Molecular Basis of Retinal Angiogenesis

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DESCRIPTION (provided by applicant): Pathological ocular angiogenesis occurs in retinopathy of prematurity, proliferative diabetic retinopathy and age-related macular degeneration; the leading causes of blindness in infants, working age individuals and the elderly, respectively. It causes visual loss through increased vascular permeability leading to retinal edema, vascular fragility resulting in hemorrhage, and fibrovascular proliferation with tractional and retinal detachment. New vessels may be asymptomatic until these complications develop. Although angiogenesis tends to occur at a relatively late stage in the course of many ocular disorders, it is nonetheless a highly attractive target for therapeutic intervention, since it represents a final common pathway in processes that are multifactorial in etiology, and it is the event that typically leads directly to visual loss. The ultimate goal of this project is to develop methods to prevent ocular angiogenesis based upon understanding gained from studies of relevant models. We propose to use pure cultures of Muller cells and retinal microvascular endothelial cells (RMEC), as well as mouse and rat models of oxygen-induced retinopathy (OIR). With these tools, we will address three interrelated aims: Aim 1) we will examine of the role of prostanoids in hypoxia-induced VEGF production by Muller cells; Aim 2) we will examine the role of prostanoids in VEGF-stimulated angiogenic responses of RMEC; 3) using aims 1 and 2 as guides, we will extend the studies to well-established animal models of retinal angiogenesis where specific targets of prostanoid synthesis and activity will be manipulated pharmacologically or genetically. In each case, we will follow classic loss-of-function/gain-of-function experimental strategies.