ANCA相关性小血管炎TLRs／MyD88信号通道基因多态性与表达差异性分析

ANCA associated small vasculitis ( AAV ) as an autoimmune disease, its molecular genetics mechanism is undisputed very important, but far from clear. TLRs/MyD88 signal pathway genes polymorphism especially SNPs and abnormal expression, may be involved in the AAV genetic mechanism, but the current lack of research. 1 Therefore, to observe the SNP characteristics of TLRs/MyD88 pathway and regulation of the genes by using PCR - RPLF method combined with the PCR product direct sequencing method, correlation analysis of SNPS with the AAV, find the marker genes for AAV, the basic study may help elucidate the molecular genetic significance of gene polymorphisms in TLRs/MyD88 signal pathway in AAV. 2 By the TLR signal pathway gene chip hybridization,to observe the expression of signal transduction genes in period of activity in AAV patients, to find out of the expression profiles of TLRs/MyD88 channels of peripheral blood PMN and MN cell membrane and renal local tissue. A complete understanding of relationship in AAV between actived TLRs/MyD88 signal pathway gene expression and respiratory burst, inflammation, chemokine, renaltissue damage. This helps to interpret the TLRs/MyD88 signal pathway's function in the molecular mechanism of AAV, and to provide basis for design of artificial intervention for AAV gene therapy in multiple targets.

自身免疫性疾病ANCA相关性小血管炎（AAV）的分子遗传学机制越来越受重视，但远未阐明。TLRs/MyD88信号转导机制的基因谱特征及基因多态性尤其是SNP，可能参与AAV分子遗传学机制，但当前缺乏研究。为此，1 采用PCR－RPLF法结合PCR产物直接测序法观察TLRs/MyD88途径及调控基因的SNP特征，分析其与AAV的相关关系，寻找AAV连锁及标记基因，为阐明TLR介导途径的基因多态性在AAV中的分子遗传学意义，提供资料。2.采用TLR信号转导基因表达芯片杂交法,观察AAV患者活动期肾组织局部，外周血PMN和MN细胞膜TLRs/MyD88通道的基因表达谱。完整地了解AAV活动期TLRs/MyD88通道基因表达与呼吸爆发，炎症，趋化，组织损害等的相互关系.这有助解读TLRs/My88通道在AAV的分子遗传学机制中的作用，并为设计人工干预的多靶点基因治疗提供基础依据。

自身免疫性疾病ANCA相关性小血管炎（AAV）的分子遗传学机制越来越受重视，但远未阐明。我们项目研究了TLRs/MyD88信号转导机制的基因谱特征及基因多态性尤其是单核苷酸多态性(SNP)在广西人群AAV发生发展中的作用。采用PCR－RPLF法结合PCR产物直接测序法观察TLRs/MyD88途径及调控基因的SNP特征，完成了TLR信号通道及负调控基因SNP共19个位点与AAV相关性的研究。结果表明TLR信号通路上多个相关基因SNP与AAV遗传易感性及临床与实验室指标方面的具有相关性，为TLR介导途径的基因多态性在AAV中的分子遗传学意义提供了资料。采用TLR信号转导基因表达芯片杂交法，观察AAV患者活动期外周血PMN，MN，CD4+，CD8+细胞膜TLRs/MyD88通道的基因表达谱，分析各级调控基因及下游激活的各种相关因子基因的表达及相互关系，结果表明单个核细胞（MN），中性粒细胞（PMN）,CD4+,CD8+ T淋巴细胞中的TLR/MyD88信号通路可能是导致显微镜下多血管炎发病的一条重要免疫调节信号通路。. 项目研究成果深入了解AAV中TLRs/ MyD88通道机制在疾病中的基因表达特征及在疾病活动中意义，进一步解读TLRs/My88通道在AAV的分子遗传学机制中的作用，并为设计人工干预的多靶点基因治疗提供基础依据。研究结果以论文的方式表现，目前共发表论文10篇，其中SCI收录2篇，中文核心8篇。本项目完成时共培养硕士研究生7名。