Glucose/lipid metabolism and vessel development in phase I ROP

I 期 ROP 中的葡萄糖/脂质代谢和血管发育

基本信息

批准号：
10311520
负责人：
Lois Smith
金额：
$ 42.92万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10311520
关键词：
Affect Angiogenic Factor Area Astrocytes Attenuated Blindness Blood Blood Vessels Cell Culture Techniques Cells Cellular Metabolic Process Child Development Dyslipidemias Early treatment Enzymes Erythropoietin Fatty Acids Fertilization in Vitro Fibroblast Growth Factor Receptors Gene Expression Profiling Genus Hippocampus Gestational Age Glucose Glucose Transporter Glycolysis Growth Growth Factor Hyperglycemia Hypertriglyceridemia Incidence Infant Inner Nuclear Layer Ischemia Life Lipids Low Birth Weight Infant Measurement Metabolic Metabolic dysfunction Metabolic stress Metabolism Mitochondria Muller&apos s cell Multiple Birth Offspring Mus Neonatal Neuroglia Oxygen Oxygen Consumption Pathway interactions Phase Premature Birth Premature Infant Process Production Proteins Proteomics Retina Retinopathy of Prematurity Risk Factors Role Serum Small Interfering RNA Source Transforming Growth Factor beta Triglycerides Variant Vascular Endothelial Growth Factors Vascularization Western Blotting Wild Type Mouse Work bevacizumab brain dysfunction effective therapy fibroblast growth factor 21 glucose metabolism glucose uptake improved in vivo inhibitor knock-down laser photocoagulation lipid metabolism metabolic abnormality assessment mouse model neovascularization novel organ growth oxidation postnatal prevent protective effect receptor retina blood vessel structure transcriptomics

项目摘要

ROP, a leading cause of blindness in children, afflicts ~16,000 premature infants yearly in the US1. ROP incidence is increasing because of more in vitro fertilization resulting in more multiple births with lower birth weight. Also, increasingly low gestational age infants survive. Oxygen is supplemented at higher levels with more ROP. Current ROP treatments (laser photocoagulation and anti-VEGF therapy) are not always effective, and long-term anti-VEGF therapy may potentially impair brain and organ development. We need to find ways to treat early to prevent phase I ROP, and thus prevent neovascularization. Hyperglycemia and associated dyslipidemia, commonly see in preterm infants and associated with ROP development, may contribute to vessel loss in phase I ROP. We must understand the mechanism to develop safe and effective treatment for early ROP to prevent late phase II neovascularization. We preliminarily found that fibroblast growth factor 21 (FGF21), a significant glucose/lipid metabolic modulator, prevents retinal vascular delay in a mouse model of phase I ROP. Therefore, we propose that In dyslipidemia/hyperglycemia-exacerbated phase I ROP, FGF21 improves glucose/lipid metabolism and vessel development. In the mouse model of ROP with neonatal metabolic dysfunction (NMD-ROP), we will examine if 1) FGF21 improves retinal vascular development; 2) FGF21 effect on lipid/glucose metabolism; 3) does FGF21 promote normal vascularization by regulating glial cell metabolism and angiogenic factors. This study will determine 1) the role of FGF21 in a novel mouse model of hyperglycemia-exacerbated phase I ROP; 2) the metabolic impact of FGF21 on retinal lipid and glucose use; 3) the role of retinal glial cell metabolism in supporting retinal vessel growth. FGF21 may prevent and treat ROP at an early stage.

罗普（Rop）是儿童失明的主要原因，每年在US1中折磨约16,000名早产儿。 ROP 由于更多的体外受精，发病率正在增加重量。而且，胎龄越来越低。氧气以较高的水平补充更多ROP。当前的ROP治疗（激光光凝和抗VEGF疗法）并不总是有效的，长期的抗VEGF疗法可能会损害大脑和器官发育。我们需要找到方法尽早治疗以防止I期ROP，从而防止新血管形成。高血糖和相关血脂异常，通常在早产儿中看到，并且与ROP发育相关，可能有助于 I期ROP中的船只损失。我们必须了解为开发安全有效治疗的机制早期的ROP，以防止晚期II期新血管形成。我们初步发现成纤维细胞生长因子21 （FGF21）是一种显着的葡萄糖/脂质代谢调节剂，可防止视网膜血管延迟第一阶段。因此，我们建议在血脂异常/高血糖异常的I期ROP中，FGF21改善了葡萄糖/脂质代谢和血管发展。在具有新生儿代谢功能障碍（NMD-ROP）的ROP的小鼠模型中，我们将检查1）FGF21 改善视网膜血管发育； 2）FGF21对脂质/葡萄糖代谢的影响； 3）FGF21促进通过调节神经胶质细胞代谢和血管生成因子的正常血管化。这项研究将确定1）FGF21在高血糖异常I期的新小鼠模型中的作用 rop; 2）FGF21对视网膜脂质和葡萄糖使用的代谢影响； 3）视网膜神经胶质细胞的作用代谢支持视网膜血管生长。 FGF21可以在早期预防和治疗ROP。