Pmel17表达受阻诱发色素细胞自噬在白癜风发病中的作用研究

Vitiligo is a common skin disease that presents as loss of melanin. The current pathogenesis of the disease is still unclear, which seriously affects its therapeutic effect. The melanosome specific structural protein Pmel17 which is closely related to the biosynthesis of melanin has a potential role in the pathogenesis of vitiligo, but the mechanism in detail is unknown. In previous study, we found that the number of melanosomes and lysosomes were changed and the expression of autophagy gene ATG4 and autophagy molecule LC3-II were increased in Pmel17 silencing melanocytes. Therefore we propose a new hypothesis: if the expression of Pmel17 is inhibited, the melanocyte will undergo autophagy which can affect the melanosomes and lysosomes, and then destroy the melanocytes, and finally induce the vitiligo’s development. First, this study will confirm the correlation between Pmel17, autophagy of melanocytes and vitiligo. Then we intend to construct a melanocyte model of Pmel17 gene silencing and clarify the effect of Pmel17 on melanocyte autophagy and its mechanism by detecting melanogenesis, autophagosome, autophagy protein, autophagy related signaling molecules and degradation of melanosome proteins by lysosomes. Finally, a mouse model of down-regulation of skin Pmel17 expression will be construct to verify the role and mechanism of Pmel17. This study will clarify the pathogenesis of vitiligo from a new perspective and supply a new idea of clinical treatment.

白癜风是一种常见的色素脱失性皮肤病，发病机制复杂。研究发现黑素体结构蛋白Pmel17与黑色素的生物合成密切相关，其在白癜风的发病中具有潜在作用，具体机制不明。我们前期证实沉默Pmel17的表达可导致黑素体数目减少而溶酶体数目增加，同时发现自噬分子的表达升高，从而提出“Pmel17表达受阻通过黑素细胞自噬影响黑素体和溶酶体的功能，破坏黑素细胞而诱发白癜风”的假说。本课题首先在白癜风病人组织中证实Pmel17、黑素细胞自噬与白癜风发病的相关性，然后构建Pmel17基因沉默的黑素细胞模型，通过检测色素合成、自噬体、自噬蛋白、自噬相关信号分子的表达及自噬对黑素体蛋白的降解，明确Pmel17对黑素体和溶酶体的作用及对黑素细胞自噬的影响和机制，最后在动物水平上构建局部皮肤Pmel17表达下调的小鼠模型来验证Pmel17的作用和机制。本课题将从新的视角阐明白癜风的发病机制，为白癜风的临床诊治提供新思路。

白癜风是一种常见的色素脱失性皮肤病，发病机制复杂。研究发现黑素体结构蛋白Pmel17与黑色素的生物合成密切相关，其在白癜风的发病中具有潜在作用，具体机制不明。我们首先在白癜风病人组织中验证Pmel17、黑素细胞自噬与白癜风的发病是否具有相关性，然后构建Pmel17基因沉默的黑素细胞模型，通过检测色素合成、自噬体、自噬蛋白及溶酶体对黑素体蛋白的降解，明确Pmel17对黑素体和溶酶体的作用及对黑素细胞自噬的影响，最后在动物水平上构建局部皮肤Pmel17表达下调的小鼠模型来验证Pmel17的作用和机制。我们的研究结果显示白癜风病人组织中Pmel17表达下调，自噬基因LC3表达升高，初步证实Pmel17、黑素细胞自噬与白癜风的发病具有相关性。细胞水平将Pmel17基因敲低后，黑素体蛋白表达降低而溶酶体蛋白表达升高，同时黑素合成减少，自噬小体增多，黑素体蛋白被溶酶体降解，以上结果明确了Pmel17对黑素体和溶酶体的作用及对黑素细胞自噬的影响。动物水平上我们构建了小鼠模型进一步验证。本课题的研究从新的视角阐明了白癜风的发病机制，为白癜风的临床诊治提供了新思路。