The proposed studies are relevant to the treatment of retinopathy of prematurity (ROP), the leading cause of preventable blindness in children. An important trigger for ROP development is the exposure of premature infants to oxygen after birth. This delays normal retinal vascular growth, still taking place in the premature retina. When the infant is brought back to room air, this leads to tissue ischemia, abnormal retinal neovascularization, and, possibly, retinal detachment and blindness. Available interventions are applied in the most advanced stages of the disease and consist of ablation of retinal neovascular tufts or intravitreal injections of anti-angiogenic factors (i.e., VEGF). All these procedures and treatments are associated with severe side effects, including significant loss of visual field and late recurrences. We have recently found that agonists of the nuclear receptor farnesoid-X-receptor (FXR) exert protective effects in an experimental model of ROP (oxygen-induced retinopathy; OIR). Interestingly, we have also found that FXR expression and levels of FXR endogenous ligands are downregulated in OIR, further supporting the hypothesis that leveraging/restoring FXR-dependent signaling could exert key protective effects in ROP/OIR. To confirm this, we found that FXR is present in retinal astrocytes and endothelial cells that are primarily affected in OIR. FXR stimulation may elicit anti-apoptotic responses in astrocytes and anti-angiogenic effects in retinal endothelial cells, thus targeting two key events involved in the induction and progression of OIR. Our working hypothesis is that alterations in retinal FXR signaling play a key role in ROP pathogenesis and the pharmacological modulation of these pathways represents a new therapeutic tool in limiting ROP pathology. We have designed experiments to be conducted in vivo, using the OIR model and in vitro experimental settings to 1) investigate the effects of modulating FXR receptor signaling in OIR; 2) investigate FXR signaling in retinal astrocytes and endothelial cells in OIR. The potential outcomes of the proposed studies could fill the need for new and better therapies for ROP.

Retinopathy of prematurity (ROP) is the leading cause of blindness in children. There are limited therapeutic options for this severe ocular pathology. Our overall goal is to identify new and more effective therapies for ROP. In particular, we will explore and characterize the potential therapeutic effects of the nuclear receptor farnesoid- X-receptor (FXR) agonists in experimental models of ROP.