ERα/MAPK/Caspase信号轴在银屑病角质形成细胞凋亡中的作用机制研究

Psoriasis is an chronic inflammatory skin disease. Its pathogenesis is not clear. Treatments for psoriasis are currently insufficency. Study shows that the dynamic imbalance of psoriatic skin lesions is one of the pathogenic factors for psoriasis. In addition to abnormal proliferation, apoptosis of keratinocytes (KC) may be abnormal, but the mechanism is not clear. Topology analysis showed that ERα was most closely related to KC apoptosis. Our previous work found that: the expression of ERα in psoriatic lesions is down regulated. One of the MAPK members p38 was upregulated. Caspase-3 and 5 were up-regulated. Overexpression of caspase-5 gene is associated with the pathogenesis of psoriasis. The genetic polymorphism of caspase-7, 8 is related to psoriasis. We speculate that psoriasis KC apoptosis may be abnormal, and it may occur through the ERα / MAPK / Caspase signal axis. On the basis of previous studies, this study will explore the role of this signal axis in the apoptosis of psoriasis KC and the regulation mechanism: 1. Detect the expression of various factors on this axis by tissue samples of psoriasis patients. The effect of ERα on KC apoptosis in psoriatic lesions was investigated by in vitro and in vivo. 2. In vitro study on the regulation of this signal axis on KC apoptosis. So to find the key factors related to the pathogenesis of psoriasis, and to promote the targeted therapy of psoriasis.

银屑病是一种慢性炎症性皮肤病，发病机制尚不明确，治疗缺乏特异性。研究认为银屑病皮损动力学失衡是其病因之一，角质形成细胞（KC）除了增殖异常，凋亡也可能存在异常，但机制并不明确。拓扑分析发现，ERα与银屑病KC凋亡关系最大。我们前期工作发现：ERα在银屑病皮损中表达下调，MAPK 成员p38、caspase-3和-5表达上调；caspase5基因过表达与银屑病病理机制相关；caspase-7，8的基因多态性与银屑病相关。我们推测：银屑病KC凋亡存在异常，并通过ERα/MAPK/Caspase信号轴发生。本项目拟在前期基础上，探讨此信号轴在银屑病KC凋亡中的作用及调节机制：1、银屑病患者组织样本中检测此信号轴上各因子的表达情况。体内和体外实验探讨ERα对银屑病皮损 KC 凋亡的作用。2、体外实验探讨此信号轴对KC凋亡的调节。寻找与银屑病发病相关的关键因子，推进银屑病的靶向治疗。

本项目致力于银屑病这一常见的慢性炎症性免疫性皮肤病的发病机制研究。鉴于银屑病的遗传性以及炎症相关性和局部皮肤角质形成细胞增殖凋亡失衡的特点我们从炎症相关因子和凋亡相关蛋白与分子水平（银屑病在基因多态性）方面和蛋白水平（蛋白在皮肤组织中的表达水平）方面，以及作用机制方面研究了银屑病的相关机制。发现1）JNK、p38、ERK1/2、STAT3、STAT5A/B 在寻常型银屑病中表达增高，且 STAT5A/B与 p38、ERK1/2、JNK、STAT3 有正相关性，表明 STAT5A/B 与 MAPK 因子互相作用，可能共同参与银屑病发病机制。2）我们检测了凋亡和免疫相关的caspase 家族和CARD8在银屑病中的基因型，发现CARD8、CASP7 和 CASP8 基因多态性与中国东北汉族人群 PsV 风险显着相关，这暗示了 PsV 和 caspase 和CARD8基因之间的功能关系。3）我们研究过程中发现miR-205-5p，Ang-2，VEGFA和BAMBI对银屑病的发生发展有一定作用，因此我们评估了它们在银屑病患者皮损和正常人群皮肤组织中的表达。并重点研究了miR-205-5p对Ang-2、VEGFA和BAMBI的调控及在增殖、迁移和血管形成的功能。研究发现miR-205-5p可以靶向下调Ang-2，VEGFA和BAMBI的表达，从而降低HUVECs增殖、迁移和小管形成能力及Hacat增殖，进而抑制银屑病的血管生成和角质形成细胞增殖。此外，发现miR-205-5p降低p38和ERK的磷酸化以及β-catenin的表达，提示了miR-205-5p可能通过调节MAPK/β-catenin信号通路参与银屑病的发病。这些结果进一步表明上调miR-205-5p可能是银屑病的潜在治疗方法。

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