TRPC5通道对变应性鼻炎嗜酸性粒细胞功能调节及其机制研究

The incidence of allergic rhinitis (AR) is increasing quickly. Eosinophils play a very important role in the pathogenesis of AR. Recently scientists have paid more attention to the role of classic transient receptor potential channels (TRPC channels) in regulating cell function and diseases. In order to investigate the role of TRPC5 in the pathogenesis of AR and in regulating function of eosinophils, we establish a mice AR model. Then the effect of gene silencing TRPC5 channel in AR is studied. Furthermore, we culture eosinophils and knockdown TRPC5 channel gene expression. The role of TRPC5 in regulating function of eosinophil and the related signal transduction pathway are studied through the techniques of patch clamp, calcium imaging, molecular and cell biology. Through these experiments, we will make it clear that TRPC5 channel play a very important role in pathogenesis of AR by activating eosinophils through the MAPKs- NF-κB signal transduction pathway. Meanwhile, ion channels are membrane proteins and easier to be intervened by drugs, these results will certainly have an important theoretical and social value for prevention and treatment of allergic rhinitis.

变应性鼻炎(Allergic rhinitis, AR)发病率呈现快速增长趋势，其中嗜酸性粒细胞在AR发病机制中起重要作用，近年来classic transient receptor potential (TRPC)通道在细胞功能及疾病中的作用受到重视，为了探讨TRPC5在AR及嗜酸性粒细胞功能调节中的作用，本研究建立AR小鼠模型，分析AR嗜酸性粒细胞TRPC5通道改变，基因沉默抑制TRPC5后探讨其在AR中的作用；体外培养嗜酸性粒细胞，基因沉默TRPC5后，综合利用膜片钳、钙离子成像、分子和细胞生物学技术探讨TRPC5通道在调节嗜酸性粒细胞功能中的作用及信号转导通路；阐明TRPC5通道激活MAPKs- NF-κB信号转导通路增强嗜酸性粒细胞功能而在AR发生发展中发挥重要作用。并且离子通道是细胞膜表面的蛋白，更易进行药物干预，这些结果对于防治AR将产生重要的理论价值和社会价值。

变应性鼻炎(Allergic rhinitis, AR)发病率呈现快速增长趋势，其中嗜酸性粒细胞在AR发病机制中起重要作用，近年来classic transient receptor potential (TRPC)通道在细胞功能及疾病中的作用受到重视，但是TRPC5在AR中的作用及机制尚未清楚。为了探讨TRPC5在AR及嗜酸性粒细胞功能调节中的作用，本研究建立AR小鼠模型，发现AR小鼠鼻粘膜中TRPC5通道表达增高、炎症反应增强（炎症因子MCP-1、IL-5和MMP-9表达明显增高）和嗜酸性粒细胞明显增多，这些与人AR特征非常相似。体内转染TRPC5-siRNA降低TRPC5能够明显降低变应性鼻炎症状，降低鼻粘膜TRPC5通道表达，降低鼻粘膜嗜酸性粒细胞浸润和炎症因子表达。体外分离、培养嗜酸性粒细胞，通过基因沉默TRPC5通道后，发现TRPC5通道参与了嗜酸性粒细胞细胞内钙稳态的增加，降低TRPC5通道能够抑制嗜酸性粒细胞的炎症因子产生、核转录因子NF-κB、ERK1/2的磷酸化。这些结果证明TRPC5通道可以调控细胞内钙稳态和炎症反应在AR发生发展中起重要作用，其作用是通过调节NF-κB-ERK1/2信号通路参与的嗜酸性粒细胞炎症反应。由于TRPC5通道是细胞膜的表面蛋白，更易进行药物干预，这些结果对于防治AR将产生重要的理论价值和社会价值。