RNF114基因多态性在银屑病发病和治疗中的机制研究

Psoriasis has the high characteristics of complicated pathogeny complications. Therefore, one key point of psoriasis is to explore the new therapeutic targets and improve the response. GWAS studies had shown that RNF114 genetic polymorphisms were closely related to psoriasis. Meanwhile, our team for the first time found that RNF114 genetic polymorphism rs4287819 were associated with the efficacy of acitretin. However, how does RNF114 participate the pathogenesis and prognosis of psoriasis and the influence of genetic polymorphisms is still unknown. Based on cell and mouse models, this study explores to verify that RNF114 was involved in multiple pathways in the pathogenesis of psoriasis, such as promote the proliferation and inhibit the differentiation of epidermal keratinocytes; to verify that acitretin increases the binding ability of transcription factor Sp1 and RNF114, then regulates the expression of RNF114 and affects the responses of acitretin; To explore that RNF114 participates the process of acitretin innate immune in psoriasis via RIG-I ubiquitination; In addition, in vitro and clinical studies, explore whether RNF114 genetic polymorphic rs4287819 can significantly change the expression and function of RNF114, and thus affect the progression and prognosis of psoriasis. This topic combines the basic researches and clinical application, not only helps us to understand the mechanisms of psoriasis pathogenic and acitretin mechanism, and to find new therapeutic targets of psoriasis and benefit the precise response to acitretin during the treatment of psoriasis.

银屑病具有病因复杂、病程顽固等特点，发现新治疗靶点和提高治愈率是目前的研究重点。国内外GWAS研究表明，RNF114基因多态性与银屑病易感相关，申请人首次发现RNF114基因多态rs4287819与阿维A疗效相关。然而，该基因多态影响银屑病发病和治疗的具体机制尚无明确报道。本项目以细胞和小鼠为模型，拟证实RNF114参与银屑病致病中多条通路，促进角质形成细胞增殖、抑制分化等过程；其次，证明阿维A可增强转录因子Sp1与RNF114结合从而调控RNF114表达并影响疗效；阐明RNF114通过泛素修饰RIG-I分子参与阿维A抗银屑病的固有免疫通路；此外，从体外和临床水平证实RNF114基因多态rs4287819可改变RNF114分子的表达和功能，进而关联银屑病的发病和治疗。本课题将基础研究与临床应用相结合，有助于理解银屑病发病机理和阿维A作用机制，为发现新靶点和实现精准用药提供理论依据。

银屑病具有病因复杂、病程顽固等特点，且发病率逐年增加。传统药物阿维A具有疗效确切，不良反应少，且价格低廉等特点，因此在亚洲国家应用广发。但阿维A在不同银屑病人群中疗效差异不一等特点，因此如何提高阿维A药物有效率是本研究重点。国内外GWAS研究表明，RNF114基因多态性与银屑病易感相关，申请人首次发现RNF114基因多态rs4287819与阿维A疗效相关；此外，通过候选基因位点筛选出转运体基因多态性SLCO1B1 rs4149056T>C 和SLC22A1 rs2282143C>T的突变显著增加了阿维A的疗效；通过，通过全基因组芯片的数据发现rs1898359A>G位点与阿维A疗效相关，且通过结合BMI能预测63.9%的疗效差异。最后，在银屑病患者中证明了阿维A具有降低患者血糖和BMI的作用，其可能机制是通过调节RNF114分子表达而达成。本课题将基础研究与临床应用相结合，有助于理解银屑病致病机理和阿维A作用机制，为银屑病患者实现精准用药提供理论依据。

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