我们发现甲羟戊酸通路上的遗传变异可导致汗孔角化症，已知该通路上的多种磷酸化代谢产物能够有效激活γδT细胞，由此，我们推测该通路可能参与皮肤炎症的发生机制。本项目以汗孔角化症和寻常型银屑病为范例，对皮肤炎症性疾病中甲羟戊酸通路调控γδT细胞的作用机制进行比较研究。首先，分别采用靶向蛋白质学技术和流式细胞仪来检测甲羟戊酸通路的异常情况和皮肤炎症反应程度；其次，采用海马代谢分析和RNA原位杂交来明确甲羟戊酸通路调控γδT细胞的内外双重机制；第三, 采用CRISPR/Cas9技术构建甲羟戊酸通路上基因定点突变的细胞模型，在细胞水平上进行分组干预甲羟戊酸通路，分析其对γδT细胞调控的直接和间接影响，为皮肤炎症的治疗提供新思路。

We previously found that the genomic variations on mevalonate pathway can cause porokeratosis. It is well-known that multiple phosphorylated mevalonate metabolites are potent agonists of γδT cells. Thus, we supposed that mevalonate pathway might be involved in the pathogenesis of skin inflammation. In this project, porokeratosis and psoriasis vulgaris are served as paradigms to comparatively study the regulation of γδT cells by mevalonate pathway in skin inflammatory diseases. First, targeted proteomics and flow cytometry are used to detect the abnormal mevalonate metabolites and with accompanying changes of inflammatory cytokines, respectively; Secondly, Seahorse extracelluar flux analyzer and RNA in situ hybridization are applied to identify the intracellular and extracellular dual regulation of γδT cells by mevalonate pathway; Thirdly, CRISPR/Cas9 techniques are used to construct cell models of site-directed mutagenesis in genes on mevalonate pathway, and different groups are designed to intervene in mevalonate pathway at the cellular level, whose direct and indirect effects on the regulation of γδT cells are analyzed. This study would provide new ideas for the treatment of skin inflammation.