苯乙双胍通过AMPK激活Calcineurin/NFAT抑制角质形成细胞促炎因子的表达

与炎症相关的许多皮肤疾病如银屑病、特异性皮炎等在治疗上仍有很大挑战，因而研究调节皮肤炎症反应分子机制具有重要意义。研究表明皮肤最外层表皮中的角质形成细胞是调节皮肤炎症反应的关键细胞。申请人前期研究报道正调节免疫反应中的Calcineurin/NFAT通路却能负调控角质形成细胞促炎因子的表达，提示皮肤抗炎研究应该靶向角质形成细胞。申请人前期工作发现AMPK激活剂苯乙双胍能显著地抑制角质形成细胞的炎症因子表达，且在体内能拮抗佛波脂TPA诱导的皮肤炎症反应。为进一步探讨苯乙双胍抑制皮肤炎症的分子机制及其潜在的转化应用，本研究将聚焦于原代角质形成细胞，利用申请人创建的不同人皮肤器官模型并结合皮肤炎症小鼠模型，进行系统的研究和验证苯乙双胍通过AMPK激活Calcineurin/NFAT信号通路来调节表皮细胞中炎症因子表达的分子机理及拮抗银屑病的作用，为开发AMPK激活剂转化为皮肤抗炎药提供基础。

There is still a great challenge to treat many skin inflammatory diseases such as psoriasis and atopic dermatitis and so on, therefore it is always important to investigate the molecular mechanism of regulating skin inflammatory response. It has been shown that keratinocytes located in the outermost epidermis of the skin are the key cells to regulate the inflammatory response in the skin. According to the applicant's previous research, the calcineurin/NFAT signaling pathway, which positively regulates the immune response, negatively controls the expression of pro-inflammatory cytokines in keratinocytes, suggesting that anti-inflammatory study in the skin should target keratinocytes. The applicant's previous works found that AMPK activator phenformin could significantly inhibit the expression of pro-inflammatory factors in keratinocytes, and antagonize the skin inflammatory response induced by 12-O-Tetradecanoylphorbol-13-acetate (TPA) in vivo. In order to further explore the molecular mechanism of phenformin inhibiting skin inflammation and its potential application, the present study will focus on primary keratinocytes, and use different human skin organ models, which has been established by the applicant, in combination with the mouse model of skin inflammatory disease to systematically study and verify that phenformin regulates the expression of inflammatory factors in keratinocytes through AMPK to activate the calcineurin/NFAT signaling pathway, and produces anti-psoriasis effect in the skin. This study will provide a solid basis for the development of AMPK activator to be translated into skin anti-inflammatory drugs in the clinics.