Short-chain fatty acid signaling in retinopathy of prematurity - The goal of the current application is to identify novel mechanisms and, develop a new and effective therapy for retinopathy of prematurity (ROP), the leading cause of preventable blindness in children. Important triggers for ROP are exposure of premature infants to high oxygen after birth resulting in delayed formation of the normal retinal vasculature, a process that is still taking place in the premature retina, and hyperglycemia, also common in many premature infants. These processes contribute to tissue ischemia, abnormal retinal neovascularization, and in severe cases, retinal detachment and blindness. Currently, there are no treatments to prevent ROP or intervene early in the course of its development. Existing strategies are applied in the most advanced stages of ROP and include the surgical ablation of abnormal vessels or intravitreal injections of anti-angiogenic factors (i.e., VEGF). However, these strategies are associated with severe side effects, including significant loss of visual field and late recurrences. Our preliminary studies demonstrate a deficiency in butyrate-producing gut bacteria leading to reduced butyrate concentrations in premature infants that develop ROP and in mouse models of the disease, compared to non-ROP controls. Additionally, treatment of relevant ROP mouse models with butyrate reduces the size of the avascular area and limits pathologic neovascularization, implicating butyrate as a promising potential non-invasive therapy for ROP. To validate these findings, we propose three specific aims: 1) to investigate the therapeutic efficacy of butyrate therapy in mouse models of phase I and phase II ROP, 2) to determine the relevance of GPR109A-dependent molecular signaling to microglia activation, retinal inflammation (phase I), and neovascularization (phase II) ROP and 3) to demonstrate the importance of butyrate- mediated HDAC1 signaling in endothelial cells to retinal neovascularization and vaso-obliteration in ROP. Successful completion of these aims will better our understanding of the signaling mechanisms and retinal cell types responsible for butyrate’s effects in the premature retina and the potential of butyrate to counter early and late pathogenic events in ROP, thereby filling the critical need for new and improved therapies for ROP.
