A Molecular and Cellular Characterization of Ocular Angiogenesis
My long-standing interest is in the molecular basis of ocular angiogenesis. The over-reaching goal of my research is to characterize the process of retinal angiogenesis, and to begin to develop preventive strategies based on understanding gained from in vitro and in vivo studies. During the past decade, we have continued to refine and characterize our experimental models, and we find them particularly well suited for investigations of the cellular and molecular aspects of angiogenesis in blinding diseases. We now propose to utilize these tools (e.g., retinal microvascular endothelial cells, Muller cells and astrocytes in culture, and rodent models of retinopathy of prematurity) to address two basic aims. The first aim is to investigate the mechanism by which non-steroidal anti-inflammatory drugs (NSAID) inhibit angiogenesis. The angiostatic activity of NSAID has long been recognized in several tumor types. However, their potency and the role of their target, cyclo-oxygenase, in ocular angiogenesis is largely undefined, although it is clear that important differences exist between the effects of NSAID on angiogenesis in tumors and in the retina.
The second aim is to investigate the angiostatic effect of penetrating ocular injury. Recently, we have discovered that dry needle penetration of the eye globe inhibits abnormal retinal and preretinal neovascularization. We call this phenomenon ?ocupuncture?. The pattern of the inhibitory influence implies that an antiangiogenic factor is released from the wound site and diffuses throughout the eye, exerting a stronger effect in the injured quadrant and a weaker effect in the opposite quadrant. Vitreous protein harvested from injured eyes shows potent angiostatic activity, both in VEGF-treated retinal microvascular endothelial cells and when administered to rats induced to display ROP-like pathology. This suggests that the ultimate answer to limiting retinal angiogenesis may lie within the retina's natural battery of inducible factors. We have begun the search for candidates using 2-D gel electrophoresis and gene microarray analysis to identify the responsible factors. We plan to characterize this phenomenon, using several genomics and proteomics methods to determine which one or more of these factors may play a role in the injury effect. Identification of endogenous retinal angiostatic factors will allow for the development of novel therapies for retinal neovascular pathologies. Therapeutic strategies that seek to regulate the synthesis and release of candidate endogenous factors provide distinct advantages over administration of exogenous agents.