角质形成细胞氧化应激活化促凋亡因子Par-4在白癜风发病中的作用及机制研究

Vitiligo is characterized by depigmentation as a consequence of local melanocyte destruction. Despite the fact that its etiology is not fully understood, oxidative stress induced-melanocytes (MC) destruction may be the primary factor in the pathogenesis of vitiligo, in which keratinocytes serve as the main player to regulate the process. We recently found that the pro-apoptotic factor Par-4 was increased in the lesion samples from vitiligo patients. Moreover, Par-4 can be induced by oxidative stressed keratinocytes and promote the apoptosis of melanocytes. However, whether the pro-apoptotic factor Par-4 is participated in the pathogenesis of vitiligo and how the pro-apoptotic factor Par-4 trigger the apoptosis process in vitiligo remain unclear. For further investigation of this program, we will firstly explore the activation of Par-4 induced by oxidative stressed keratinocytes, and then investigate the underlying mechanism of the apoptosis of melanocytes under pro-apoptotic factor Par-4, finally we will illustrate the critical role of Par-4 in vitiligo. The results will fully elucidate the mechanism of abnormal apoptosis of melanocytes in vitiligo, which may provide important basis for vitiligo prevention and treatment.

黑素细胞氧化应激损伤是白癜风发病的重要原因，角质形成细胞在此过程发挥重要作用。我们前期研究发现，促凋亡因子Par-4在白癜风患者皮损处高表达；体外实验发现，氧化应激作用下角质形成细胞中Par-4也呈现高表达并参与黑素细胞凋亡。但Par-4介导黑素细胞凋亡的内在机制及其是否参与白癜风发病过程目前仍未阐明。本项目拟在前期工作基础上，系统研究Par-4在氧化应激作用下角质形成细胞中的活化情况，同时揭示Par-4介导的黑素细胞异常凋亡的内在机制及其在白癜风发病中的作用，为深入研究氧化应激诱导白癜风发病提供重要依据，并为白癜风治疗提供新的方向。

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。我们前期研究发现，促凋亡因子Par-4在白癜风患者皮损处高表达；体外实验发现，氧化应激作用下角质形成细胞中Par-4也呈现高表达并参与黑素细胞凋亡。但Par-4介导黑素细胞凋亡的内在机制及其是否参与白癜风发病过程目前仍未阐明。本项目就角质形成细胞氧化应激活化促凋亡因子Par-4在白癜风发病中的作用及机制进行了研究。本研究首先就Par-4及其受体GRP78在不同发病阶段白癜风患者中的表达水平及在表皮细胞中的定位进行了研究分析。其次在体外，对氧化应激影响Par-4及其受体GRP78在黑素细胞和角质形成细胞的表达和定位进行了研究。最后对Par-4-GRP78诱导黑素细胞凋亡的机制进行了研究。通过本项目研究，明确了Par-4及其受体在白癜风患者皮损呈高表达，并与患者疾病进展程度密切相关。阐明了氧化应激诱导角质形成细胞和黑素细胞Par-4表达及黑素细胞核内cleaved Par-4的活性剪切。同时氧化应激诱导角质形成细胞和黑素细胞GRP78表达及GRP78在黑素细胞的细胞膜转位。通过突变实验证实Par-4通过诱导核内cleaved Par-4活性剪切形式诱导黑素细胞凋亡。回复实验证实氧化应激下的角质形成细胞分泌的Par-4与黑素细胞膜表面GRP78结合，通过激活NF-κB通路诱导黑素细胞凋亡。本项目揭示氧化应激下角质形成细胞与黑素细胞活化并通过Par-4-GRP78通路介导的黑素细胞异常凋亡的内在机制，丰富了白癜风疾病的发病机制，为该疾病治疗提供新的方向。