AHR通路保护线粒体功能对抗白癜风氧化应激损伤的关键机制研究

The oxidative stress in melanocytes plays a vital role in vitiligo. Mitochondria are not only the major resource of intracellular reactive oxygen species (ROS), but also the main target of ROS. Increasing evidence has demonstrated that ROS induces oxidative damage of mitochondria and further triggers mitochondria-induced apoptosis of melanocytes. Aryl hydrocarbon receptor (AHR), an important transcription factor, contributes to protection of mitochondria against oxidative stress, but the molecular mechanism remains unclear. Our previous study found that the functional mutations of AHR gene were closely associated with vitiligo risk, and decreased AHR expression was also detected in the PBMCs of vitiligo patients. Additionally, H2O2-induced oxidative stress activated AHR signal pathway and further decreased the mitochondria-generated ROS. Thus, we hypothesized that AHR may play an important role in protecting mitochondria against oxidative stress through regulating biosynthesis of mitochondria in human melanocytes. In the present research project, we plan to study the regulatory mechanism of AHR involved in mitochondria protection against oxidative stress in human melanocytes, which may open a new horizon in the etiology of oxidative damage of melanocytes and may be beneficial to therapy of depigmentation disorder in the future.

黑素细胞氧化应激是白癜风发病的中心环节。氧化应激能够破坏线粒体结构及功能，可导致线粒体严重损伤，激活内源性凋亡途径、诱发黑素细胞凋亡，但是白癜风中线粒体氧化损伤过程及具体调控机制尚不清楚。我们近期研究发现，芳香烃受体（AHR）遗传变异可致白癜风易感，患者外周血PBMCs中AHR明显下调且与病程负向相关，氧化应激条件下抑制AHR信号通路可导致线粒体功能障碍并加重黑素细胞氧化应激损伤。据此我们提出新假说：AHR信号通路在保护线粒体功能对抗黑素细胞氧化损伤中具有重要作用，当该通路异常时，细胞无法有效缓解线粒体氧化损伤，导致黑素细胞内源性凋亡增加，诱发白癜风。依此研究假说，本项目拟利用细胞和分子生物学技术以及体外实验和临床样本，系统研究AHR信号通路对线粒体功能和黑素细胞氧化损伤的影响及其具体分子机制，揭示其在白癜风氧化应激中的作用，为全面了解白癜风发病机制及指导白癜风治疗提供新的理论依据及策略。

黑素细胞氧化应激损伤是白癜风发病的中心环节。氧化应激能够破坏线粒体结构及功能，可以导致线粒体严重损伤，激活线粒体内源性凋亡途径、诱发白癜风黑素细胞凋亡，但是白癜风中线粒体氧化损伤过程及其具体调控机制尚不清楚。我们近期研究发现，芳香烃受体（AHR）遗传变异可致白癜风易感，白癜风患者外周血PBMCs中AHR明显下调且与病程负向相关，氧化应激条件下抑制AHR信号通路可导致线粒体功能障碍并加重黑素细胞氧化应激损伤。AHR信号通路在保护线粒体功能对抗黑素细胞氧化应激损伤中具有重要作用，当该通路异常时，细胞无法有效缓解线粒体氧化损伤，导致黑素细胞内源性凋亡增加，诱发白癜风。本项目首先明确了AHR信号通路在正常黑素细胞抵御氧化应激损伤及保护线粒体功能中的作用。其次确定了调控 AHR 信号转导通路可影响黑素细胞线粒体抵御氧化应激的作用，并阐明其作用机制，对AHR信号通路在黑素细胞对抗氧化应激损伤中的作用和意义有全新和系统的认识，为色素性疾病的防治奠定基础。本项目运用 Western-Blot、Real-time PCR 、siRNA、激光共聚焦和流式细胞术等研究技术和手段，以正常人黑素细胞、白癜风患者黑素细胞及皮损组织为研究对象，系统研究AHR信号通路对线粒体功能和黑素细胞氧化损伤的影响及其具体分子机制，揭示其在白癜风氧化应激中的作用，为全面了解白癜风发病机制及指导白癜风治疗提供新的理论依据及策略方向。