Understanding the Molecular Genetic Mechanisms of Asthma Risk Loci: IL33, IL1RL1, and GSDMB

项目总结 在这个新的R01应用程序中，标题为“了解哮喘风险基因座的分子遗传机制： IL33、IL1RL1和GSDMB，“最重要的假设是，常见的遗传多态改变了 呼吸道对环境提示的反应，从而影响哮喘患者发生2型炎症的风险。 研究人员解决了传统遗传流行病学研究在确定如何 可遗传的危险基因影响疾病的发展。他们认为，常见的基因变异会相互作用 增加2型炎症的风险，2型炎症是哮喘患者呼吸道的主要病理变化。这个 研究人员已经开发出方法来表征呼吸道中存在的2型炎症的程度。 并使用这些测量方法将受试者分类为2型高或低，以便定义 基因对分子疾病内型的贡献。这项申请提出了三个目标：1)识别 应用CRISPR-Cas9 DNA研究IL1RL1基因中与哮喘相关的致病遗传变异 缺失，2)探讨IL-33释放的细胞生物学和Gasdermin蛋白在该细胞中的作用 3)探讨IL-33和GSDMB在呼吸道上皮细胞中的表达遗传学，为进一步研究IL-33和GSDMB在呼吸道上皮细胞中的表达奠定基础 对观察到的“表达数量性状基因座”进行精细定位，并将这些SNP与2型高哮喘的风险联系起来。 总之，这些研究将有助于1)进一步定义影响遗传风险的基因多态 2型高度哮喘的发展，2)将阐明治疗干预的新途径，以及3) 从基因上定义最有可能从新疗法中受益的目标人群。

PROJECT SUMMARY In this new R01 application entitled “Understanding the Molecular Genetic Mechanisms of Asthma Risk Loci: IL33, IL1RL1, and GSDMB,” the overarching hypothesis is that common genetic polymorphisms alter the airway responses to environmental cues thus influencing the risk of type 2 inflammation in asthma. The investigators address the limitations of traditional genetic epidemiological studies in identifying how heritable risk loci influence the development of disease. They suggest that common genetic variants interact to increase the risk of type 2 inflammation, the dominant pathology present in the airway of asthmatics. The investigators have developed methods to characterize the degree of type 2 inflammation present in the airways of asthmatics and use these measures to classify subjects as type 2 high or low for the purposes of defining the genetic contribution to molecular disease endotypes. This application proposes in three aims to: 1) identify the causal genetic variants that are associated with asthma in the IL1RL1 gene using CRISPR-Cas9 DNA deletion, 2) to explore the cell biology of IL-33 release and the role of gasdermin proteins in this cellular process, and 3) to explore the expression genetics of IL33 and GSDMB in airway epithelial cells in order to fine-map the observed “expression quantitative trait loci” and relate these SNPs to risk of type 2 high asthma. Together these studies will serve to 1) further define the genetic risk polymorphisms that influence the development of type 2 high asthma, 2) will elucidate novel pathways for therapeutic intervention, and 3) to define genetically the target population most likely to benefit from novel therapeutics.