、DNAH5、SPRR2B、ADCY2、PDE4B、PLAU、EGFR)将展示独特的 和儿童哮喘、特应性皮炎和/或食物过敏的重叠关联，以及 这些基因的遗传贡献被与上皮细胞关键基因的上位性相互作用所改变 维持粘膜屏障的完整性和/或促进Th2反应。

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.