Corneal Epithelial Differentiation and Regeneration

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DESCRIPTION (provided by applicant): The unique organization and structure of the corneal epithelium, stroma and endothelium are critical to the shape, transparency and protective functions of the cornea. Physical, chemical or infectious damage can result in repair tissues that have compromised structure, function poorly or have recurrent healing problems, often requiring corneal surgery or transplantation. Therefore, we wish to understand the basic mechanisms that regulate the migration, proliferation, and differentiation of these cells during normal development and during regeneration or repair. Specifically, we are focusing on the molecular regulation of these critical, active processes. Our previous work strongly implicates the small GTPase, Rho, and its downstream target kinase named ROCK in regulating corneal epithelial proliferation, cell-cell communication and corneal stromal activation. The Specific Aims are directed at testing some very reasonable, yet crucial, hypotheses about the mechanism of involvement of Rho signaling in these processes. Specifically: 1) Rho/ROCK signaling directs corneal epithelial proliferation, through regulation of the cell cycle. 2) Rho/ROCK signaling regulates corneal epithelial cell-cell communication via connexin 43 gap junctions during the cell cycle progression and, in turn, has direct effects on gap junctional regulation of cell cycle progression. 3) Corneal stromal cell activation and inactivation is controlled by conjoint Rho/ROCK and Rho/mDial signaling. The first two aims will employ rabbit corneal epithelial cells and the third aim employs rabbit corneal stromal cells, in culture. The evaluation of these hypotheses will advance our knowledge of the molecular signaling mechanisms that sustain corneal homeostasis and wound healing. That knowledge may lead to the development of methods for modulating cellular activation, cell-cell communication, differentiation and proliferation, which are critical to new interventions to improve corneal wound healing.