The Role of sFlt in Corneal Avascularity

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DESCRIPTION (provided by applicant): Avascularity of the cornea is necessary for optical transparency in the visual axis. Vision-threatening corneal angiogenesis can be caused by diseases, aging, infection, or trauma. The basis of the cornea's physiological avascularity remains to be elucidated. This proposal will apply RNA interference, a promising new efficient & specific molecular technology that targets specific mRNAs, to elucidate mediators and mechanisms of normal corneal avascularity. We hypothesize that corneal avascularity is maintained at least in part by extracellular soluble VEGF receptor-1 (sVEGFR-1) Our specific aims are to test the hypotheses that: 1. To rigorously determine if adult corneal avascularity requires sFlt-1. 2. To determine whether selective genetic ablation of sFlt-1 in the corneal epithelium induces corneal vascularization. 3. To determine the expression profile of sFlt-1 in Pax6 and cornl mice with spontaneous corneal vascularization and whether sFlt-1 can restore corneal avascularity in Pax61 and cornl in these mice. This line of inquiry will have broad relevance to public health. The cornea is commonly used as a platform for testing the efficacy of anti-angiogenic therapies for use in cancer, macular degeneration, and diabetes. Understanding the molecular basis of how the cornea normally maintains its avascularity will have significant ramifications for the reliance on and validity of such anti-angiogenesis efficacy studies. Furthermore, sVEGFR-1 plays a pathogenic role in pre-eclampsia, lupus, and certain nephropathies. Our development of an siRNA against VEGFR-1 may eventually be of benefit for the management of these disorders, and it may also prove valuable in promoting beneficial angiogenesis, e.g., in stroke & heart disease.