银屑病中Cornulin介导LL-37促进炎症反应及KC增殖的作用机制

LL-37 plays an important regulatory role in the pathogenesis of psoriasis, but the mechanism has not been clarified. Our preliminary data showed that LL-37 could promote the production of Cornulin in keratinocytes (KC), whose expression is also elevated in skin lesions from psoriatic patients and imiquimod-induced psoriasis mouse models, suggesting that Cornulin may mediate the function of LL-37 to promote the occurrence and development of psoriasis. This study aim to: 1.Verify the up-regulation of Cornulin expression and its correlation with LL-37 in skin lesions from psoriatic patients and imiquimod-induced psoriasis mouse models; 2. Using cocultured models of M5-stimulated, Cornulin-depleted/overexpressed KC and inflammatory cells to investigate the functional roles and mechanisms of Cornulin in the chemotaxis and cytokine release of inflammatory cells and in the proliferation, differentiation and apoptosis of KC, and to identify the downstream effector signaling pathways and molecular mechanism of Cornulin; 3.Validate the identified functions of Cornulin in knock-out or over-expression imiquimod-induced psoriasis mouse models in these inflammatory cells, factors and KC. This project not only unravels the roles of Cornulin in the pathogenesis of psoriasis and its functional relationship with LL-37, but also provides a new target and theoretical basis for the clinical treatment of psoriasis.

LL-37在银屑病发病中发挥着重要的调节作用，但其机制不清。我们的预实验发现，LL-37可促进KC表达Cornulin，后者在银屑病皮损及咪喹莫特鼠模型中表达均升高，提示Cornulin可能介导LL-37促进银屑病的发生发展。本项目拟研究：1.在银屑病患者及咪喹莫特模型鼠皮损中验证Cornulin的过表达及其与LL-37的关系；2.在Cornulin敲除/过表达的M5银屑病细胞模型和炎症细胞共培养模型中，找到介导其功能的下游信号通路及效应分子，并观察Cornulin对炎症细胞的趋化、炎症因子的释放、KC的增殖分化和凋亡的作用及其分子机制；3.在Cornulin敲除/过表达小鼠上利用咪喹莫特诱导银屑病，验证Cornulin对上述炎症细胞、炎性因子及KC的作用及其路径。本项目不仅揭示了Cornulin在银屑病发生过程中的作用及其与LL-37的关系，也为银屑病的临床治疗提供新的靶点和理论依据。

LL-37在银屑病发病中发挥着重要的调节作用。LL-37可促进KC表达Cornulin，后者在银屑病皮损及咪喹莫特鼠模型中表达均升高，提示Cornulin可能介导LL-37促进银屑病的发生发展。本项目证实：1.Cornulin在银屑病患者、咪喹莫特模型鼠皮损、银屑病细胞模型中的表达均显著升高；2.在Cornulin敲除/过表达的M5细胞模型中，介导其功能的下游途径为Akt信号通路，并检测了Cornulin对炎症因子的释放、KC增殖、细胞周期的作用及分子机制；3.在银屑病鼠模型中，下调Cornulin可以通过细胞周期蛋白D1和磷酸化Akt水平降低来延缓银屑病皮损的进展，并确定了卡泊三醇对银屑病中Cornulin表达的影响；本项目不仅揭示了Cornulin在银屑病发生过程中的作用及其与LL-37的关系，也为银屑病的临床治疗提供新的靶点和理论依据。