The role of GSH in cornea and lens development

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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.