CELL SIGNAL TRANSDUCTION IN CORNEAL WOUND HEALING

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DESCRIPTION: (adapted from the applicant s abstract) Corneal re-epithelization after trauma or surgery is fundamental to restore normal vision. The PI plans to test the hypothesis that phosphotidylinositol-3-kinase (PI-3K) and protein kinase C (PKC) are essential steps in the signal transduction pathway leading to repair. These pathways transmit stimuli from the cell surface to the nuclei in a cascade of events that involve mitogen-activated protein kinase (MAPK). The debridement of the corneal epithelial layer will be used as a model of wound healing. The PI proposes to test if PKC isoforms can directly activate transcription by translocating to the nuclei or indirectly by activating the MAPK cascade, regulating cell proliferation and wound healing. She also proposes to perform studies to establish how the receptors for epidermal growth factor (EGF) and keratinocyte growth factor (KGF) associate with PI-3K and to define which PKC isoforms are targets of PI-3K. Selective inhibitors will be used to correlate the studies with wound closure. Analytical procedures such as HPLC and FPLC will be used. Identification of pathway components will be accomplished by Western blot with specific antibodies, and kinase assays will be performed in enzyme immunocomplexes and quantified by phosphor imaging. The results obtained will define the involvement of PI-3K, PKC and MAPK in corneal wound healing and help target drugs to selective steps of signal transduction to modulate corneal epithelial repair.