BDNF SNP rs10767664调控p65磷酸化参与变应性鼻炎肥大细胞的活化及其机制的研究

The incidence of allergic rhinitis (AR) shows a trend of increasing year by year. Gene related researches have become a hot spot in the study of pathogenesis of AR. Our previous study showed that BDNF SNP rs10767664 increased the risk of moderate-severe AR. Our pre-experiments confirmed different expression level of serum inflammatory cytokines in different BDNF SNP rs10767664 genotype AR patients. Bioinformatics analysis showed that the BDNF SNP rs10767664 was the binding site of transcription factor p65’s conserved REL homology, and p65 could be phosphorylated at this site. Moreover, phosphorylated p65 was up-regulated in mast cells (MC) infiltrated in AR. Therefore, we propose that BDNF SNP rs10767664 may be involved in AR inflammatory pathology through the regulation of p65 phosphorylation and activation of MC functions. This subject intends to use human mast cell line, AR tissue isolated MC in vitro and humanized AR mouse model to make a comprehensive and in-depth study on BDNF SNP rs10767664’s regulation of p65 phosphorylation which involved in MC function and AR inflammatory pathology. It will be helpful to elucidate the mechanism of BDNF SNP rs10767664 regulatory p65 phosphorylation involved in MC function，and provide new targets for clinical diagnosis and treatment of AR.

变应性鼻炎（AR）的发病率呈逐年上升的趋势，基因相关研究已成为AR发病机制的研究热点。我们的前期研究表明，BDNF SNP rs10767664增加了中重度AR的患病风险；预实验证实了不同BDNF SNP rs10767664基因型AR患者外周血清炎症因子的表达存在差异；生物信息学分析显示此位点是转录因子p65保守REL同源区的结合位点，p65可在此位点磷酸化；而在AR鼻黏膜浸润的肥大细胞（MC）中，磷酸化p65表达上调。因此我们提出BDNF SNP rs10767664可能通过调控p65磷酸化激活MC功能参与AR炎症病理过程这一科学假说。本项目拟在人肥大细胞系、AR组织分离MC体外培养及人源化AR小鼠模型中，全面深入的阐明BDNF SNP rs10767664调控p65磷酸化参与MC功能的机制，并探讨这种机制在AR炎症反应中的作用，可能对未来AR的治疗新思路和新靶点提供理论依据。

变应性鼻炎（AR）的发病率呈逐年上升的趋势，而BDNF参与AR的发病机制尚不完全清楚。基于前期研究基础，我们提出BDNF/p65/肥大细胞（MC）轴参与AR炎症反应的假说。我们通过多种检测手段检测了BDNF在AR及对照中鼻黏膜组织及外周血中的表达水平，发现BDNF 在变应性鼻炎中的表达上调，在体外试验中，验证了BDNF促进p65磷酸化，活化肥大细胞释放II型炎性介质参与变应性鼻炎的发病机制；发现血清BDNF水平可评价变应性鼻炎的严重程度，有望成为预测变应性鼻炎伴或不伴哮喘患者AIT反应的候选标志物；发现hsa_circRNA_404013可能作为变应性鼻炎的外周血循环检测标志物，在人体中hsa_circRNA_404013可能通过has-miR-182-5p调控BDNF的表达水平；发现BDNF在非变应性鼻息肉发病中可能参与局部嗜酸性验证浸润，并可能影响下呼吸道的功能，BDNF可能是一个嗜酸性NPs的潜在治疗靶点。因此，BDNF可能作为过敏性鼻炎/鼻息肉等鼻黏膜慢性炎症性疾病的诊断和治疗的监测指标，以及成为新的治疗靶点，通过抑制BDNF在鼻腔局部的表达水平抑制鼻黏膜炎症反应，缓解症状。