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/b-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 redox status of key signaling molecules of three aforementioned signaling pathways and establish ocular thiol proteome profile in mutant mice. The results derived from these studies will enhance our understanding of the process of eye development in greater molecular detail and thereby lay an important foundation for future studies. 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.

Public Health Relevance

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 thio;l contributing to cellular redox buffer. Through redox modulation, GSH modifies the function of redox-sensitive proteins that are key players of pathways controlling cell proliferatio, migration, differentiation and apoptosis. We will test the following hypotheses: (1) GSH synthesis is essential for normal development of ocular surface tissues, and (2) GSH, through its redox modulation, regulates key signaling pathways during ocular morphogenesis. The results derived from these studies will enhance our understanding of the process of eye development in greater molecular detail and thereby lay an important foundation for future studies.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EY021688-02
Application #
8534128
Study Section
Special Emphasis Panel (BVS)
Program Officer
Mckie, George Ann
Project Start
2012-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$220,757
Indirect Cost
$78,257
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Monte, Andrew A; Heard, Kennon J; Campbell, Jenny et al. (2014) The effect of CYP2D6 drug-drug interactions on hydrocodone effectiveness. Acad Emerg Med 21:879-85