Photoreceptor Determination of Retinal Blood Vessel Growth in Retinopathy

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PROJECT SUMMARY/ABSTRACT Retinopathy of prematurity (ROP) is a major cause of blindness and disability in children. With advances in neonatal care, smaller and more premature infants are saved who are at high risk for ROP. Therefore, the incidence of ROP continues to increase. Current laser ablation surgery destroys retina and anti-VEGF (vascular endothelial growth factor) treatment may cause systemic suppression of vessel growth in fragile neonates. The long-term goal is to understand the molecular mechanisms of ROP development to devise earlier preventative therapies. Inflammatory mediators are known key regulators in retinopathy but the causal link has been elusive and standard anti-inflammatory drugs such as steroids or NSAIDS are not effective in ROP. Inflammation is often thought to come from infiltrating inflammatory cells including macrophages, neutrophils and resident microglia. But photoreceptors, which play an important role in the pathogenesis of ROP, also signal for blood vessel growth through inflammatory proteins. The overall objective in this application is to identify how photoreceptors determine blood vessel growth. We found that in photoreceptors, transcription factor c-Fos, an immediate early gene and pro-oncogene, and a master regulator of many inflammatory factors, controls retinal angiogenesis by modulating photoreceptor-derived inflammatory signals in a mouse model of retinopathy. c-Fos is found in the human photoreceptor cells throughout their development. c-Fos is also important in regulating rod-specific gene expression and photoreceptor apoptosis. Our preliminary data show that c-Fos is increased in photoreceptors and that suppression of c-Fos in photoreceptors inhibits neovascularization in an oxygen-induced retinopathy (OIR) mouse model of ROP. These findings suggest that c-Fos may be a major signaling pathway used by stressed photoreceptors to convey the need for blood vessels and is a potential target to control the development of neovascularization. We hypothesize that photoreceptors determine pathological retinal angiogenesis in ROP by modulating the inflammatory signals via c-Fos. The rationale for the proposed research is that understanding the molecular mechanisms of ROP development has the potential to help develop treatment of ROP (now affecting ~16,000 US infants per year). We propose to test this hypothesis with three Aims. Aim 1: To determine whether photoreceptor c-Fos controls retinal angiogenesis in OIR; Aim 2: To determine whether photoreceptor c-Fos controls angiogenesis through modulating inflammatory signals; and Aim 3: To determine whether pharmacological inhibitors of c-Fos suppress pathological retinal angiogenesis in OIR. The proposed research is innovative because it represents a substantive departure from the status quo by identifying a photoreceptor- initiated inflammatory signal to control pathological retinopathy in ROP. The proposed research is significant because it will provide a novel target (c-Fos) for developing therapeutic strategies that have broad translational importance in the prevention and treatment of ROP and a wide range of other vascular eye diseases.