Retinal neovascularization and vascular leakage are common causes leading to retinal damage in diabetic retinopathy. Currently, there is no satisfactory treatment to stop neovascularization or to reduce vascular permeability in diabetic retinopathy, which is a leading cause of blindness in the US and the industrialized countries. Accumulating evidence suggests that decreased levels of endogenous angiogenic inhibitor (e.g. pigment epithelium-derived factor, PEDF) in the retina and vitreous as well as increased angiogenic stimulators (e.g. vascular endothelial growth factor, VEGF) play a critical role in the development of retinal neovascularization. Therefore, delivery of angiogenic inhibitors into the eye is believed to be a promising therapy for retinal neovascularization. Kallikrein-binding protein (KBP, or kallistatin) is a specific inhibitor of tissue kallikrein. It belongs to the family of serine proteinase inhibitors (serpin) and has significant sequence homology with the potent angiogenic inhibitor, PEDF. Recently, we have found that KBP specifically inhibits the proliferation of primary endothelial cells and down-regulates VEGF expression. This vascular activity is independent of its interactions with tissue kallikrein. Moreover, KBP levels are decreased in the vitreous of patients with proliferative diabetic retinopathy and in the retina of a diabetic animal model. Our hypothesis is that KBP is a potent angiogenic inhibitor, which inhibits retinal neovascularization and reduces vascular leakage. The principal objective of this Phase I project is to determine the efficacy of KBP as an antiangiogenic agent in vivo. This Phase I project will determine if KBP can inhibit retinal neovascularization in an animal model of oxygen-induced retinopathy. Recombinant KBP will be injected intravitreally into newborn rats with oxygen-induced retinopathy. Its effect on retinal neovascularization will be evaluated by fluorescein angiography and quantification of pre-retinal vascular cells. This project will also determine if KBP can reverse vascular hyper-permeability in the retina of diabetic animals. VEGF is a major factor responsible for hyper-permeability in diabetic retinopathy. Given that KBP decreases VEGF levels, it may reverse hyper-permeability. This study will use oxygen-induced retinopathy and streptozotocin (STZ)- induced diabetic rats as models. The effect of KBP injection on vascular permeability will be evaluated by the Evans Blue leakage method.
Thesaurus Terms: angiogenesis inhibitor, diabetic retinopathy, drug design /synthesis /production, drug screening /evaluation, kallikrein, retina circulation, vascular endothelium permeability retina circulation disorder, vascular endothelial growth factor, vascular endothelium laboratory rat
