人角质形成细胞蛋白酶体α亚单位7等蛋白在特应性皮炎中的作用

Atopic dermatitis (AD) is a chronic, itching, inflammatory skin disease.Previous studies have focused on the infection and colonization by microorganisms in skin lesions of AD patiens. Especially, the interaction between Staphylococcus aureus (S.A)and immune cells has received attention by many investigators in AD research. More resecently, some investigators found that the interaction between S.A and keratinocytes also contributed to the inflammatory effects of S.A on the skin lesions of AD patients. However, the molecular basis for the induction of inflammation on AD skin lesions mediated by the interaction between S.A and keratinocytes is largely unknown.First, as a pilot study, human keratinocytes were infected with S.A. Then, 2D gel electrophoresis and MALDI-TOF-MS technology were used to select proteins that showed significant differences in expressions after S.A infection. Furthermore, we also found that the expression of all three genes was significantly correlated with the expressions of both MHC-II and pro-inflammatory cytokines at RNA level. This study aims to investigate possible roles of the three identified proteins such as Proteasome subunit alpha type 7 in the pathogenesis of AD.Moreover, signaling pathways latreed to the three proteins will also be investigated by designing shRNAs that specifically knock down the expression of each of the three genes. This study will likely provide a new paradigm for treating AD by revealing new theapeutic targets for AD.

特应性皮炎（AD）是一种遗传性、慢性、瘙痒性和炎症性皮肤病。各种微生物感染尤其是细菌感染或定植成为研究热点。近年来，在AD患者的皮损部位金葡菌和表皮角质形成细胞的相互作用引起的皮肤炎症已越来越引起人们的重视，但其机制尚不十分清楚. 我们前期的研究发现，应用2D双向电泳及MALDI-TOF-MS 联合磁珠技术筛选了金葡菌感染人角质形成细胞前后多种相关蛋白质组表达改变,并用实时聚合酶链反应进一步证实这一组蛋白中包括蛋白酶体α亚单位7在内的三种蛋白与人角质形成细胞合成并释放MHC-Ⅱ类分子以及炎性介质密切相关。本研究通过证实蛋白酶体α亚单位7等三种蛋白在特应性皮炎中的重要作用并探索其相关信号通路,从而为特应性皮炎的治疗提供新的思路。

特应性皮炎（AD）是一种遗传性、慢性、瘙痒性和炎症性皮肤病。各种微生物感染尤其是细菌感染或定植成为研究热点。近年来，在AD患者的皮损部位金葡菌和表皮角质形成细胞的相互作用引起的皮肤炎症已越来越引起人们的重视，但其机制尚不十分清楚. 我们前期的研究发现，应用2D双向电泳及MALDI-TOF-MS 联合磁珠技术筛选了金葡菌感染人角质形成细胞前后多种相关蛋白质组表达改变,并用实时聚合酶链反应进一步证实这一组蛋白中包括蛋白酶体α亚单位7在内的三种蛋白与人角质形成细胞合成并释放MHC-Ⅱ类分子以及炎性介质密切相关。 本研究通过细胞、动物及人体实验，主要探讨了特应性皮炎的发病机制，并得出了有意义的研究结果。简要总结如下：1）通过探讨蛋白酶体α亚单位7基因(PSMA7)在金葡菌感染引发特应性皮炎过程中的作用，发现PSMA7在特应性皮炎的发生及发展中具有重要作用，并探讨了其相关信号传导通路。另外发现PSMA7的下游分子，谷胱甘肽过氧化物酶3（GPX3）的甲基化与黑色素瘤的发病机制密切相关，GPX3可为黑色素瘤患者的诊断及治疗提供新的分子生物学靶标。2）研究了中国延边朝鲜族人群中, filaggrin (FLG)基因的单核苷酸多肽性，发现 filaggrin (FLG)基因的单核苷酸多肽性与特应性皮炎的发生密切相关。3）通过探讨特应性皮炎抑制剂，发现JAK1/JAK2抑制剂外用对特应性皮炎小鼠模型具有显著疗效。在项目进展期间，共发表了标注‘国自然基金资助’的论文三篇，培养毕业3名博士生。