白介素1受体相关激酶-M（IRAK-M）在葡萄膜炎发病机制中所起的作用的研究

新型药物靶向治疗及基因治疗是葡萄膜炎治疗研究中的热点。我们通过对HLA-B27相关急性前葡萄膜炎进行的基因芯片研究，筛选出了起重要作用的差异表达基因IRAK-M。以前期对IRAK-M在内毒素诱导葡萄膜炎及眼部免疫耐受状态中所起作用的研究为基础，通过IRAK-M基因敲除小鼠进一步研究IRAK-M在内毒素诱葡萄膜炎及眼部内毒素耐受中所起的作用，观察IRAK-M在葡萄膜炎及眼部内毒素耐受过程中对TLR-4通路相关重要节点分子及重要负调节因子表达及磷酸化的影响，以进一步阐明IRAK-M在葡萄膜炎发生发展及控制过程中的作用机理及分子通路。通过玻璃体腔注射慢病毒载体转染，观察大鼠眼内IRAK-M过表达或下调对葡萄膜炎炎症的影响，以及对房水中所分泌的炎症细胞因子的干预，并由此观察IRAK-M对葡萄膜炎发生时T细胞亚群极化和功能的影响。从而研究IRAK-M是否为治疗葡萄膜炎的潜在有效靶点及其作用机制。

Targeted therapy and Gene therapy have been the hot areas of research in uveitis. We screened out Interleukin 1 Receptor Associated Kinase M (IRAK-M) as an important differentially expressed gene from our former Gene chip analysis research on HLA-B27 related acute anterior uveitis, and demonstrated the significant effect of IRAK-M during the endotoxin tolerance in the uveitis. Thus, we propose to further investigate the role of IRAK-M in the pathogenesis of uveitis and endotoxin tolerance in the eye by IRAK-M knockout mice. To identify the impact of IRAK-M on cytokines and negative regulators in the TLR-4 signaling pathway, in order to unveil the mechanism of how IRAK-M controls the inflammatory responses in uveitis. To study the influence of upregulation or interference of IRAK-M expression on the inflammation degree, secretion level of inflammatory cytokines in the aqueous humor, and the T cells polarization during uveitis by intravitreal injection of recombinant IRAK-M-overexpressing lentivirus and short hairpin RNA targeting IRAK-M recombinant lentivirus, in order to find the possibility of further development of anti-inflammatory therapeutic strategies.