汗孔角化症是一种遗传性皮肤角质化异常疾病，影响人的外貌，且有癌变可能，目前没有特别有效的治疗办法。MVK是汗孔角化症的致病基因，但是致病原因仍然未知。前期工作中我们发现了导致汗孔角化症的MVK致病突变P11S，其稳定性比野生型WT显著性降低；进一步发现MVK可以调控caspase-14的表达；质谱分析MVK与核纤层蛋白Lamin A/C存在相互作用，但MVK致病突变体则丧失这一功能。本项目将在前期工作的基础上，深入分析MVK是否通过Lamin A/C调节caspase-14的表达，从而影响对filaggrin的水解以及对细胞的保护。该研究将阐明MVK P11S突变导致汗孔角化症发生的分子机制，并为汗孔角化症提供可能的靶向治疗方案。

Porokeratosis is recognized as an inherited epidermal keratinization disorder, which ruins the sufferers’ appearances and may also be prone to malignant tumor formation. Up to date, there is no effective treatment for porokeratosis. Mutations in MVK gene have been found to cause porokeratosis. We also detected a novel mutation P11S, which made the mutated protein less stable than the wild type (WT). Nevertheless, the stability alteration could not elucidate the pathogenesis of porokeratosis clearly. In our previous work, we found caspase-14, which degradated filaggrin to protect keratinocytes from environment stress, was down regulated by P11S. However, caspase-14 bound to neither MVK WT nor P11S. MVK WT and P11S shared the same location in cytoplasm, which indicated neither of them could translocate into nucleus to affect the expression of caspase-14. Meanwhile, we found that Lamin A/C especially bound to MVK WT but not P11S detected by Mass Spectrometry. This project will involve an in depth analysis of the molecular mechanism of how MVK regulated the expression of caspase-14, and whether the regulation was associated with Lamin A/C. Further investigation into the pathogenesis of porokeratosis caused by MVK mutation will help to improve treatment strategies and may lead to a better understanding of the disease mechanisms that are essential to provoke the development of target therapeutic strategies.