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).

早产视网膜病变（ROP），这是儿童失明的主要原因，折磨约14,000名早产儿 一年一度在美国。大约有1,500人患有严重的ROP，需要治疗。 ROP在最后一个 由于（1）在体外受精后增加了多个（和更多早产）的十年； （2）增加 在高ROP风险下的低胎龄生存； （3）更高水平的补充氧气具有更多的ROP 发病率。当前处理（激光光凝和抗血管内皮生长因子（VEGF） 药物）靶向后期视网膜新血管形成，并具有不良反应。我们需要找到新的方法来治疗 ROP。营养缺乏发生在早产儿中，与ROP的发育有关。早期全氨基 从生命的第一天开始补充酸会改善体重增加，进而降低了ROP风险。 但是，特定的氨基酸需求尚不清楚。循环L-丝氨酸水平较低 胎龄较低且ROP风险较高的婴儿。我们初步发现L丝氨酸 补充可防止ROP小鼠模型中的视网膜新血管形成，视网膜神经胶质可能是 原代视网膜细胞响应L塞林。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血管化。 在ROP的小鼠模型中，我们将检查（1）L-丝氨酸补充剂是否抑制视网膜新血管形成； （2） 视网膜神经胶质细胞（控制新血管化）介导L链抑制作用对OIR； （3）l-serine 通过通过乳酸调节神经胶质前血管生成因子来减少OIR。 这项研究将确定（1）是否口服或i.p. L塞林抑制OIR中的新血管形成，对ROP进行建模和（2） 神经胶质细胞L链合成和关键机械途径在控制病理视网膜血管中的作用 生长。成功完成我们的研究可能会确立L塞琳在ROP预防中的关键作用。 这项工作中有很高的翻译价值，例如口头或i.v.将L塞林传递到早产 婴儿非常可行。全身性L-塞林补充可能会阻止ROP，并可能阻止 早产的其他并发症（脑室内出血或支气管肺发育不良）。