敲除CCR3基因对变应性鼻炎发病的影响实验研究

Allergic rhinitis has become a serious public health problem, although a large of work has been done, its pathological mechanism has not yet been fully elucidated. Today, we still have not found specific and effective therapeutic targets and interventions to stop this disease. Therefore , it's necessary to find new treatments. Eosinophils play a crucial role in allergic rhinitis, the disease involving an eosinophil-rich infiltrate has been linked with nasal mucosa remodeling. Furthermore, studies of mice specifically deficient in eosinophils have suggested that eosinophils are an integral part of experimental asthma, involved in the recruitment and activation of eosinophils in the asthmatic lung, as well as the mechanism by which eosinophils contribute to asthma.As "one airway,one disease",the same process was found in allergic rhinitis. But for allergic rhinitis, the related mechanism of eosinophils has not been fully illustrated. As such, there is a pressing need to develop new approaches to block eosinophils in the allergic rhinitis for better understanding the process. CCR3, a receptor abundantly expressed on eosinophils, Although chemokines are notorious for stimulating several receptors, the eotaxins are unusual in that they signal through a single chemokine receptor CCR3 . Recent studies have demonstrated that CCR3 gene deletion impairs eosinophil recruitment in models of experimental asthma. It remains unknown whether CCR3 is a dominant pathway in models of allergic rhinitis. The contribution of CCR3 toward other important allergic rhinitis parameters, including mucus production,has not yet been addressed. Gene knockout is an important way to research gene action.To clarify the role and regulation of eosinophils, we subjected the key eosinophil-related genetically engineered mice(CCR3 knockout) to a model of allergic rhinitis aiming to identify the result that was independent of the genetic targeting strategy for treatment of allergic rhinitis.

变应性鼻炎已成公众健康的严重问题，其相关的病理机理过程尚未完全阐明，临床上缺乏特异而有效的治疗靶点和干预手段，迫切需要寻找新治疗方法。大量嗜酸性细胞浸润是变应性鼻炎的重要特征,也是变应性鼻炎的一个重要发病环节，因此抑制嗜酸性细胞的作用有助于变应性鼻炎疾病过程的控制。变应性鼻炎不仅是局部疾病也是全身性疾病,而骨髓中嗜酸性细胞的迁移起到了关键作用,控制其迁移、促使其凋亡在清除嗜酸性细胞的影响中起着重要作用。CCR3是嗜酸性细胞的主要表达受体,在调控嗜酸性细胞作用方面起着重要作用，而基因敲除是研究控制基因作用的重要手段，目前，运用基因敲除技术敲除靶基因CCR3，进而研究其对变应性鼻炎发病机制的影响报道不多见。因此，我们设计这一课题运用基因敲除技术敲除CCR3，从而全面研究其在控制嗜酸性细胞的迁移、活化及凋亡中的作用，发现其作用机制，了解其在变应性鼻炎中的治疗效果及可行性。

变应性鼻炎已成公众健康的严重问题，其相关的病理机理过程尚未完全阐明，临床上缺乏特异而有效的治疗靶点和干预手段，迫切需要寻找新治疗方法。嗜酸性细胞是变应性鼻炎发病的重要效应细胞，因此抑制嗜酸性细胞的作用有助于变应性鼻炎疾病过程的控制CCR3是嗜酸性细胞的主要表达受体,在调控嗜酸性细胞作用方面起着重要作用，而基因敲除是研究控制基因作用的重要手段，目前，运用基因敲除技术敲除靶基因CCR3，进而研究其对变应性鼻炎发病机制的影响报道不多见。在此背景基础上开展了可以设计及研究并获得重要研究结果如下：1成功进行构建敲除CCR3基因小鼠模型构建及鉴定，奠定后续体内外实验基础。2发现敲除 CCR3 基因对小鼠生长情况良好，主要脏器病理结构无改变，鼻腔黏膜病理改变明显减轻。3发现通过敲除CCR3基因，阻断Eotaxin/CCR3通路可抑制EOS增殖、成熟，促进EOS凋亡，能缓解变应性疾病中EOS的炎症反应。4发现CCR3-/-小鼠变应性鼻炎小鼠 IFN-γ 水平升高，Ig E、IL-4 水平降低，提示 CCR3 基因在变应性鼻炎疾病的发生发展过程的的 Th1 细胞因子和 Th2 细胞因子失衡中有着非常重要的作用。在本课题基础上进一步成功构建骨髓CCR3基因敲除并鉴定成功并开展相关研究，为后续开展嗜酸性细胞迁移机制的相关研究构建良好基础。本实验结果表明CCR3基因可做为变应性鼻炎治疗靶基因，在变应性鼻炎疾病的发病发展及治疗方面具有重要作用，可进一步在临床实践中开发利用。本项目的顺利完成为进一步开展变应性鼻炎靶基因CCR3相关系列研究打下良好的科学实验基础。