The role of GSH in cornea and lens development

项目总结/摘要 本课题旨在阐明谷胱甘肽（GSH）在眼表发育中的作用 组织中GSH是细胞内最丰富的非蛋白巯基，与GSSG一起形成细胞内主要的非蛋白巯基。 氧化还原缓冲液。通过氧化还原调节，GSH改变了氧化还原敏感蛋白的功能， 参与细胞增殖、迁移、分化和凋亡的调控途径。先前的研究 表明GSH氧化还原状态代表了体外胚胎发育过程中的关键代谢开关， 是小鼠早期发育所必需的。眼睛表面充满了GSH。既有线 有证据表明，GSH在眼形态发生过程中是活跃合成的。此外，主要信号 调节眼表组织发育（包括成纤维细胞生长）的转导途径 因子受体（FGFR）、Notch和经典Wnt/β-连环蛋白途径是氧化还原调节的靶点。是 因此推测：（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，调节眼组织中的关键信号通路， 形态发生该假设将通过两个特定目的进行检验：（1）表征眼部表型 一种突变小鼠品系，不能特异性合成GSH， 将专门致力于眼表发育的谱系细胞;（2）评估活性的变化 突变小鼠中的三种信号通路。这些研究的结果将 增强我们对眼睛发育过程的分子细节的理解。以来 上述信号通路并不局限于眼睛，新的知识来源于 拟议的研究可能具有相关性，并可扩展到一般的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.