中国人自身炎症性疾病的临床和基因表型谱及发病机制研究

Autoinflammatory diseases (AUID) are newly introduced hereditary periodic disorders and their prevalence are underestimated. The proteins encoded by mutant genes are involved in the dysregulation of innate immune system. Autoinflammatory mechanisms are not clear and mainly related to inflammatory signal transduction. Still, in many cases of autoinflammation no genetic abnormalities are detected and treatment remains suboptimal, raising the question of novel pathogenic mutations in unexplored genes and pathways. To date, no systematic study addressing the phenotype and genotype of AUID in Chinese patients has yet been reported, not to mention pathogenesis research of AUID. In our previous study, we found that in NOD2-associated autoinflammatory disease, the encoded protein function is dependent on the genotype. We hypothesize that Chinese AUID patients may have different phenotype and genotype from Caucasians, and the pathogenesis is associated with signal transduction and autophagy. In order to confirm this hypothesis, we will identify the phenotype and genotype of Chines AUID patients using Chinese Rheumatism Data Center and Next-generation sequencing technology. We will also observe the signal transduction and autophagy mechanisms and determine the function of mutant genes in AUID, in plasm, peripheral blood mononeuclear cells and macrophages from AUID patients, using technique of molecular biology. This study will determine the phenotype and genotype of Chinese AUID patients, throw more light on the pathogenesis, and raise new evidence for the drug targeting therapies of AUID.

自身炎症性疾病（AUID）是新近认识的遗传性周期性疾病，患病率远被低估。因基因突变编码蛋白改变致固有免疫失调。AUID确切机制尚未阐明，现认为与炎症信号转导通路有关。但仍有患者未发现可证实的基因突变，且应用生物制剂无效，提示存在新的基因突变和发病机制。中国人AUID临床和基因表型谱无人知晓，发病机制研究更属空白。前期研究中，我们发现某些AUID不同基因型致信号转导蛋白活化、促炎因子和自噬发生不同改变。我们推测中国人AUID可能存在与非亚洲人种不同的临床和基因表型，发病与信号转导通路和自噬有关。为证实这一假说，我们将利用国家风湿病数据中心和基因二代测序技术，明确AUID临床和基因表型；采用分子生物学技术，从血浆、外周血单个核细胞、巨噬细胞三个层面，观察信号转导通路和自噬，并明确突变基因的致病作用。本课题将探明中国人AUID临床和基因表型，进一步揭示其发病机制，为药物靶点治疗提供新证据。

自身炎症性疾病（AUIDs）是新近被认识的一组罕见的遗传性周期性疾病，由于基因突变致编码蛋白改变，引起固有免疫失调。患病率远被低估，可导致致残，损害患者生活质量。项目组围绕中国人AUIDs临床和基因表型谱、发病机制和诊疗开展了系统研究，取得创新性成果如下：第一、利用国家风湿病数据中心平台，首次建立了中国人AUIDs临床数据库和生物标本数据库；第二、建立了高通量测序的AUIDs诊断体系平台，突破了AUIDs漏诊和误诊的瓶颈，实现了AUIDs的精准诊断；第三、首次建立中国人AUIDs前瞻性队列，确定了中国人AUIDs的疾病谱、临床表型和基因型谱；第四、对AUIDs发病机制进行了研究，揭示了信号转导通路NF-κB、p38/MAPK、caspase-1在AUIDs发病中的作用；第五、通过药物干预实验探索了可能对AUIDs具有潜在靶向治疗作用的药物；第六、积极探究AUIDs诊疗关键技术并积极推广原创性成果，提升了AUIDs转化研究和临床诊治水平。本项目组在研究期间共发表研究论文18 篇，其中SCI论文7篇，影响因子总分23.688。项目组多次受邀在国内大型学术会议作大会专题报告，在重要国际会议上作论文壁报交流，为成果在全国的广泛推广和该领域学科发展起到了有力的促进作用，并推动了中国AUIDs研究在国际社会的进步。