Serine control of retinal neovascularization in retinopathy

丝氨酸控制视网膜病变中视网膜新生血管

• 批准号: 10390484
• 负责人: Zhongjie Fu
• 金额: $ 42.92万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10390484
• 关键词: Adverse effects; Affect; Amino Acids; Angiogenic Factor; Angiopoietin-2; Area; Attenuated; Birth; Blindness; Blood Vessels; Bronchopulmonary Dysplasia; Cells; Child; Citric Acid Cycle; Development; Disease; Dose; Drug Targeting; Enzymes; Fertilization in Vitro; GLAST Protein; Genetic Transcription; Gestational Age; Glial Fibrillary Acidic Protein; Growth; Hypoxia Inducible Factor; In Vitro; Incidence; Intervention; Knock-out; Knowledge; Life; Mediating; Metabolic; Mitochondria; Modeling; Mus; Mutation; Neuroglia; Nutrient; Oral; Organ; Oxygen; Pathogenesis; Pathologic; Pathway interactions; Phase; Phosphoglycerate dehydrogenase; Premature Birth; Premature Infant; Prevention; Process; Rattus; Regulatory Pathway; Retina; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Risk; Role; Serine; Serum; Source; Supplementation; TNF gene; Tamoxifen; Vascular Endothelial Growth Factors; Viral; Viral Vector; Weight; Weight Gain; Western Blotting; Work; early satiety; high risk; improved; in utero; in vivo; intraventricular hemorrhage; laser photocoagulation; mouse model; neovascular; neovascularization; neurosensory; postnatal; prevent; response; retina blood vessel structure; supplemental oxygen; transcriptomics

Retinopathy of prematurity (ROP), a leading cause of blindness in children, afflicts ~14,000 premature infants yearly in the US. About 1,500 of those develop severe ROP, requiring treatment. ROP has increased in the last decade due to (1) increased multiple (and more preterm) births after in vitro fertilization; (2) increased survival at low gestational ages at high ROP risk; and (3) higher levels of supplemental oxygen with more ROP incidence. Current treatments (laser photocoagulation and anti-vascular endothelial growth factor (VEGF) drugs) target late-phase retinal neovascularization and have adverse effects. We need to find new ways to treat ROP. Nutrient deficiency occurs in preterm infants and is associated with ROP development. Early full amino acid supplementation, starting the first day of life, improves weight gain, which in turn reduces ROP risk. However, specific amino acid requirements are unknown. Circulating L-serine levels are lower in premature infants with lower gestational age and higher risk for ROP. We preliminarily found that L-serine supplementation prevents retinal neovascularization in a mouse model of ROP, and retinal glia might be the primary retinal cells in response to L-serine. Therefore, we propose that: L-serine affects retinal neovascularization by controlling glial cell angiogenic factors. In the mouse model of ROP, we will examine if (1) L-serine supplements inhibits retinal neovascularization; (2) retinal glial cells (which control neovascularization) mediate L-serine inhibitory effect on OIR; and (3) L-serine decreases OIR by regulating glial pro-angiogenic factors via lactate. This study will determine (1) if oral or i.p. L-serine inhibits neovascularization in OIR, modeling ROP and (2) the role of glial cell L-serine synthesis and key mechanistic pathways in controlling pathologic retinal vessel growth. Successful completion of our study will likely establish a critical role of L-serine in ROP prevention. There is high translational value in this work, as oral or i.v. delivery of L-serine to preterm infants is very feasible. Systemic L-serine supplementation may prevent ROP and might possibly prevent other complications of preterm birth (intraventricular hemorrhage or bronchopulmonary dysplasia).

早产儿视网膜病变（ROP）是儿童失明的主要原因，约有14000名早产儿受到影响