Chromosome 17q, allergic inflammation, and remodeling

描述（由申请人提供）：全基因组关联研究已经确定染色体17q21与哮喘之间有很强的联系。该提案的重点是ORMDL-3，这是一种定位于染色体17q21的蛋白质，在几项全基因组关联研究中与哮喘高度相关。本提案中ORMDL-3在哮喘患者肺部功能的研究将通过研究者实验室独特试剂的开发而得到加强（例如通用和细胞特异性ORMDL-3转基因和ORMDL-3缺陷小鼠；ORMDL抗体的开发进行免疫组织学检查）。根据我们的初步数据，我们假设过敏原诱导的ORMDL-3表达调节多种上皮通路（炎症、重塑、修复）以及ER ATF6通路的表达，这些通路共同在哮喘的发病机制中发挥重要作用。拟议的研究将通过体外（肺细胞中ORMDL-3的敲除或过表达）和体内研究（ORMDL-3转基因和ORMDL-3缺陷小鼠）来确定ORMDL3在过敏原和鼻病毒诱导的哮喘发病机制中的作用。

DESCRIPTION (provided by applicant): Genome wide association studies have identified strong linkage between chromosome 17q21 and asthma. The focus of this proposal is on ORMDL-3, a protein localized to chromosome 17q21, which has been highly linked to asthma in several genome wide association studies. The investigation of the function of ORMDL-3 in the lung in asthma in this proposal will be enhanced by the development of unique reagents in the investigators lab (e.g. universal and cell specific ORMDL-3 transgenic and ORMDL-3 deficient mice; development of antibody to ORMDL to perform immunohistological). Based on our preliminary data we hypothesize that allergen induced ORMDL-3 expression regulates expression of multiple epithelial pathways (inflammation, remodeling, repair), as well as the ER ATF6 pathway which together play an important role in the pathogenesis of asthma. The studies proposed will use in vitro (knock down or over-expression of ORMDL-3 in lung cells) and in vivo studies (ORMDL-3 transgenic and ORMDL-3 deficient mice) to determine the role of ORMDL3 in the pathogenesis of allergen and rhinoviral induced asthma.