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

项目摘要 在这个新的R 01申请题为“了解哮喘风险位点的分子遗传机制： IL 33、IL 1 RL 1和GSDMB，”总体假设是常见的遗传多态性改变了 气道对环境因素的反应，从而影响哮喘中2型炎症的风险。 研究人员指出了传统的遗传流行病学研究在确定 遗传风险基因座影响疾病的发展。他们认为，常见的遗传变异与 增加2型炎症的风险，2型炎症是哮喘患者气道中存在的主要病理学。的 研究者已经开发出表征存在于气道中的2型炎症程度的方法 并使用这些措施将受试者分类为2型高或低，以确定 基因对分子疾病内型的贡献。本申请提出了三个目的：1）识别 使用CRISPR-Cas9 DNA在IL 1 RL 1基因中与哮喘相关的致病遗传变异 2）探讨IL-33释放的细胞生物学和gasdermin蛋白在这种细胞中的作用。 研究IL 33和GSDMB在气道上皮细胞中的表达， 精细绘制观察到的“表达数量性状基因座”，并将这些SNP与2型高哮喘风险相关。 总之，这些研究将有助于1）进一步确定影响遗传风险的多态性， 2型高哮喘的发展，2）将阐明治疗干预的新途径，3） 从遗传学上确定最有可能受益于新疗法的目标人群。

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.