黏着斑通路相关突变基因在过敏性鼻炎发病中的作用机制研究

过敏性鼻炎（allergic rhinitis, AR）是最常见的慢性鼻病，现有相关常见变异只能解释39%遗传效应。申请人通过前期国家自然科学基金项目研究发现黏着斑通路VEGFB_c.322 A>C、FLT1_c.603A>T和ITGA2_c.502+1G>A三个罕见突变与尘螨AR发生相关。本研究拟通过在散发AR患者和正常对照人群中筛查VEGFB_c.322 A>C、FLT1_c.603A>T 、ITGA2_c.502+1G>A三个突变的频率，评估突变的致病生物学效应，观察基因型-表型之间的关系；构建突变型和野生型融合蛋白表达体系，在体外细胞水平明确突变影响蛋白功能的具体机制；在体内构建基因突变敲入小鼠模型研究VEGFB、FLT1和ITGA2黏着斑相关通路参与尘螨AR发生的病理过程。本研究将有助于明确AR新的遗传基础，为突变基因引起的AR提供精准诊断，为靶向基因治疗药物开发提供有力的证据。

Allergic rhinitis (AR) is the most common chronic nasal disease. The existing related common variants can only explain 39% of the genetic effects. Based on the study supported by previous national natural science foundation of China, the applicant found that three rare mutations of VEGFB_c.322 A> C, FLT1_c.603A> T and ITGA2_c.502 + 1G> A in focal adhesion pathway are related to the development of dust mite AR. The aim of present study is firstly to evaluate the pathogenic biological effects of mutations and observe the genotype-phenotype relationship by screening the frequency of VEGFB_c.322 A> C, FLT1_c.603A> T and ITGA2_c.502 + 1G> A in sporadic patients with AR and normal controls. Moreover, the study will construct a mutant and wild-type fusion protein expression system to clarify the specific mechanism of mutations affecting protein function at the cellular level in vitro. In addition, the pathological process of VEGFB, FLT1 and ITGA2 in focal adhesion pathway involved in pathogenesis of dust mite AR will be further expounded through setting up a gene mutation knock-in mouse model in vivo. This study will shed lights on clarifying the new genetic basis of AR, providing strong evidence for precise diagnosis and targeted gene therapy.