申请人致力于遗传性掌跖角化病（PPK）的病因学和发病机制研究，主要发现包括1）确定4种PPK的致病基因及发病机理：发现TRPV3、GJA1功能增强可以促进角质形成细胞凋亡；AQP5的功能增强可以引起手、足多汗；钙蛋白酶抑制蛋白CAST功能缺失可以导致皮肤桥粒结构出现异常；2）发现国内最常见的PPK类型及其基因突变热点，改变了非综合征型PPK的基因诊断流程；3）发现纯发-甲型外胚叶发育不良的致病基因为HOXC13。通过以上研究，揭示了一系列基因在皮肤生理功能中所发挥的重要作用，为常见皮肤病的研究提供全新思路。近3年发表第一或责任作者文章共16篇，包括5篇IF>10分的第一作者文章和2篇皮肤科领域最高的J Invest Dermatol杂志的责任作者文章。申请人未来研究主要集中在AQP5与手、足多汗症关系，CAST在桥粒异常性皮肤病的致病意义，以及PPK新致病基因及发病机理确定三方面，有望为PPK的治疗提供全新分子靶点。

The applicant has been endeavoring to the etiology and pathogenesis of palmoplantar keratoderma (PPK). Currently his findings include 1) identification of 4 novel causative genes and the pathogenesis for different PPK: gain-of-function mutations in TRPV3 or GJA1 lead to elevated apoptosis of keratinocytes; gain-of-function mutation in AQP5 lead to a leaky aquaporin water channel and resultant palmoplantar hyperhidrosis; and loss-of-function mutations in CAST result in desmosomal defects; 2) detection of the most common type and the mutation hotspot of PPK in China, which modified the procedure of PPK gene diagnosis; 3) identifying the HOXC13 as the underlying gene for pure hair and nail ectodermal dysplasia. Through these studies, the applicant unraveled the important functions of several genes in skin, which may provide new molecular mechanism for the etiologic research of common skin disorders. In the recent 3 years, as the first or corresponding author, he had 16 papers published in SCI journal, including 5 papers as the first author in the journal with impact factor over 10, and 2 papers as the corresponding author in the Journal of Investigative Dermatology, the top journal of dermatology. In the future research, the applicant will continue to focus on studying the pathogenesis of the AQP5 in palmoplantar hyperhidrosis, the calpastatin in skin disorders with desmosomal deficiency, and identification of the new causative genes and their pathogenic roles in PPK. These studies may shed new light on the studies of new therapeutic targets for PPK.