哮喘是严重危害公共健康的常见病，与遗传因素高度相关。在不同种族人群已证实ORMDL3为哮喘易感基因，然而其功能及机制尚未明确。国外报道，下调肥大细胞（mast cell，MC）中ORMDL3表达，炎症反应增强；本课题组前期结果显示，MC活化后ORMDL3表达显著下调；过表达ORMDL3的MC活化后，炎症介质释放水平显著下调，内质网应激及自噬水平上调。据此我们推测：ORMDL3可能是MC活化的"负调控"因子，其通过内质网应激激活自噬，降解胞内蛋白，抑制MC活化，调控哮喘发生发展。为证实假设，拟通过:①ORMDL3-/-小鼠哮喘模型探讨其对哮喘表型、MC内质网应激、自噬及活化功能的影响；②低表达和过表达ORMDL3，明确"ORMDL3→内质网应激→启动自噬→抑制活化"负调控作用轴中的相互关系，找到关键信号通路及分子，为更全面认识过敏性疾病自我调节机制，寻找保护因子干预哮喘奠定良好的基础。

Asthma is a common disease that seriously endangers public health and is highly related to genetic factors. ORMDL3 has been proved to be an asthma susceptibility gene in different ethnic groups, but its function and mechanism are not clear. It was reported abroad that down-regulation of mast cell （MC） ORMDL3 expression increased the inflammatory response. The results of our previous study showed that the expression of ORMDL3 in mast cells was significantly down-regulated after sensitization and activation of mast cells. The release level of inflammatory mediators were significantly down-regulated, endoplasmic reticulum stress and autophagy were up-regulated after overexpression of ORMDL3. Therefore, we speculate that ORMDL3 may be a "negative regulatory" factor in activation of MC, activate autophagy through endoplasmic reticulum stress, degrade intracellular protein and inhibit MC activation to regulate the development of asthma. To confirm the hypothesis, this study will explore the effects of ORMDL3 on asthma phenotype, mast cell endoplasmic reticulum stress, autophagy and MC activation in ORMDL3-/- mice. The relationship of ORMDL3 with endoplasmic reticulum stress and autophagy and the signal pathway will be analyzed by low and over expression of ORMDL3 in MC/9. Elucidation of the role of "ORMDL3 → endoplasmic reticulum stress → initiate autophagy → inhibition of activation " as a negative regulation axis in asthma, will lay a good foundation for a more comprehensive understanding of the self-regulation mechanism of allergic diseases and the search for new targets for asthma intervention.