Spred-1蛋白抑制Ras/ERK信号通路在寻常型银屑病发病中的作用及清血毒颗粒合剂的干预作用

Psoriasis vulgaris is one of the common skin diseases in dermatology. psoriasis is a chronic disease which is easy to relapse and difficult to cure, it seriously affecting the patient's quality of life and health physically and mentally.At present, there are some shortcomings of western medicine systemic drug therapy, such as adverse reactions, curative effects, etc. Therefore, it is imperative to study the therapeutic target of psoriasis treated by traditional Chinese medicine.Qing Xue Du granule mixture is a empirical fomula of the applicant,which is based on the "Xue re du yun"pathology. previous studies have shown that the treatment has significant effect on curing psoriasis vulgar. The study shows that Ras / ERK signaling pathway is closely related to the pathogenesis of psoriasis, and Spred-1 protein is a new inhibitor of this pathway. therefore, we speculate that Spred-1 is involved in the pathogenesis of psoriasis through Ras /ERK signaling pathway,And qing xue du granule mixture can effectively treat psoriasis by enhancing the expression of Spred-1 and inhibiting the Ras / ERK signaling pathway. By studying the psoriasis mice model Spred-1 gene over expression and conditional knockout, this issue explored the evidence and mechanism of the pathogenesis of psoriasis when Spred-1 involved in;To investigate the relationship between Spred-1/Ras/ERK signaling pathway and Qingxuedu granule mixture treating psoriasis, Qingxuedu Granule mixture was used in psoriasis mice mode after Spred-1 knockout, which provide experimental evidence for cooling blood and detoxification method curing psoriasis.

银屑病是常见皮肤病之一，由于该病缠绵反复、顽固难愈的特点，严重影响患者的生活质量和身心健康。目前西医系统性药物疗法存在不良反应大等缺点，因此，研究中医药治疗的银屑病靶点势在必行。申请人基于银屑病“血热毒蕴”病机形成清血毒颗粒合剂经验方，前期研究表明治疗银屑病疗效显著。研究表明Ras/ERK信号通路与银屑病发病密切相关，Spred-1蛋白是该通路新型抑制剂，因此我们推测Spred-1通过Ras/ERK信号通路参与银屑病的发病；而清血毒颗粒合剂通过增强Spred-1表达抑制Ras/ERK信号通路从而达到治疗银屑病。本课题对银屑病小鼠模型Spred-1基因过表达及条件性基因敲除的研究，探讨Spred-1参与银屑病发病的证据及机制；通过凉血解毒法代表方清血毒颗粒合剂对Spred-1基因敲除银屑病小鼠干预实验，探讨Spred-1通路与清血毒颗粒合剂治疗银屑病相关性，为凉血解毒法治疗银屑病提供依据。

银屑病是常见皮肤病之一，由于该病缠绵反复、顽固难愈的特点，严重影响患者的生活质量和身心健康。目前西医系统性药物疗法存在不良反应大等缺点，因此，研究中医药治疗的银屑病靶点势在必行。申请人基于银屑病“血热毒蕴”病机形成清血毒颗粒合剂经验方，前期研究表明治疗银屑病疗效显著。研究表明Ras/ERK信号通路与银屑病发病密切相关，Spred-1蛋白是该通路新型抑制剂，因此我们推测Spred-1通过Ras/ERK信号通路参与银屑病的发病；而清血毒颗粒合剂通过增强Spred-1表达抑制Ras/ERK信号通路从而达到治疗银屑病。经过课题组临床研究表明，Spred-1、Spred-2、Spred-3 蛋白表达于正常人表皮全层，但在各层表达具有细微差别；同时，三种蛋白在银屑病皮损区、近皮损区、非皮损区表达定位与正常人表达一致，但平均荧光密度值降低，上述结果表明 Spred-1、Spred-2、Spred-3 均可能参与银屑病的发病。进一步动物实验：在银屑病样小鼠皮肤组织中，Spred-1蛋白表达降低，Ras/ERK通路相关蛋白及 mRNA表达升高；Spred-1过表达后能够抑制Ras/ERK通路相关蛋白表达，缓解银屑病小鼠症状；而Spred-1基因被敲低后，皮损区Ras/ERK通路相关蛋白及mRNA表达均升高，加重了小鼠的银屑病病情；Spred-1 基因被敲低后，清血毒颗粒合剂和复方青黛胶囊的疗效相差不显；而清血毒颗粒合剂治疗Spred-1基因未被敲低及被敲低后的银屑病样小鼠， 二者疗效相差明显。上述结果说明Spred-1通过Ras/ERK信号通路参与银屑病的发病，清血毒颗粒合剂可通过干预Spred-1/Ras/ERK通路达到治疗银屑病的作用。综上，我们的研究进一步明确了Ras/ERK通路与银屑病的相关性，确定了银屑病的新治疗靶点——Spred-1，Spred-1/Ras/ERK通路为银屑病治疗研究提供了新方向，同时，我们研究对完善从毒论治银屑病治疗机制具有重要意义。