TRPV3调控毛囊BMP信号通路的分子机制

Hair disorders are common in dermatology. So far, a number of genes have been found to be causes of hairlessness or hair loss, and signaling pathways that regulate hair morphogenesis and hair cycle, such as wnt, BMP and EGFR, are gradually being elucidated. We ever found that Olmsted syndrome (OS), a congenital disorder, is caused by gain-of-function mutations of transient receptor potential vanilloid-3 (TRPV3). These mutations cause the channel to open continuously and Ca2+ flowing inside the cell increases significantly, which induces apoptosis, leading to hyperkeratosis. Most OS patients suffer from hairlessness, and our TRPV3 gain-of-function knock in mice also show hairless phenotype. What interests us is the molecular mechanism through which TRPV3 regulates hair physiology. Based on the analysis of pathological characteristics and hair cycle of TRPV3 knock in mice, we speculate that hairless phenotype may be mediated by BMP-Smad signaling pathway. We are here trying to explore the function of BMP-Smad signaling pathway in regulation of hair morphogenesis and hair cycle by TRPV3 at molecular, cellular and animal level, and we expect to find clues enlightening for future research on mechanism of hair disorders as well as their therapy.

毛发疾病是皮肤科的常见病，目前发现多种基因缺陷可以引起少毛或脱发，调控毛发发育和周期的信号通路如Wnt、骨形成蛋白（BMP）、表皮生长因子（EGFR）等也正在被逐步揭示。我们确定了一种遗传病，Olmsted综合征，是由于瞬时受体电位通道 V3亚型（TRPV3）的功能增强型突变所致，突变引起通道的持续开放，使角质形成细胞中的钙内流增加，诱发凋亡，出现严重的角化。患者多伴有毛发减少，而近期我们制备的功能增强型TRPV3 基因敲入小鼠也有少毛的表现。TRPV3调控毛发发育的分子机制是我们所关注的问题。在分析TRPV3基因敲入小鼠病理表现、毛发周期等基础上，我们推断BMP-Smad信号通路可能在介导TRPV3 功能增强型突变所致的少毛表型中发挥了重要作用。我们拟在分子、细胞和动物水平，系统揭示BMP-Smad信号通路在TRPV3调控毛发发育和毛发周期中的作用，为毛发疾病的发病机制及治疗提供新思路。

2012年，我们在国际上首次发现TRPV3基因突变可以引起Olmsted综合征。患者除掌跖角化和瘙痒外，还有不同程度的毛发稀疏，严重者可出现全秃。我们拟在前期工作的基础上，进一步探究TRPV3突变导致毛发减少的机制。利用RNAscope技术，以及构建Trpv3-Flag报告小鼠，我们明确指出：TRPV3均主要表达在成熟毛囊的中段-近段内毛根鞘和毛干。进一步地，我们构建了Trpv3-G568V小鼠模型，成功模拟了Olmsted综合征患者的少毛症表型。Trpv3-G568V小鼠毛囊的结构异常与其过早发生晚期分化以及细胞凋亡增加有关，这可能是瓜氨酸化修饰异常以及调控毛囊晚期分化的转录因子（Foxn1、Msx2、Dlx3 和Gata3）水平下降所致。此外，Trpv3-G568V小鼠的毛囊角质形成细胞发生继发性过度增殖，导致其毛囊周期加速，毛囊干细胞减少，毛囊再生能力下降，进一步加重了其少毛症表型。本研究通过建立动物模型，揭示了 Olmsted 综合征中毛发减少的关键病理过程，拓展了我们对钙离子通道调控毛囊翻译后修饰过程和转录因子表达的认识，为包括 Olmsted 综合征在内的遗传性少毛症的治疗提供了新的理论基础。