瞬时受体电位（TRP）通道通过介导阳离子内流使机体感受外界刺激并做出应答。人类皮肤中表达多种TRP通道，对维持皮肤基本功能具有重要作用。申请人前期发现TRPM4功能获得性突变可导致进行性对称性红斑角化症，并证实TRPM4突变可导致角质形成细胞（KC）异常增殖。为深入研究TRPM4导致皮肤角化过度的分子通路，申请人构建了Trpm4点突变基因敲入小鼠且成功模拟出皮肤过度角化表型，高锌饮食可逆转表型。基于前期工作基础，我们提出假设：TRPM4突变通过影响KC中钙离子浓度，导致皮肤增殖/分化信号通路异常，从而引起小鼠皮肤角化过度；而锌离子可能通过阻断TRPM4通道恢复KC内钙稳态，使皮肤异常增殖/分化信号通路回归正常。本项目拟以小鼠模型为主要对象，通过钙荧光、电生理、转录组测序等手段研究明确TRPM4突变导致皮肤角化异常及补锌逆转表型的机制，为进一步寻找治疗本病更加安全、有效的靶向药物奠定基础。

Transient receptor potential (TRP) channels sense and response to the ambient stimuli by mediating cation influx. Human skin expresses a variety of TRP channels to maintain its basic functionality. Our previous work has found that gain-of-function mutations in TRPM4 could lead to progressive symmetric erythrokeratoderma, and proved that the mutants could lead to promoted proliferation of the keratinocytes. To further elucidate the underlying molecular pathway, we constructed a Trpm4 mutated mice model, which successfully mimicked the phenotype of the patients and could be reversed by zinc supplement. Based on this work, we posed a hypothesis that TRPM4 mutations may disturb the proliferation/differentiation-related signaling pathway by interfering intracellular calcium metabolism, leading to skin hyperkeratotic phenotype in the mouse model. The zinc supplement may restore the calcium homeostasis into normal status by blocking the opening of the TRPM4 channel. The current project aims to use this model to investigate the concrete pathogenetic mechanism of TRPM4 mutations and the zinc therapeutic mechanism by techniques of calcium imaging, electrophysiology, and transcriptome sequencing. This research will provide a foundation for searching safer and more effective targeted agents.