Serine control of retinal neovascularization in retinopathy

早产儿视网膜病（ROP）是儿童失明的主要原因，困扰着约14，000名早产儿 每年在美国。其中约有1,500人患有严重的ROP，需要治疗。在过去的一年里， 十年来，由于（1）体外受精后多胎（和更多早产）增加;（2）增加 ROP高风险时低胎龄的存活率;（3）ROP越多，补充氧气水平越高 发病率。目前的治疗（激光光凝和抗血管内皮生长因子（VEGF）） 药物）靶向晚期视网膜新生血管形成并具有副作用。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。早期全氨基 从出生的第一天开始补充酸，可以改善体重增加，从而降低ROP风险。 然而，具体的氨基酸需求是未知的。早产儿的循环L-丝氨酸水平较低， 胎龄较低和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生血管形成，视网膜胶质细胞可能是 初级视网膜细胞对L-丝氨酸的反应。因此，我们建议： 丝氨酸通过调控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;和（3）L-丝氨酸 通过乳酸调节神经胶质促血管生成因子降低OIR。 本研究将确定（1）口服或腹腔注射L-丝氨酸是否抑制OIR中的新血管形成，模拟ROP，以及（2） 神经胶质细胞L-丝氨酸合成及其调控视网膜血管病变机制 增长我们的研究的成功完成将可能建立L-丝氨酸在ROP预防中的关键作用。 这项工作有很高的转化价值，因为口服或静脉注射L-丝氨酸给早产儿 婴儿是非常可行的。全身性补充L-丝氨酸可以预防ROP， 早产的其他并发症（脑室内出血或支气管肺发育不良）。

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).