嗜中性皮病是一组异质性炎症性皮肤病，病理机制不清，易反复，治疗棘手，是临床难点问题。课题组前期研究发现EGFR-TKI抑制EGFR-Src-STAT3-ERK调节claudin1/2/4的表达；相关文献提示ERK、claudin均可调节IL-1家族表达。因此申请人提出假设：EGFR-TKI影响claudin表达，间接调节ERK通路及IL-1家族表达，导致炎症细胞聚集。本研究拟观察EGFR-TKI所致痤疮样疹皮损中claudin、ERK蛋白及IL-1家族的改变；利用knockdown技术构建TJ蛋白减弱表达细胞系和小鼠模型，外源性添加EGFR-TKI，观察ERK蛋白和IL-1家族表达谱的差异，体内外探明EGFR-TKI是否影响claudin调节ERK通路和IL-1家族表达。以EGFR-TKI所致痤疮样疹为突破口，阐明claudin、ERK通路在嗜中性皮病发病中的作用，探索其治疗的新策略。

Neutrophilic dermatosis is a group of heterogeneous inflammatory skin diseases with unclear pathological mechanism, easy recurrence and intractable treatment, which is a difficult clinical problem. Our previous research found that EGFR-TKI can regulate the expression of claudin1/2/4 by inhibiting the EGFR-Src-STAT3-ERK signaling pathway. Since both ERK and claudin can regulate the expression of IL-1 family, therefore the applicant make a hypothesis that EGFR-TKI regulates the ERK pathway and monitor the expression of IL-1 famliy by affecting the expression of claudin, leading to abnormal aggregation of inflammatory cells and promoting the occurrence of acne-like rash. In this study, we intend to observe the change of claudin, ERK protein and IL-1 family in skin lesions of EGFR-TKI indiced acneiform rash. Then, knockdown technology is applied to construct claudin-attenuated cell line and mouse model, after adding exogenous EGFR-TKI, we verify whether claudin is involved in the process of EGFR regulating ERK pathway and IL-1 family. Taking EGFR-TKI induced acne-like rash as a breakthrough point, the study aims to clarify the correlation between claudin, ERK pathway and neutrophilic dermatitis,reveal the pathogenesis of neutrophilic dermatitis, explore the new therapeutic target of these disease.