KERATOCYTE REGULATION IN CORNEAL REPAIR

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DESCRIPTION: Keratocytes play an important role in repair of the wounded cornea. A critical step for initiation of the corneal healing process is the dramatic conversion of the network of normally quiescent keratocytes into activated fibroblasts. These, in turn, differentiate into actin-rich myofibroblasts which play a critical role in wound closure. The PI has developed an in vitro model that reproduces the transition of keratocytes to fibroblasts and then to myofibroblasts. The central hypothesis of this proposal is that myofibroblast differentiation during wounding and healing is controlled by the interplay of three dominant factors: the loss of cell-cell contact, the presence of TGF-B, and altered cell-matrix interaction. The researchers propose that 1) disconnection of one corneal fibroblast from another that occurs soon after wounding initiates a series of biochemical/ molecular events that causes fibroblasts to be responsive to TGF-B and to differentiate into myofibroblasts; 2) re-establishment of cell-cell contact attenuates the cellular response to TGF-B; and 3) matrix-generated signals are additional, essential modulators of myofibroblast differentiation and function. The specific aims of the proposal are to test the following hypotheses: 1. Gap junction-mediated intercellular communications regulate myofibroblast differentiation. 2. Absence of myofibroblast differentiation in response to TGF-B in confluent fibroblasts results from down-regulation of cell-surface TGF-B receptors. 3. Alterations in expression of connexins precede cadherin expression and are early events of the corneal response to wounding in vivo. 4. Matrix-generated signals from alternative fibronectin isoforms and altered integrin expression are critical modulators of myofibroblast differentiation and /or function.