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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：
10540713
负责人：
Lois Smith
金额：
$ 44.25万
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 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540713
关键词：
Affect Angiogenic Factor Area Astrocytes Attenuated Birth Blindness Blood Blood Vessels Cell Culture Techniques Cell Separation 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.

ROP是儿童失明的主要原因，在美国每年约有16，000名早产儿受其折磨1。ROP 由于更多的体外受精导致更多的多胞胎和低出生率，发病率正在上升重量.此外，越来越多的低胎龄婴儿存活下来。氧气补充在更高的水平，更多ROP目前的ROP治疗（激光光凝和抗VEGF治疗）并不总是有效的，长期抗VEGF治疗可能会损害大脑和器官发育。我们需要找到方法早期治疗以防止I期ROP，从而防止新血管形成。高血压及相关血脂异常，常见于早产儿，与ROP的发展有关，可能有助于第一阶段ROP中的血管损失。我们必须了解开发安全有效治疗的机制，早期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 FGF 21是一种重要的葡萄糖/脂质代谢调节剂，可防止视网膜血管延迟。第一阶段ROP。因此，我们建议，在血脂异常/高血糖加重的I期ROP中，FGF 21改善了血糖/血脂代谢和血管发育。在具有新生儿代谢功能障碍的ROP的小鼠模型（NMD-ROP）中，我们将检查1）FGF 21是否改善视网膜血管发育; 2）FGF 21对脂质/葡萄糖代谢的影响; 3）FGF 21促进视网膜血管发育; 4）FGF 21促进视网膜血管发育; 5）FGF 21促进视网膜血管发育; 6）FGF 21促进视网膜血管发育; 7）FGF 21促进视网膜血管发育; 8）FGF 21促进视网膜血管发育; 9）FGF 21促进视网膜血管发育。通过调节神经胶质细胞代谢和血管生成因子来促进正常血管形成。本研究将确定1）FGF 21在一种新的高血糖加重I期小鼠模型中的作用 ROP; 2）FGF 21对视网膜脂质和葡萄糖利用的代谢影响; 3）视网膜神经胶质细胞的作用。支持视网膜血管生长的代谢。FGF 21可能在早期预防和治疗ROP。