MTHFR调控黑素细胞内质网应激在白癜风发病中的作用及机制研究

Vitiligo, caused by epidermal melanocyte destroyed, is a depigmentation disease with complex pathogenesis. Our previous studies have revealed that MTHFR SNP site relevant the vitiligo susceptibility. Vitiligo patients serum MTHFR activity are lower than control group, and negatively correlated with the degree of progress of vitiligo. Silence MTHFR can promote the apoptosis of melanocytes.We can get the conclusion that MTHFR are closely related to the development of vitiligo, but the mechanism is not clear. Endoplasmic reticulum stress plays an important role in the induction of apoptosis, we found that silence MTHFR can upregulate expression of endoplasmic reticulum stress PERK pathway and pro-apoptotic related factor PHLDA1, increase melanocytes apoptosis. Thus, we propose that, reduce MTHFR activity, resulting in its metabolic substrate Hcy accumulation, causing the melanocytes endoplasmic reticulum stress, further activate PHLDA1 and lead to apoptosis, causing vitiligo. In this project, we plan to find out the MTHFR regulation of ER stress signaling pathways at the cellular level, further clarify endoplasmic reticulum stress via PHLDA1 lead to apoptosis molecular mechanisms. Furthermore, we investigated the effect of folic acid supplementation via MTHFR on apoptosis of melanocyte and the effect of restore color. These studies will enrich and improve the pathogenesis of vitiligo, and provide new ideas for the treatment of this disease.

白癜风是由表皮黑素细胞破坏所导致的一种色素脱失性疾病，发病机制尚未充分阐明。我们前期研究发现，亚甲基四氢叶酸还原酶（MTHFR）基因多态性与白癜风发病风险相关；患者血清中MTHFR表达水平降低并与白癜风分期负相关；干涉MTHFR可促进黑素细胞凋亡，但其调控黑素细胞凋亡的作用机制尚不清楚。文献及我们的研究证实，内质网应激在诱导黑素细胞凋亡中发挥重要作用，我们发现干涉MTHFR可激活内质网应激PERK通路及促凋亡相关因子PHLDA1表达，增加黑素细胞凋亡。因此我们提出假说：MTHFR表达降低，造成其代谢产物Hcy积累，引起黑素细胞内质网应激，激活PHLDA1导致细胞凋亡，引发白癜风。本项目拟明确MTHFR调控内质网应激，诱导PHLDA1表达引起黑素细胞凋亡的分子机制，并进一步考察补充叶酸通过MTHFR降低细胞凋亡，促进患者复色的效果。预期结果将丰富和完善白癜风发病机制，为该疾病治疗提供新思路。

白癜风是表皮黑素细胞破坏所致的一种色素脱失性疾病，发病机制尚未充分阐明。我们前期研究表明，白癜风患者血清中酶活性明显下降且与白癜风进展程度负相关。此外，MTHFR可同时参与叶酸代谢及甲硫氨酸代谢循环，是两条代谢通路中的关键调控单元。提示白癜风患者MTHFR存在障碍从而导致底物利用不足以及中间产物堆积最终造成疾病的发生，但作用机制不明。本项目就MTHFR在白癜风疾病发生中的作用及机制进行了研究。本研究首先就MTHFR代谢底物同型半胱氨酸在患者中的表达水平及与患者临床特征之间的关系进行了分析。其次对同型半胱氨酸影响黑素细胞生命活动及其在白癜风疾病发生中的作用机制进行了研究。最后提出通过补充叶酸可以纠正黑素细胞的MTHFR代谢通路，抵抗内质网应激并恢复黑素合成。通过本项目研究，明确了MTHFR代谢底物同型半胱氨酸在白癜风患者血清中呈高表达，并与患者疾病进展程度密切相关。阐明了同型半胱氨酸可抑制黑素细胞增殖、促进黑素细胞凋亡。揭示了同型半胱氨酸在白癜风疾病发生中的作用，同型半胱氨酸一方面可诱导黑素细胞内质网应激，通过激活PERK-eIF2α-CHOP通路诱导黑素细胞凋亡。另一方面，同型半胱氨酸还可抑制黑素合成相关分子表达水平降低，减少黑素合成。并证实补充叶酸可减少同型半胱氨酸诱导的黑素细胞凋亡，恢复由同型半胱氨酸引起的黑素合成相关分子表达降低，促进黑素合成。本研究丰富了白癜风疾病的发病机制，提出补充叶酸可作为进展期白癜风患者治疗的有效手段，为该疾病治疗提供了新思路。