ARRB1介导HNF4α在神经激肽1受体调控色素合成中的作用及机制研究

Pigmentation disorder is a skin disease that seriously affects the patient’s appearance and mental health. Its etiology and pathogenesis has not yet been clarified. Our research group firstly demonstrated the existence of neurokinin 1 receptor (NK1R) in primary human melanocytes. In addition, we found that NK1R regulates the synthesis of melanin in the skin through Wnt/β-catenin signaling pathway. Subsequent proteomics studies showed that NK1R could affect the expression of ARRB1 and hepatocyte nuclear factor 4α (HNF4α). Our preliminary experimental results indicated that ARRB1 and HNF4α were expressed in both animal and human skin. Besides, the NK1R agonist SP can promote the dissociation of ARRB1 and NK1R, inhibit the expression of HNF4α, and finally lead to an increase of the melanin content. On the basis of preliminary experiments, our project would verify a scientific hypothesis through in vivo and in vitro experiments: The activation of NK1R can lead to the dissociation of ARRB1 from NK1R, and the free ARRB1 further regulates the expression of HNF4, or produces some kind of protein modification to HNF4, which affects the activity of tyrosinase, finally regulates the synthesis of melanin in the skin, which reveals the molecular mechanism of NK1R regulating skin pigment synthesis, provides experimental and theoretical basis for the prevention and treatment of pigmented skin disorders.

色素障碍性皮肤病严重影响患者的容貌和心理健康，其病因及发病机理不明。本项目组在前期工作中首次证实人原代黑素细胞中存在神经激肽1受体（NK1R），该受体通过Wnt/β-catenin信号通路调节色素的合成。后续蛋白质组学研究发现，NK1R能够影响ARRB1和肝细胞核因子4α(HNF4α) 的表达。申请人预实验结果提示：（1）ARRB1和HNF4α在人和动物皮肤组织中均有表达；（2）NK1R激动剂能促进ARRB1与NK1R解离，上调HNF4α的表达，最终导致黑素含量增加。在预实验的基础上，本项目拟通过体内外实验验证科学假说：NK1R激活后能导致ARRB1从NK1R上解离，游离的ARRB1进一步调控HNF4α的表达，或对HNF4α产生某种形式的蛋白修饰，进而影响酪氨酸酶的活性，最终促进皮肤色素合成，揭示了ARRB1调节皮肤色素合成的分子机制，为治疗色素障碍性皮肤病的防治提供实验和理论依据。

色素障碍性皮肤病是临床上较为常见的皮肤病，主要有色素减少性和色素增加性皮肤病，虽然不会对个体造成很大的生命威胁和生理不适，但由于其严重影响患者外观，造成患者心理负担而降低生活质量。该疾病其病因及发病机理不明，至今国内外尚无理想的治疗药物。本项目组已证实人原代黑素细胞中存在神经激肽1受体（NK1R），该受体通过Wnt/β-catenin信号通路调节色素的合成，通过蛋白质组学研究发现，NK1R能够影响ARRB1和肝细胞核因子4α(HNF4α) 的表达。项目组研究证实ARRB1和HNF4α在人和动物皮肤组织中均有表达；NK1R激动剂能促进ARRB1与NK1R解离，上调HNF4α的表达，最终导致黑素含量增加。通过体内外实验验证科学假说：NK1R激活后能导致ARRB1从NK1R上解离，游离的ARRB1进一步调控HNF4α的表达，或对HNF4α产生某种形式的蛋白修饰，进而影响酪氨酸酶的活性，最终促进皮肤色素合成，揭示了ARRB1调节皮肤色素合成的分子机制，为合理有效治疗该病提供新的生物学靶点，为治疗色素障碍性皮肤病的防治提供实验和理论依据，具有重要的理论价值和潜在的应用前景。