Inflammation is a component of the corneal wound healing process. This proposal under the two-year support provided by the National Institutes of Health under the American Recovery and Reinvestment Act of 2009 will continue to test novel hypotheses about lipid mediators in corneal inflammation and remodeling after injury. The general hypothesis is that platelet-activating factor (PAF) plays a key role in contributing to tissue destruction and neovascularization during excessive corneal inflammation, the arachidonic acid (AA)-mediator, lipoxin ~ (L~, a lipoxygenase derivative.
The Specific Aims are to test two specific corollaries of this general hypothesis: [I] PAF receptor activation of myofibroblasts impairs stroma repair through matrix metalloproteinase-9 (MMP-9) induction, which promotes fibronectin degradation. [II] PAF promotes neovascularization in inflamed cornea by inducing upregulation of vascular endothelial growth factor (VEGF) and down-regulation of thrombospondin-1 (TSP-1) via ERK1/2 Signaling and NFkB activation. A novel selective PAF-receptor antagonist, LAU-0901, as well as PAF-receptor knockout mice will be used to determine the site of action. Debridement of corneal epithelium and anterior stroma in vivo and de-epithelization of corneas in organ culture will be employed as models of wound healing. Primary cultures of myofibroblasts will be used to address the signaling pathways involved. Silencing of specific MMPs will be done using siRNAs. Quantification of different mRNAs will be accomplished by real time peR. Protein expression and kinase activation will be assessed by Western blot analysis and immunofluorescence. Inflammation is a response to corneal injury. However, extensive damage occurs when the homeostasis is lost between lipid mediators with pro- and anti-inflammatory bioactivity. If our hypothesis and its corollaries are correct, then PAF antagonists can become effective therapeutic tools for maintaining the transparency and integrity of the cornea.
This renewal application tests novel hypotheses about the critical balance between signaling mechanisms that promote corneal cellular damage and repair, such as those that occur in corneal inflammation following chemical burns and in corneal remodeling after injury or surgery. This balance is fundamental to the maintenance of corneal integrity and function;however, extensive damage occurs when equilibrium is lost between lipid mediators with pro- and anti-inflammatory properties. If our hypothesis and its corollaries are correct, then PAF antagonists, lipoxins and epi-lipoxins can be important therapeutic tools for maintaining the transparency and integrity of the cornea.
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