EGFR-MEDIATED CORNEAL EPITHELIAL WOUND HEALING

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Corneal epithelial wound healing and homeostasis is regulated by EGFR activity. This process is mediated by three cellular changes: cell migration, proliferation, and stratification. Inhibition of ligand-stimulated EGFR activation, either through small molecule inhibitors or blocking antibodies, results in a decrease in all three cellular changes as well as impaired wound healing. Based on our own findings and the work of others, we hypothesize that corneal wound healing can be enhanced by promoting EGFR-mediated signals that enhance cell migration. To test this hypothesis, we must understand EGFR-mediated signaling on the molecular and cellular level. This information will be used to target molecules and mechanisms that promote epithelial cell migration, which can ultimately accelerate coverage of the damaged area and healing of the wounded cornea. In the first aim of this proposal, we will study other endogenous EGFR ligands that have been reported to be more potent activators of corneal wound healing. We hypothesize that these ligands promote different endocytic trafficking itineraries of the EGFR than EGF (i.e. recycling rather than degradation) and this is the basis of their enhance wound healing. In the second aim, we will disrupt EGFR endocytic trafficking at discrete stages along the endocytic pathway and assess the magnitude and duration of the EGFR phosphorylation, effector signaling, and cell physiology. These findings will indicate whether enrichment of the activated receptor at discrete endocytic location will specifically promote the molecular and cellular events associated with corneal wound healing.