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: 10179542
• 负责人: Zhongjie Fu
• 金额: $ 44.25万
• 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/10179542
• 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) 是导致儿童失明的主要原因，约 14,000 名早产儿深受其苦 每年在美国。其中约 1,500 人出现严重 ROP，需要治疗。 ROP 在过去有所增加 十年由于（1）体外受精后多胎（和更多早产）出生的增加； (2)增加 高 ROP 风险下低胎龄的存活率； (3) 更高水平的补充氧气和更多的 ROP 发生率。目前的治疗方法（激光光凝和抗血管内皮生长因子（VEGF） 药物）针对晚期视网膜新生血管形成并产生不良影响。我们需要寻找新的治疗方法 罗普。营养缺乏发生在早产儿中，并且与 ROP 的发育有关。早期全氨基 从出生第一天开始补充酸可以改善体重增加，从而降低 ROP 风险。 然而，具体的氨基酸需求尚不清楚。早产儿的循环 L-丝氨酸水平较低 胎龄较低、ROP 风险较高的婴儿。我们初步发现L-丝氨酸 补充剂可预防 ROP 小鼠模型中的视网膜新生血管形成，而视网膜神经胶质细胞可能是 原代视网膜细胞对 L-丝氨酸的反应。因此，我们建议： L-丝氨酸通过控制神经胶质细胞血管生成因子影响视网膜新生血管形成。 在 ROP 小鼠模型中，我们将检查 (1) L-丝氨酸补充剂是否抑制视网膜新生血管形成； (2) 视网膜神经胶质细胞（控制新生血管形成）介导 L-丝氨酸对 OIR 的抑制作用； (3) L-丝氨酸 通过乳酸调节胶质细胞促血管生成因子来降低 OIR。 这项研究将确定 (1) 是口服还是腹腔注射。 L-丝氨酸抑制 OIR 中的新生血管形成，模拟 ROP 和 (2) 胶质细胞L-丝氨酸合成的作用及控制病理性视网膜血管的关键机制途径 生长。我们的研究的成功完成可能会确定 L-丝氨酸在预防 ROP 中的关键作用。 这项工作具有很高的翻译价值，无论是口头还是静脉注射。向早产儿输送 L-丝氨酸 婴儿是非常可行的。全身性 L-丝氨酸补充剂可预防 ROP，并可能预防 早产的其他并发症（脑室内出血或支气管肺发育不良）。