The role of GSH in cornea and lens development

项目摘要/摘要 本项目的目的是阐明谷胱甘肽(GSH)在眼表发育中的作用。 纸巾。GSH是细胞内含量最丰富的非蛋白硫醇，与GSSG一起形成主要的细胞 氧化还原缓冲液。通过氧化还原调节，GSH改变氧化还原敏感蛋白的功能，而氧化还原敏感蛋白是关键 控制细胞增殖、迁移、分化和凋亡的通路的参与者。之前的研究已经 研究表明，GSH氧化还原状态是体外胚胎发育过程中的一个关键代谢开关，而GSH 对于小鼠的早期发育来说是不可或缺的。眼表充满了谷胱甘肽。现有线路 有证据表明，在眼部形态发生过程中，GSH的合成非常活跃。此外，主要信号 调控眼表组织发育的信号转导途径，包括成纤维细胞的生长 因子受体、Notch和典型的Wnt/β-catenin通路是氧化还原调节的靶标。它是 因此假设：(1)GSH合成是眼表正常发育所必需的 (2)GSH通过其氧化还原调节调节眼球运动中的关键信号通路 形态发生。这一假设将通过两个具体的目标来检验：(1)表征眼睛的表型(S) 一种突变的小鼠品系不能合成GSH 专门致力于眼表发育的谱系细胞；(2)评估活动的变化 在突变小鼠的上述三个信号通路中。从这些研究得出的结果将 增强我们对眼睛发育过程的更多分子细节的理解。自.以来 上述信号通路并不局限于眼睛，新的知识来自于 所提出的研究可能具有相关性，并可扩展到一般胚胎发生和器官发生。

Project Summary/Abstract The goal of this project is to elucidate the role of glutathione (GSH) in the development of ocular surface tissues. GSH is the most abundant cellular non-protein thiol and together with GSSG forms the major cellular redox buffer. Through redox modulation, GSH modifies the function of redox-sensitive proteins that are key players of pathways controlling cell proliferation, migration, differentiation and apoptosis. Previous studies have shown that GSH redox state represents a key metabolic switch during in vitro embryo development, and GSH is indispensable for early mouse development. The ocular surface is replete with GSH. Existing lines of evidence suggest that GSH is actively synthesized during ocular morphogenesis. In addition, major signaling transduction pathways that regulate the development of ocular surface tissues, including fibroblast growth factor receptor (FGFR), Notch and canonical Wnt/β-catenin pathways, are targets of redox modulation. It is therefore hypothesized that: (1) GSH synthesis is essential for normal development of ocular surface tissues; (2) GSH, through its redox modulation, regulates key signaling pathways during ocular morphogenesis. This hypothesis will be tested by two Specific Aims: (1) characterize the ocular phenotype(s) of a mutant mouse line rendered incapable of GSH synthesis specifically in lineage cells that will commit exclusively to ocular surface development; (2) assess the changes in the activity of three aforementioned signaling pathways in mutant mice. The results derived from these studies will enhance our understanding of the process of eye development in greater molecular detail. Since the aforementioned signaling pathways are not restricted to the eye, the new knowledge derived from the proposed studies may have relevance and be extended to general embryogenesis and organogenesis.