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

• 批准号: 10673008
• 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
• 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/10673008
• 关键词: Address; Affect; Ammonia; Arginine; Aspartate; Astrocytes; Biochemical; Blindness; Blood; Blood Vessels; Brain; Brain Injuries; Brain Pathology; Bronchopulmonary Dysplasia; Carbamyl Phosphate; Carbon; Cerebral Palsy; Child; Childhood; Circulation; Citric Acid Cycle; Compensation; 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' s cell; Mus; Nitrogen; Organ; Oxygen; Oxygen Therapy Care; Pathway interactions; Phase; Plasma; Premature Birth; Premature Infant; Process; Procollagen-Proline Dioxygenase; Protein Inhibition; 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; experimental study; hepatic ureagenesis; human model; hypoxia inducible factor 1; in vivo; liver hypoxia; maternal separation; metabolomics; mortality; myelination; novel; oxidation; pharmacologic; premature; preservation; preterm newborn; prevent; response; retina blood vessel structure; small molecule; stable isotope; synergism; transcription factor; transcriptome sequencing; urea cycle; white matter injury; Address; Affect; Ammonia; Arginine; Aspartate; Astrocytes; Biochemical; Blindness; Blood; Blood Vessels; Brain; Brain Injuries; Brain Pathology; Bronchopulmonary Dysplasia; Carbamyl Phosphate; Carbon; Cerebral Palsy; Child; Childhood; Circulation; Citric Acid Cycle; Compensation; 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' s cell; Mus; Nitrogen; Organ; Oxygen; Oxygen Therapy Care; Pathway interactions; Phase; Plasma; Premature Birth; Premature Infant; Process; Procollagen-Proline Dioxygenase; Protein Inhibition; 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; experimental study; hepatic ureagenesis; human model; hypoxia inducible factor 1; in vivo; liver hypoxia; maternal separation; metabolomics; mortality; myelination; novel; oxidation; pharmacologic; premature; preservation; preterm newborn; prevent; response; retina blood vessel structure; small molecule; stable isotope; synergism; transcription factor; transcriptome sequencing; urea cycle; white matter injury

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.

该提议的目的是开发一种保护永久性血管免受氧气的安全方法 与早产相关的视网膜病变。氧疗法是必要的 这些婴儿的死亡率，但对过早残留组织有害。氧诱导的视网膜病， 每年被称为早产视网膜病变（ROP），每年在全球范围内为150,000-200,000名儿童提供视野。 小鼠和大鼠模型的视网膜和肺脉管系统的定量分析 证明通过HIF脯氨酰羟化酶保留缺氧诱导因子（HIF）活性 结构蛋白蛋白（PHD）抑制可以安全防止氧诱导的肺部疾病和视网膜病变 （oir）。我们明确地证明了我们的系统性抑制策略会创造 肝脏与眼睛之间通过肝脏特异性HIF-1α激活的协同作用。我们的研究使用 HIF-1稳定野生型小鼠的肝，视网膜和血清的无靶向代谢分析 揭示了一个完全新颖的发现，即肝尿素化及更多的发现 同化是HIF-1依赖性的。我们使用高氧视网膜的基于同位素的代谢实验 支持氨气对保护的重要性，因为它们揭示了氧气引起的 麦石细胞中谷氨酸/谷氨酰胺循环的进化，这增加了需要 该过程释放的氨气。这些发现使HIF稳定成为统一 通过生物化学来解决两种早产过氧的方法来防止ROP（通过 在高氧中稳定HIF）和与物物循环的分离（通过刺激肝脏 上调保护的代谢途径）以保护肺，而CNS组织（例如 视网膜和大脑。该应用程序的具体目标是发现代谢变化如何 由高氧诱导的，被描述为谷氨酰胺驱动的无链球菌，由HIF-1补偿 依赖的代谢可塑性和氨气同化。