Wednesday, April 2, 2025
4/2/2025
Metabolic basis of retinopathy of prematurity and potential treatment with anaplerotic substrates - Project summary/abstract Supplemental oxygen is provided to premature infants to prevent mortality. Hyperoxia prevents mortality, however, hyperoxic exposure of premature infants inhibits retinal neurovascular development and causes retinopathy of prematurity (ROP). Findings from our work and other groups indicate that ROP development involves deficits in liver metabolism. For example, DHA, AA are produced in the liver, and these have been associated with the ROP. In addition, we have demonstrated that the liver-based HIF1-α is required to produce the retinal serine/one-carbon metabolites to prevent oxygen-induced retinopathy (OIR). Infants with low weight at birth are more prone to ROP, implying that nutrition plays a role in ROP development. In addition, premature infant mothers have different fat compositions in their milk. There are higher amounts of medium- chain fatty acids (MCFAs) and long-chain polyunsaturated fatty acids (LCPUFAs) in the milk of mothers of premature infants. Although LCPUFAs have been studied, both in the OIR model and in ROP clinical trials, the role of energy-generating MCFAs remains unknown. Our recent publication highlights that hyperoxia downregulates the entry of glycolytic carbon into the tricarboxylic acid cycle (TCA cycle) and upregulates glutamine-fueled anaplerosis in the Müller cells in response to hyperoxia. This lowers the amount of glutamine available for endothelial cell proliferation. We hypothesize, providing a substrate that can feed into TCA, can prevent glutamine diversion into TCA cycle. One of the top alternative substrates in the early stages of development is MCFA from maternal nutrition. We compared the fatty acid β-oxidation genes in the retina. We found statistically significantly higher expression of only MCFA utilization and ketone body utilization enzymes in OIR-resistant mouse strain. Our preliminary data shows a higher availability of MCFA octanoate in the blood of OIR-resistant strain. In addition, our liver RNAseq data indicates higher conversion of MCFA-CoAs into free fatty acid MCFAs and ketone bodies. We tested the utilization of medium-chain fatty acid-octanoate in the retinal explant experiments and found increased utilization in response to hyperoxia. Altogether, our data indicate that a balance between fatty acid utilization and nitrogen compound-based anaplerosis may be the underlying cause of oxygen-induced retinopathy development. The Aim of this grant is to study fatty acid metabolic exchanges between liver and retina at systems levels, and to use anaplerotic substrates in conjunction with Adeno-associated viruses (AAVs) based genetic manipulations of the fatty acid metabolic genes, to prevent oxygen-induced retinopathy.
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