Reversal of glutamine/glutamate metabolism and Retinopathy of Prematurity

谷氨酰胺/谷氨酸代谢的逆转和早产儿视网膜病变

基本信息

批准号：
10298578
负责人：
JONATHAN E SEARS
金额：
$ 40.25万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10298578
关键词：
Address Affect Ammonia Arginine Aspartate Assimilations Astrocytes Biochemical Blindness Blood Blood Circulation Blood Vessels Brain Brain Injuries Brain Pathology Bronchopulmonary Dysplasia Carbamyl Phosphate Carbon Cerebral Palsy Child Childhood Citric Acid Cycle Corpus Callosum Cytoprotection Dependence Diabetic Retinopathy Disease Enzymes Excretory function Eye Glutamate Metabolism Pathway Glutamates Glutamine Goals Growth Hepatic Hyperoxia Hypoxia Inducible Factor Infant Injury Ischemia Isotopes Knockout Mice Ligase Link Liver Lung Lung diseases Mediating Metabolic Metabolic Pathway Metabolism Methods Mole the mammal Muller&apos s cell Mus Nitrogen Organ Oxides Oxygen Oxygen Therapy Care Pathway interactions Pharmacology Phase Plasma Premature Birth Premature Infant Process Rattus Reporting Research Resistance Retina Retinal Diseases Retinopathy of Prematurity Serum Systemic Therapy Tamoxifen Tertiary Protein Structure Tissues Up-Regulation Urea Weight Gain Wild Type Mouse alpha ketoglutarate arginase base experimental study hepatic ureagenesis human model hypoxia inducible factor 1 in vivo liver hypoxia maternal separation metabolomics mortality myelination novel oxidation premature preservation preterm newborn prevent response retina blood vessel structure small molecule stable isotope synergism transcription factor transcriptome sequencing urea cycle white matter injury

项目摘要

The goal of this proposal is to develop a safe method of protecting retinal blood vessels from oxygen induced retinopathy associated with premature birth. Oxygen therapy is necessary to prevent mortality in these infants but is harmful to premature retinal tissue. Oxygen induced retinopathy, known as retinopathy of prematurity (ROP), blinds 150,000-200,000 children worldwide annually. Quantitative analysis of retinal and lung vasculature in mouse and rat models of human ROP demonstrate that preservation of hypoxia inducible factor (HIF) activity through HIF prolylhydroxylase domain protein (PHD) inhibition safely prevents oxygen-induced lung disease and retinopathy (OIR). We have definitively demonstrated that our systemic strategy of PHD inhibition creates synergy between the liver and the eye through liver specific HIF-1α activation. Our studies using untargeted metabolic profiling of liver, retina, and serum from HIF-1 stabilized wild type mice revealed the completely novel finding that hepatic ureagenesis and retinal ammonia assimilation is HIF-1 dependent. Our isotopic based metabolic experiments using hyperoxic retina support the importance of ammonia assimilation to protection because they reveal an oxygen-induced derangement in glutamate/glutamine cycling in Müller cells that increases the need to assimilate ammonia released by this process. These findings make HIF stabilization a unified approach to preventing ROP by biochemically addressing both hyperoxia of prematurity (by stabilizing HIF in hyperoxia) and separation from the maternal circulation (by stimulating the liver to upregulate protective metabolic pathways) in order to protect lung, and CNS tissues such as the retina and brain. The specific goal of this application is to discover how metabolic change induced by hyperoxia, described as glutamine-fueled anaplerosis, is compensated by HIF-1 dependent metabolic plasticity and ammonia assimilation.

该提案的目标是开发一种保护视网膜血管免受氧气影响的安全方法与早产相关的诱发性视网膜病变对于预防是必要的。这些婴儿的死亡率，但对早产儿视网膜组织有害，称为早产儿视网膜病变 (ROP) 的疾病导致全世界 150,000-200,000 名儿童失明。人类 ROP 小鼠和大鼠模型中视网膜和肺血管系统的定量分析证明通过 HIF 脯氨酰羟化酶保留缺氧诱导因子 (HIF) 活性结构域蛋白 (PHD) 抑制可安全预防氧诱导的肺部疾病和视网膜病变（OIR）我们已经明确证明我们的 PHD 抑制系统策略会产生我们的研究使用肝脏特异性 HIF-1α 激活来实现肝脏和眼睛之间的协同作用。对 HIF-1 稳定的野生型小鼠的肝脏、视网膜和血清进行非靶向代谢分析揭示了肝脏尿素生成和视网膜氨的全新发现同化作用依赖于 HIF-1。我们使用高氧视网膜进行基于同位素的代谢实验。支持氨同化对保护的重要性，因为它们揭示了氧诱导的穆勒细胞中谷氨酸/谷氨酰胺循环的紊乱，增加了对同化该过程释放的氨，这些发现使 HIF 稳定化成为一个统一的结果。通过生化解决早产儿高氧血症来预防 ROP 的方法（通过稳定高氧状态下的 HIF）并与母体循环分离（通过刺激肝脏）上调保护性代谢途径）以保护肺和中枢神经系统组织，例如该应用程序的具体目标是发现新陈代谢如何变化。由高氧引起的，被描述为谷氨酰胺驱动的回补，由 HIF-1 补偿依赖代谢可塑性和氨同化。