The human corneal epithelium plays an important role in the ocular system by providing a uniform refractive surface and protecting the eye from environmental insults. The functional properties of the corneal epithelium result from its homogeneous nature, as it is composed of a single cell type. In order for the corneal epithelium to maintain its cellular architecture and function as a tissue, cell-cell interactions through a number of adhesion junction proteins are required. Blood vessel epicardial substance (Bves) is a novel adhesion protein which we have demonstrated to be important in embryologic eye development and in cellular migration during wound healing. In this proposal, our central hypothesis is that Bves is important to corneal epithelial cell migration and proliferation mediated by regulation of adhesion junctions. We propose to study the role of Bves in the human corneal epithelium at 3 levels. First, at the molecular level, we will study Bves'role in adhesion junction assembly and its interaction with other junction proteins. To do so, we will perform immunohistochemistry in a cell culture model. Second, we will study the role of Bves in the formation and maintenance of an epithelial monolayer in a cell culture system. In order to do so, we have generated human corneal epithelial cell lines that overexpress a functional chick Bves and a non-functional mutant Bves. We propose to create 2 additional cell lines with modified Bves constructs. Finally, we will alter Bves expression in vivo and study its effects in a mouse corneal wounding assay. Bves expression will be altered using ionophoresis to deliver both the Bves constructs and Morpholinos used in Aim 2 to the mouse cornea. We will observe the effects on re-epithelialization of the wound area followed by stratification. Our long term objective is to understand the molecular basis of corneal regeneration both in homeostasis and wound repair. Identification of a new molecular pathway and its players in corneal epithelial wound healing and regeneration may lead to new pharmacologic strategies to promote wound healing and maintenance of a uniform corneal epithelium. Therefore, an understanding of Bves in the human corneal epithelium has potential therapeutic benefits.
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| Williams, Christopher S; Zhang, Baolin; Smith, J Joshua et al. (2011) BVES regulates EMT in human corneal and colon cancer cells and is silenced via promoter methylation in human colorectal carcinoma. J Clin Invest 121:4056-69 |
| Jayagopal, Ashwath; Yang, Jin-Long; Haselton, Frederick R et al. (2011) Tight junction-associated signaling pathways modulate cell proliferation in uveal melanoma. Invest Ophthalmol Vis Sci 52:588-93 |
| Russ, Patricia K; Kupperman, Asher I; Presley, Sai-Han et al. (2010) Inhibition of RhoA signaling with increased Bves in trabecular meshwork cells. Invest Ophthalmol Vis Sci 51:223-30 |
| Kawaguchi, Michiya; Hager, Hillary A; Wada, Aya et al. (2008) Identification of a novel intracellular interaction domain essential for Bves function. PLoS One 3:e2261 |
