C10orf99在角质形成细胞及银屑病中的促炎效应及机制研究

Keratinocytes play a pivotal role in the pathogenesis of psoriasis, but the mechanism remains to be clarified. My previous studies showed that C10orf99 protein was over-expressed in psoriatic skin, and it participated in the regulation of the keratinocyte proliferation and the activity of the NF-κB signaling pathway. My preliminary data showed that C10orf99 could promote the production of TNFα and IL-1β in keratinocytes, suggesting that C10orf99 may be involved in the pathogenesis of psoriasis by promoting the keratinocyte-mediated inflammation. This study aim to: 1. Using the cell model of psoriasis and coculture model of keratinocytes and inflammatory cells to investigate the functional roles of C10orf99 in the local immune function of keratinocytes, chemotaxis and cytokine release of inflammatory cells; 2. Explore the upstream and downstream molecular mechanism of C10orf99; 3. Validate the identified function and mechanism of C10orf99 in C10orf99 locally knock-out imiquimod-induced psoriatic mouse models. This study will not only unravel the pro-inflammatory effect and mechanism of C10orf99 in the pathogenesis of psoriasis, but also provide theoretical basis for a novel therapeutic target in the treatment of psoriasis.

角质形成细胞在银屑病发病机制中发挥着至关重要的作用，但具体机制尚不清楚。申请人前期研究发现，新促炎因子C10orf99蛋白在银屑病皮损中高表达，并参与了角质形成细胞增殖和NF-κB信号通路的调控。预实验发现C10orf99能够促进角质形成细胞产生TNFα和IL-1β，提示C10orf99可能通过促进角质形成细胞介导的炎症反应参与银屑病的发生发展。本项目拟：1.通过银屑病细胞模型、角质形成细胞和炎症细胞共培养模型，研究C10orf99表达的干扰对于角质形成细胞局部免疫功能、淋巴细胞/中性粒细胞趋化和相关炎症因子的影响；2.进一步研究C10orf99上下游的分子机制；3.靶向干扰咪喹莫特银屑病鼠模型中C10orf99的表达，在体验证其促炎效应及具体路径。本项目不仅揭示了C10orf99在银屑病发病中的促炎作用机制，更为寻找银屑病治疗新靶点提供了思路。

银屑病是常见的慢性炎症性皮肤病，该病目前尚不能治愈。角质形成细胞在银屑病发病机制中发挥着至关重要的作用，但具体机制尚不清楚。申请人前期研究发现，新促炎因子C10orf99蛋白在银屑病皮损中高表达，并参与了角质形成细胞增殖和NF-κB信号通路的调控。预实验发现C10orf99能够促进角质形成细胞产生TNFα和IL-1β，提示C10orf99可能通过促进角质形成细胞介导的炎症反应参与银屑病的发生发展。本项目欲阐明C10orf99在角质形成细胞及银屑病中的促炎效应及具体分子机制，为银屑病的临床治疗提供新的潜在靶点。研究发现C10orf99在银屑病角质形成细胞介导的炎症中发挥促炎效应，其通过调节TNFα、IL-1β、S100A7、IL-1α、CXCL8和LCN2等炎性介质的表达参与调控银屑病炎症微环境；双荧光素酶检测实验示基因C10orf99与转录因子PU.1存在靶向互作关系；利用M5细胞模型，进一步探寻发现TNFα、IL-17A、IL-1α、IL-22和Oncostatin M均上调了C10orf99蛋白的表达。本项目不仅揭示了C10orf99在银屑病发病中的促炎效应，更为寻找银屑病治疗新靶点提供了理论基础。