CyclinE-CDK2/Rb/E2F通路调控银屑病角质形成细胞过度增殖的分子机制研究

角质形成细胞过度增殖是银屑病病理生理学特征性改变，分子机制尚未明确。细胞周期蛋白以及细胞周期蛋白依赖性激酶在调控细胞周期进程中发挥关键作用；CyclinE-CDK2磷酸化作用于底物Rb蛋白，促使细胞由G1期进入S期，促进细胞增殖。前期研究发现，银屑病皮损中转录因子FOXO的表达和活性下降；而抑制FOXO3a的表达可上调角质形成细胞CDK2的基因表达。另有文献报道银屑病皮损中CyclinE和CDK2的表达和活性显著升高，但未见关于下游Rb蛋白表达及磷酸化水平和E2F的转录活性研究的报道。本课题拟从分子、细胞、组织等多层次探讨CyclinE-CDK2/Rb/E2F通路在角质形成细胞增殖中的调控作用，揭示该通路参与银屑病表皮增殖的作用机制，为银屑病皮损形成的分子机制提供新的理论依据，同时有望为银屑病的治疗提供新靶点。

Keratinocytic hyperproliferation is the major pathophysiological characteristic of psoriasis, but the molecular mechanism remains unclear. Cyclins and cyclin-dependent kinases (CDKs) play key roles in regulating the cell cycle, and Cyclin E-CDK2 complex promotes cell cycle progression from G1 to S phase by phosphorylating Rb protein. Our previous study found that the expression and activity of FOXO were down-regulated in psoriatic lesions, and the inhibition of FOXO3a could up-regulate the gene expression of CDK2 in keratinocytes. The significantly increased expression and activity of Cyclin E-CDK2 in psoriatic epidermis was reported, but the research on the downstream Rb protein and transcription factor E2F has not been reported. In order to clarify the mechanism of psoriatic epidermal proliferation, provide the new theoretical basis of psoriatic pathogenesis, and explore potential therapeutic targets for psoriasis, the molecular mechanism of Cyclin E-CDK2/Rb/E2F pathway in keratinocytic proliferation will be investigated in this subject.