TRPV3通过组蛋白瓜氨酸化修饰调控毛囊晚期分化的机制研究

瞬时受体电位通道香草酸亚型3（TRPV3）是一种非选择性阳离子通道，主要通透钙离子。其发生功能增强型突变时可导致Olmsted综合征，患者多有少毛表现。我们成功构建了该病的小鼠模型并发现，毛囊的过早分化驱动了其少毛表型，且此过程与结构蛋白的瓜氨酸化修饰增加以及某些调控毛囊晚期分化的分子（如Foxn1）转录减少有关。既往文献显示，钙离子可激活肽酰基精氨酸脱亚胺酶（PADIs），后者可对组蛋白进行瓜氨酸化修饰进而调控一系列下游基因的表达。因此我们提出科学假说，TRPV3功能增强可通过提高细胞内钙离子的水平而激活PADIs，后者通过上调组蛋白的瓜氨酸化水平影响了一系列毛囊分化相关基因的表达，最终引起毛囊的过早分化。我们拟在前期发现的基础上，通过分子、细胞和动物等实验，详细揭示TRPV3-PADIs-组蛋白瓜氨酸化分子通路调控毛囊分化的机制，为明确相关毛发疾病的发病机理，探寻治疗的新靶点提供思路。

Transient receptor potential cation channel, subfamily vanilloid, member 3 (TRPV3) is a non-selective cation channel, which is permeable mainly for calcium ions. Gain-of-function mutations in TRPV3 cause Olmsted syndrome, most patients of which have a hypotrichosis phenotype. We have successfully constructed a mouse model which mimics the hypotrichosis of Olmsted syndrome, and found that the premature differentiation of the hair follicle drives the hair loss process, which is associated with abnormal citrullination of structural proteins and reduced transcription of certain molecules (e.g. Foxn1) which are known to regulate the late differentiation of the hair follicle. Literature shows that, calcium ion is able to activate peptidyl arginine deiminases (PADIs), and the latter can citrullinate histones and further regulate the transcription of a wide range of downstream genes. Thus, we speculate that the enhanced function of TRPV3 can activate PADIs through elevating the level of intracellular calcium ion, and the latter can promote the citrullination modification of histones, which in turn alter the transcription levels of the molecules related to late differentiation of follicular keratinocytes, finally leading to premature differentiation of the hair follicle. On the basis of our previous findings, we intend to carry out molecular, cellular and in vivo experiments to explore the detailed mechanisms of how the TRPV3-PADIs-histone citrullination axis regulates the late differentiation of hair follicles. This study will elucidate the pathogenesis of related hypotrichosis, and lay a theoretical foundation for novel therapeutic strategies.