Corneal scarring is a major cause of decreased visual quality and vision loss worldwide. Scarring follows disruption to normal corneal structure and function, whether from infection, laser refractive surgery, corneal transplantation, ocular trauma (chemical or physical) or corneal dystrophies. There is no suitable means of controlling corneal scaring despite more than 25 years trying to characterize cytokine signaling during wound healing. Our long-term objective is to understand mechanisms of corneal wound healing and our goal is to design effective therapies to treat or prevent corneal scarring. Our overall hypothesis is that peroxisome proliferator activated receptor gamma (PPAR3) ligands prevent corneal fibrosis and can be targeted as a therapy for this condition, with significantly greater efficacy than current clinical treatments or than blocking the activity of single cytokines.
Aim 1 : Test the hypothesis that PPAR3 ligands inhibit key pro-fibrotic activities of cultured corneal keratocytes. We use immunohistochemistry, proliferation assays, wounding assays, western blots, slot blots and Q-PCR to assess the relative effectiveness of PPAR3 ligands at modulating proliferation, migration, expression of CTGF, 1SMA, Thy-1, collagen I, collagen III, fibronectin and their mRNAs in cultured keratocytes stimulated by optimal doses of TGF2.
Aim 2 : Test the hypothesis that PPAR3 ligands inhibit key pro-fibrotic activities in cultured corneal keratocytes through both PPAR3-dependent and -independent pathways. We will use both pharmacological and genetic approaches to test our prediction that PPAR3 ligands act both by activating PPAR3 and by inhibiting TGF2-regulated pathways. Knowing the relative strengths of these mechanisms in corneal keratocytes is critical if we are to develop PPAR3 ligands as optimally-targeted therapies for corneal fibrosis.
Aim 3 : Test the hypothesis that PPAR3 ligands are more efficient inhibitors of fibrosis in PRK-induced corneal wound healing than anti-TGF2 antibodies, steroids or Mitomycin C. We will perform binocular PRK in cats followed by the topical administration of select PPAR3 ligands, anti-TGF2 antibodies, steroids or Mitomycin C. We will use immunohistochemistry to contrast key cellular aspects of the wound healing reaction. We predict that PPAR3 ligands will be associated with lower cell death, faster wound healing, less haze and lower induction of higher-order optical aberrations than use of anti-TGF2 antibodies, steroids or Mitomycin C post-operatively.
Current approaches to reduce corneal fibrosis and preserve visual quality following eye injury or surgery are only partially effective and carry significant side effects. The proposed experiments test the hypothesis that peroxisome proliferator activated receptor gamma (PPAR3) ligands prevent corneal fibrosis by activating multiple pro-fibrotic intracellular pathways. The results will provide significant theoretical insights into the molecular mechanisms that control corneal fibrotic activity and allow us to test PPAR3 ligands as a novel in situ therapy for corneal fibrosis, with significantly greater clinical effectiveness and fewer side-effects than current treatments or than blocking the activity of single cytokines.
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