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: 10596488
• 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/10596488
• 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; Enzymes; Fertilization in Vitro; Food; GLAST Protein; Genetic Transcription; Gestational Age; Glial Fibrillary Acidic Protein; Growth; Hypoxia Inducible Factor; In Vitro; Incidence; Intervention; Knock-out; Knowledge; Life; LoxP-flanked allele; Mediating; Metabolic; Mitochondria; Modeling; Mus; Mutation; Neuroglia; Nutrient; Oral; Organ; Oxygen; Pathogenesis; Pathologic; Pathway interactions; Pharmaceutical Preparations; 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 Vector; Weight Gain; Western Blotting; Work; early satiety; extreme prematurity; 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，困扰着约14,000名早产儿 在美国每年一次。其中约1500人出现严重的ROP，需要治疗。最近一年，ROP有所增加 由于(1)体外受精后多胎(和更多的早产)增加；(2)增加 低胎龄、高ROP风险的存活；以及(3)补充氧气水平越高，ROP越多 发病率。目前的治疗方法(激光光凝和抗血管内皮生长因子) 药物)针对晚期视网膜新生血管，并有不良影响。我们需要找到新的治疗方法 ROP。营养缺乏发生在早产儿，并与ROP的发展有关。早期全氨酸型 从出生第一天开始补充酸性物质可以改善体重增加，进而降低ROP风险。 然而，具体的氨基酸需求尚不清楚。早产儿循环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 补充剂可防止ROP小鼠模型中视网膜新生血管的形成，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丝氨酸通过调控胶质细胞血管生成因子影响视网膜新生血管。 在ROP小鼠模型中，我们将检测(1)L-丝氨酸补充剂是否抑制视网膜新生血管；(2) 视网膜胶质细胞(控制新生血管)介导L-丝氨酸抑制OIR；和(3)L-丝氨酸 通过乳酸盐调节神经胶质促血管生成因子来降低OIR。 这项研究将确定(1)是口服还是静脉注射。L-丝氨酸抑制OIR新生血管形成，建立ROP模型及(2) 胶质细胞L-丝氨酸合成及其关键机制在视网膜病理性血管调控中的作用 成长。我们研究的成功完成将可能确立L-丝氨酸在ROP预防中的关键作用。 这部作品有很高的翻译价值，无论是口头的还是静脉的。L-丝氨酸早产分娩 婴幼儿是非常可行的。系统性补充L-丝氨酸可预防ROP并可能预防 早产的其他并发症(脑室出血或支气管肺发育不良)。