我们前期发现甲羟戊酸焦磷酸脱羧酶(MVD)是国内汗孔角化症(PK)患者的最常见致病基因, 其分子机制尚不清楚, 制约着治疗药物的研发。目前该研究的重要障碍之一是缺乏PK动物模型。本项目内容主要分三部分：一，为实现可控性敲除皮肤中MVD，采用Cre/LoxP系统构建雌激素诱导皮肤MVD条件性敲除小鼠，研究MVD功能缺失与PK相关性; 二，为模拟PK的基因型，采用CRISPR/Cas9技术构建MVD-F250S突变小鼠，研究该突变能否导致MVD功能低下和影响PK的发生发展; 三, 为模拟PK皮疹的遗传学特征，将上述二种小鼠交配，筛选出同时携带MVD条件性敲除和点突变的杂合小鼠；在该小鼠局部皮内注射人工合成的雌激素，使MVD的野生型等位基因失活，从而激活点突变，尝试通过人为控制来诱导PK样皮疹的主旨。由此，我们选出与PK拟和度最佳的小鼠来填补PK动物模型的空白，具有重要的科学价值和临床意义。

We previously found that mevalonate pyrophosphate decarboxylase (MVD) is the commonest causal gene in a cohort of Chinese patients with porokeratosis (PK). However, the pathogenesis of PK is unclear, which restricts therapeutic drug discovery. To date, one of the major hurdles is lack of animal models for PK. This project consists of three main parts. First, estrogen inducible MVD conditional knockout mice are generated by Cre/LoxP system to control MVD gene knockout and study the correlation between loss of MVD function and PK; Secondly, MVD-F250S mutation knock-in mice are created to mimic PK genotype using CRISPR/Cas9 technology, and MVD deficiency caused by the point mutation is assessed in the development of PK; Thirdly, these two types of mice are interbred to generate the heterozygous mouse, carrying both conditional knockout and F250S knock-in of MVD. Artificial estrogen is injected intracutaneously to inactivate wild allele of MVD gene in the heterozygous mouse and activate F250S mutation to develop lesions, which may simulate the genetic features of PK and achieve the purpose of inducing PK-like lesions by manual control. Thus, the mouse with the best goodness-of-fit to PK would be identified among them to fill the gap in the animal models for PK, which has a great scientific value and clinical significance.