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Ming Wai Poon, Limeng Yan, Dan Jiang, Peng Qin, Hung-fat Tse, Ian Y. Wong, David S. H. Wong, Vinay Tergaonkar, Qizhou Lian; Inhibition of RAP1 Enhances Corneal Recovery Following Alkali Injury. Invest. Ophthalmol. Vis. Sci. 2015;56(2):711-721. doi: 10.1167/iovs.14-15268.
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Recently, RAP1 (Telomeric Repeat Binding Factor 2, Interacting Protein [TERF2IP]) was discovered as a modulator that selectively regulates nuclear factor light chain kappa enhancer of activated B cells (NFκB) signaling. The roles of RAP1 in regulation of inflammation and angiogenesis for corneal recovery following corneal injury remain poorly understood. The effects of RAP1 deletion on corneal resurfacing and neovascularization in a corneal alkali burn mouse model were examined.
Corneal defects and neovascularization were induced in vivo by infliction of an alkali burn to the cornea with 1 N sodium hydroxide solution in RAP1 knock-out (RKO) and wild-type (RWT) mice. Corneal resurfacing was evaluated using slit-lamp biomicroscopy. Neovascularization following injury was evaluated by bright view biomicroscopy and immunofluorescence staining with the endothelial marker platelet endothelial cell adhesion molecule (PECAM). The cytokine profiles of corneal tissue involved in inflammation and neovascularization following injury was compared between RKO and RWT mice. Corneal epithelial cells were isolated for classic scratch wound healing assay and further testing with lipopolysaccharide stimulation.
Resurfacing of the burned cornea was accelerated and angiogenesis was suppressed, faster recovery of corneal epithelial cells from classic scratch wound healing and superior tolerance of lipopolysaccharides challenge was observed in the RKO compared to RWT. Molecular investigation revealed that deletion of RAP1 reduced upregulation of inflammatory cytokine (IL1A), finely regulated the expression of angiogenic factor (VEGF), and antiangiogenic factor (PEDF), following injury for better corneal recovery.
Deficiency of RAP1 facilitates corneal recovery after injury. Specificity of RAP1 inhibition may lead to design of specific inhibitors of NFκB in the treatment of ocular injuries.
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