ADAM33在维吾尔族人群哮喘气道血管重塑中的作用和分子机制

Asthmatic airway remodeling occurs prior to clinical symptoms, the airway vascular regeneration and remodeling is the principal characteristics of airway remodeling, while the mechanism is unknown. ADAM33 is newly found and had been recognized as the susceptible gene of asthma. Our research team found that ADAM33 gene has SNPs and susceptible or protective haplotype related to Uighur asthmatic patients; T-cytokines IL-4, IL-13 and INF-γ may influence the airway vascular remodeling by regulate the expression of ADAM33 gene. But the influence and its molecular mechanism (signal pathway) of ADAM33 anomaly expression to airway vessel had not been reported worldwide yet. Our study intended to adopt the clinical data which had been confirmed among Uighur patients that the pathogenesis of asthma did have relationship with the ADAM33 gene mutation, observe the regulate effect of ADAM33 and signal transduction pathway on airway vascular remodeling (proliferation, apoptosis and motility) in the primary cultured asthmatic airway vascular endothelial/smooth muscle cell and how the T-cytokines regulate the expression of ADAM33 gene. To verify the relationship and the molecular mechanism between ADAM33 and the the severity degree of airway vascular remodeling and lung function, provide a new project in the prevention and treatment of asthma.

支气管哮喘气道重塑的发生先于临床症状的出现，气道血管的再生与重塑是气道重塑的主要特征，其机制有待阐明。ADAM33是人类新近发现，已被确定为哮喘的易感基因。课题组研究发现：ADAM33基因存在与维吾尔族哮喘人群相关的SNPs和易感性或保护性的单体型；T细胞因子IL-4、IL-13和INF-γ可能通过调控ADAM33表达影响气道血管重塑。但是ADAM33基因异常表达对气道血管所产生的影响和分子机制（信号途径），迄今国内外尚无报道。本研究拟将已证实哮喘发病与ADAM33基因突变相关的维吾尔族患者的临床资料引入到研究中，在原代培养的哮喘患者气道血管内皮/平滑肌细胞中观察ADAM33对气道血管重塑（细胞增殖、凋亡、迁移等）的影响作用和信号传导通路，以及T细胞因子对ADAM33基因表达的调控机制，并在哮喘患者临床数据中验证ADAM33与气道重塑严重程度、肺功能的关系和分子机制，为哮喘防治提供新思路。

支气管哮喘发病率和死亡率有逐年增加趋势。哮喘特征性的表现之一是气道重塑，常先于临床症状的出现，并可导致气道不可逆性的阻塞，一直以来都是呼吸科学界倍受关注的研究热点。课题组研究发现重度哮喘患者组气管壁血管密度、数量明显高于正常人；随后体外实验采用INF-γ、IL-4+IL-13处理气道血管平滑肌细胞后ADAM33的表达明显改变。为了研究气管壁血管细胞在哮喘中的功能，申请人敲减了人主动脉平滑肌细胞中ADAM33表达，发现沉默ADAM33可以引起细胞增殖能力降低、迁移能力下降，并能促进细胞凋亡及细胞周期阻滞；并同时检测出PI3K/AKT/mTOR通路及下游靶分子也发生了相应的变化，提示ADAM33基因异常表达能够调控气道血管平滑肌细胞的生物学行为，进而参与哮喘的气道血管重塑发生，其主要分子机制可能是通过PI3K/AKT/mTOR信号通路来实现的。这些研究结果提示靶向抑制ADAM33的表达在支气管哮喘的治疗中具有潜在的意义，为逆转哮喘气道重塑提供了新思路，为基础医学向临床医学转化搭建桥梁，具有重要的临床转化价值。