The investigator hypothesizes that VEGF plays a central role in the development of macular edema in ischemic retinopathies and that other factors including IGF-I may also participate. VEGF may contribute to other types of macular edema and some mediators may alter BRB integrity through VEGF. The investigator proposes three specific aims.
In aim 1, he will determine which vasopermeability agents cause breakdown of the BRB in rodents and by which mechanism. He will also determine which agents have the greatest effect on the BRB, the mechanism by which each of the agents causes BRB breakdown, and if these agents have an additive effect. Finally, he will determine the time-course and mechanism of BRB dysfunctional transgenic mice with lens-specific expression of IL-beta. The purpose of aim 2 is to determine if the location of VEGF expression in the eye alters its effect on the BRB, if transgenic mice with lens-specific expression of VEGF have breakdown of the BRB, and if localization of BRB breakdown is similar or different in transgenic mice with lens-specific expression of VEGF compared to transgenic mice with the expression of VEGF in photoreceptors or ganglion cells.
In aim 3, the investigator asks whether there is convergence in the pathways through which agents cause BRB breakdown. He will determine if agents that cause BRB breakdown increase expression of VEGF and/or IGF-I in the retina, if inhibition of VEGF signaling with kinase inhibitors prevents breakdown of the BRB in animal models and if inhibition of IGF-I with a somatostatin analog prevents breakdown of the BRB in animal models.
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