沉默CD38抑制IRE1β-RACK1信号通路稳定钙稳态对改善哮喘气道上皮屏障损伤和气道炎症的作用机制研究

气道炎症是哮喘病理机制核心，气道上皮屏障损伤是启动和维持气道炎症的关键环节，但机制未明。我们前期发现CD38在哮喘气道组织中高表达，抑制其表达可减轻哮喘气道炎症，预实验证实沉默CD38可抑制内质网应激相关蛋白IRE1、RACK1表达和细胞内钙离子浓度升高，上调气道上皮屏障标志蛋白的表达。因此推测：CD38-IRE1β-RACK1信号轴通过内质网应激-线粒体相关内质网膜（MAM）-线粒体Crosstalk机制调控钙稳态，影响气道上皮屏障功能在哮喘气道炎症中的重要作用。本项目拟；①通过构建CD38气道上皮条件性敲除小鼠模型探讨CD38调控哮喘气道上皮屏障及气道炎症的作用；②揭示CD38-IRE1β-RACK1信号轴通过内质网-MAM-线粒体交互调控钙稳态影响上皮屏障功能的分子机制及治疗价值。本研究从新角度阐释沉默CD38恢复哮喘气道上皮屏障改善气道炎症的分子机制，为哮喘防治提供新思路和新靶点。

Airway inflammation is critical in the pathogenesis of asthma. Airway epithelial barrier damage triggers and exacerbates local airway inflammation. However, the precise mechanism underlying such process remains unclear. Our previous studies confirmed that CD38 is highly expressed in airway tissue of asthma, and inhibition of CD38 significantly alleviates local inflammation. In the preliminary experiments, we further observed that CD38 silencing inhibits the expression of endoplasmic reticulum stress-related proteins, IRE1 and RACK1, and suppresses intracellular calcium concentration but upregulates airway epithelial barrier marker protein E-cadherine. Thus, we propose a new hypothesis that the CD38-IRE1β-RACK1 signaling axis participates in the airway epithelial barrier function through regulating endoplasmic reticulum stress-mitochondrial associated endoplasmic reticulum (MAM) -mitochondria crosstalk and calcium homeostasis. This project intends to: 1) investigate the role of CD38 in regulating airway epithelial barrier function in asthma through constructing conditional airway epithelial CD38 knockout mice; 2) explore the molecular mechanism and therapeutic value of CD38-IRE1β-RACK1 signal axis as regulating such endoplasmic reticulum stress-MAM-mitochondria crosstalk in epithelial barrier function. This study will not only elucidate the precise mechanism of airway epithelial barrier damage, but also provide a novel preventive or therapeutic strategy for patients with asthma.