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Grant Abstract: Dietary control of angiogenesis in retinopathy models

Grant Number: 5R01EY017017-13
PI Name: Smith
Project Title: Dietary control of angiogenesis in retinopathy models

Abstract: Retinopathy of prematurity (ROP) affects ~16,000 premature infants per year in the US and is the leading cause of blindness in children. After preterm birth there is loss of retinal vessels resulting in lack of nutrients and oxygen, ultimately stimulating pathologic vessel proliferation (ROP). At preterm birth, loss of ?3 long-chain polyunsaturated fatty acid (LCPUFA), normally provided by the maternal/placental interface prominently contributes to initiation and progression of ROP as does early postnatal hyperglycemia. In mouse pups we found that hyperglycemia delayed retinal vascular development which was greatly attenuated with dietary ?3LCPUFAs. To define the link between ?3LCPUFA dietary intake and hyperglycemia in ROP we looked to an important adipocyte-derived hormone and metabolic regulator, adiponectin (APN). In premature infants, low ?-3LCPUFA, low serum APN, and hyperglycemia all correlate with ROP. We proposed to explore ?3LCPUFA effects on the prevention and protection against hyperglycemic exacerbation of early vessel loss in ROP and the role of hormones in ?3LCPUFA protection against hyperglycemic retinopathy, which was funded through NEI (5 R01 EY017017). As part of the studies in 5 R01 EY017017, we explored glucose/lipid metabolic regulation in APN deficient mice and found decreased levels of fatty acid beta-oxidation enzymes and decreased retinal lipid levels. In mouse model of ROP, increased dietary ?3LCPUFA increased circulating APN. Photoreceptor metabolism controls retinal vessel formation and we found the APN receptor AdipoR1 is highly expressed in photoreceptors (in both rods and cones). Photoreceptors have the highest density of mitochondria in the body and are extremely metabolically demanding. We also found that lipids, in addition to glucose, are an alternative energy fuel to maintain photoreceptor function, which in turn prevents pathologic vessel proliferation. Thus, our original grant 5 R01 EY017017 explores dietary ?3LCPUFA in endothelial cells, this administrative supplement seeks a novel alternative pathway, ?3LCPUFA supplementation modulates photoreceptor lipid metabolism to prevent ROP. We aim to 1) determine retinal cell lipid metabolism in wild type and APN-deficient mice with a novel technique known as Drop-seq analysis to investigate cell function and metabolic activity in individual cells in the retina; 2) examine retinal lipid use with Seahorse analysis which measure the oxygen consumption rate to reflect the mitochondrial activity.

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