The cornea is the transparent, anterior most ocular tissue that provides most of the refractive power of the eye. Blindness due to corneal opacities is a common indication for transplantation in developed nations. Over 50,000 donor corneas were made available for transplants in the US in 2006, and demand will likely rise with the increasing age of the US population. The global objective of this proposal is to develop zebrafish as a model for human corneal development and disease. Zebrafish offers a tractable model system for because of its high fecundity and wide array of genetic tools.
The specific aims of this study are designed to test the hypothesis that the zebrafish cornea is a suitable model for the human cornea. This hypothesis will be addressed by characterizing the structure and function of wildtype zebrafish corneas and by determining whether mutations in zebrafish orthologs of genes associated with human corneal disease reproduce similar disease phenotypes. The developmental role of those genes will also be studied using confocal microscopy.
The first aim will characterize the structure of wildtype zebrafish corneas in vivo. The central corneal thickness will be measured using optical coherence tomography (OCT) and corneal endothelial cell density will be determined using specular microscopy. The imaging protocols developed in aim 1 will be used in future studies to quantitatively characterize mutant zebrafish corneas.
The first aim will also determine whether the corneal endothelial cells in zebrafish have a pump function and are arrested in cell cycle like human corneal endothelial cells.
The second aim will determine whether mutations in vsx1 and pax6b results in corneal edema and altered endothelial cell morphology. Mutations in vsx1 have been associated with keratoconus and posterior polymorphous corneal dystrophy, and mutations in pax6 have been associated with Peters anomaly, Axenfeld-Rieger syndrome, and aniridia in humans. Many of the diseases associated with vsx1 and pax6b mutations feature corneal edema secondary to corneal endothelial dysfunction, frequently requiring corneal transplantation.
The third aim will explore the developmental role of vsx1 and pax6b in corneal endothelial development. The completion of these studies will determine the extent to which zebrafish is an appropriate system for modeling developmental pathways and pathogenetics mechanisms in the human cornea. In the long term, insights from such studies could lead to new treatment strategies for diseases that currently require corneal transplantation. !

Public Health Relevance

Blindness due to corneal opacities is a common cause for transplantation in developed nations, and the demand for donor corneas in the US will likely rise due to increasing age of the US population. The objective of this proposal is to develop zebrafish models of human corneal diseases that may offer new insights into corneal disease mechanisms. The insights in turn could lead to novel treatment strategies for diseases that currently require corneal transplantation. !

National Institute of Health (NIH)
National Eye Institute (NEI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZEY1-VSN (10))
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Agarwal, Neeraj
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University of Southern California
Schools of Medicine
Los Angeles
United States
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