皮肤是人类最重要器官之一，皮肤损伤修复对人体健康具有重大医学意义。全面深入研究皮肤细胞如何响应损伤和修复伤口的细胞及分子生物学机制一直是研究人员重要的关注点。申请人在国际上率先以线虫表皮为研究对象，基于转盘式激光共聚焦显微镜活体原位时序成像技术和激光、机械损伤方法，在亚细胞和分子水平上记录表皮损伤发生和修复的全过程。申请人前期工作阐明了线虫表皮伤口愈合的分子反应过程；证实钙信号是损伤激活的最初起始信号并在伤口愈合中发挥关键作用；发现了一种由线粒体介导表皮伤口愈合的全新机制。我们将继续利用已经建立的成熟实验系统，结合显微成像技术、遗传学和分子生物学等方法研究损伤激活的H2O2信号分子在表皮损伤修复中的功能，并寻找其上游调控信号和下游靶基因，探索上下游协同作用关系。本课题将加深对表皮细胞应对损伤释放信号以及这些信号如何调控伤口修复等重要生物学过程的理解，并对人类皮肤损伤修复和再生提供重要启示。

Wound healing impairment represents a major public health problem that is increasing due to an aging population and a sharp rise in the incidence of diabetes. Thus, understanding the molecular mechanisms of skin wound healing is of both biological interest and significant clinical relevance. Our long-term goal is to understand the molecular and cellular mechanisms of wound healing, using a combination of genetics and live imaging approaches. Our previous studies have established the adult C. elegans skin as a tractable genetic model system to dissect the mechanism of wound healing. We found an ancient and evolutionarily conserved role for Ca2+ as an early wound response signal in wound repair. Ca2+ signaling promotes actin cytoskeletal reorganization at wound sites by modulating the activity of Rho small GTPases. Recent results indicate that mitochondria actively responding to wounding and provide signaling to promote wound repair. This proposal specifically focuses on the roles of reactive oxygen species hydrogen peroxide (H2O2) in response to and regulating epidermal wound repair. Our preliminary data show that wounding can triggers local production of H2O2, which requires the function of NADPH dual oxidase (DUOX). Here, we propose to further investigate the molecular mechanism of H2O2 production after wounding using a combination of genetics and live imaging in C. elegans. We will then explore the role of H2O2 in triggering wound repair and its cellular and molecular mechanism. Results from these studies will not only improve our knowledge of mechanisms of wound healing, but will also shed light on the H2O2 signaling in other biological events. More importantly, a potential outcome of this research may also enable new therapeutic approaches for impaired wound healing in humans.