Keratocyte regulation in corneal repair

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DESCRIPTION (provided by applicant): Our current goal is to investigate the potential for CCN2 (also known as Connective Tissue Growth Factor, CTGF) to promote corneal wound healing. This 38 kDa secreted protein has been classified as both a growth factor and a matricellular component whose synthesis and secretion are stimulated by TGF-3. It is highly expressed in the corneal stroma and other connective tissues after wounding. In a cell culture model that mimics corneal wound healing, we have immunodetected in addition to the 38 kDa CCN2, the 31 kDa protein (31 kDa CCN2) that has not been previously described. Our working model is that corneal fibroblast proliferation and migration are induced by full-length 38 kDa CCN2 whereas differentiation and fibrosis are induced by the 31 kDa form of CCN2. The Specific Aims to test our working model are as follows: 1. Test the hypothesis that matrix signals influence TGF-3 induction and processing of CCN2. 2. Test the hypothesis that combinatorial signaling of matrix and 31 kDa CCN2 stabilizes focal adhesions and promotes myofibroblast differentiation 3. Test the hypothesis that some of the highly divergent signals attributed to CCN2 including migration, proliferation, matrix synthesis or myofibroblast differentiation are distributed to either 38 kDa and 31 kDa CCN2. Recent studies show that after LASIK, the human cornea does not "heal". The central region has a prolonged period of hypocellularity (absence of cells), whereas the site of the incision is fibrotic with abundant myofibroblasts and matrix. As a corollary of our working model, migration of corneal fibroblasts into a wound to promote healthy repair could be stimulated if local and specific proteolysis of CCN2 were inhibited. This inhibition could also prevent myofibroblast formation and local fibrosis.