角质形成细胞通过下调ULK1的表达阻碍银屑病进程的机制研究

角质形成细胞（KC）在接受内、外因素刺激，通过正反馈促进银屑病发生并维持疾病持续状态中发挥重要作用。理论上，KC会同时启动负反馈调控机制，以维持细胞稳态，延缓疾病进程。临床上，银屑病的“自愈性”强烈提示KC负反馈机制的存在。我们预实验发现：ULK1在银屑病皮损处KC中显著下降；沉默KC内ULK1基因，可抑制KC增殖，下调银屑病相关细胞因子表达。然而，ULK1在银屑病皮损处KC中下降机制及其下降后对KC细胞的影响机制未明。既往研究认为，ULK1的表达受上游AMPK信号通路调控，而ULK1则通过自噬/I型干扰素途径调节细胞增殖分化和炎症因子分泌。由此我们推测：KC在应对刺激正反馈向银屑病发展的同时，启动AMPK-ULK1-自噬/I型干扰素负反馈机制，阻碍疾病进程；正、负反馈博弈，决定疾病的转归。该项目的实施，从新的角度认识KC在银屑病中的作用，并可从增强负反馈效应方面为疾病的治疗提供新思路。

Keratinocytes are not only the target , but also the initiator of psoriasis. Generally, keratinocytes produce amount of psoriasis-related pro-inflammatory mediators and alter their proliferation and differentiation in response to the stimulation of exogenous and endogenous factors. These proinflammatory mediators attract macrophages, neutrophils and T cells into the skin, where these cells produce various cytokines including IL-17, IL-23 and TNFa. These cytokines further promote keratinocytes to produce psoriasis-related inflammatory mediators and undergo even worse proliferation and differentiation. Thus, keratinocytes and cytokines form into a vicious circle by positive regulations. However, keratinocytes as the major cells of skin barrier must have the capacity to maintain homeostasis as in response to numerous intrinsic and environmental stimulations. In fact, some patient with mild, or even moderate/severe psoriasis recover spontaneously as observed in placebo group in clinical trials, highlighting the ability of keratinocytes in maintaining homeostasis. ULK1 is a key kinase in initiating the autophagy to maintain cell homeostasis. Our preliminary experiments demonstrated that both ULK1 and pULK1 were greatly reduced in psoriatic lesions, but not in non-lesional skin in psoriasis. The inhibition of ULK1 expression down-regulated psoriasis-related cytokines expression and the proliferation of keratinocytes, but increased cell apoptosis, suggesting the involvement of ULK1 in keratinocytes homeostasis. Previous research established that ULK1 regulated cell function mainly through autophagic and type I interferon signaling pathway. In addition, we identified that ULK1 expression was reduced in keratinocytes by incubation with TNF-a the major pathogenic cytokines in psoriasis. Together, we hypothesis that: keratinocytes maintain skin homeostasis by down-regulating ULK1 expression in response to TNF-a stimulation in psoriatic lesions. The present project will help us understand the pathogenesis of psoriasis from the aspect of negative regulation and provide therapeutic target by enhancing the negative regulators.