Metabolic origin of oxidative stress injury in brain ischemia/reperfusion

脑缺血/再灌注氧化应激损伤的代谢起源

基本信息

批准号：
10354477
负责人：
Alexander Galkin
金额：
$ 25.43万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10354477
关键词：
Adenosine Affect Amino Acids Ammonia Ammonium Bioenergetics Blood flow Brain Brain Death Brain Hypoxia Brain Hypoxia-Ischemia Brain Injuries Brain Ischemia Cell Death Cerebral Palsy Cerebrum Citric Acid Cycle Clinical Research Complex DNA Damage Data Deamination Enzymes Event Failure Flavins Generations Glucose Glutamates Glutamine Glycolysis Goals Guanine Hippocampus (Brain)Hypoxia Hypoxic-Ischemic Brain Injury Impairment Individual Infant Infant Mortality Injury Intervention Ischemia Ischemic Stroke Lead Lesion Life Lipid Peroxidation Metabolic Metabolic Pathway Mitochondria Modeling Molecular Target Morbidity - disease rate Mus Necrosis Neonatal Neurologic Neurons Outcome Oxidative Stress Oxygen Pathology Pathway interactions Patients Perinatal Hypoxia Perinatal mortality demographics Pharmacology Production Publishing Purine Nucleotides Reactive Oxygen Species Reperfusion Injury Reperfusion Therapy Rice Role Signal Pathway Slice Source Stroke Testing Therapeutic Therapeutic Intervention Tissues Wild Type Mouse Work amino acid metabolism base brain cell brain tissue deamidation deprivation dihydrolipoamide dehydrogenase disability hypoxia neonatorum hypoxic ischemic injury improved improved outcome inhibitor ketoglutarate dehydrogenase life time cost metabolomics mitochondrial permeability transition pore negative affect neonatal brain neonatal mice neonate nitrogen metabolism novel oxidative damage pre-clinical stroke model targeted treatment tissue injury

项目摘要

Summary: The annual worldwide mortality from perinatal hypoxic-ischemic (HI) insult is ~1.2 million. In the US, perinatal HI-brain injury remains one of the major causes of cerebral palsy and life- long neurological disability. The lifetime cost for patients with cerebral palsy is estimated to be $11.5 billion per affected individual. This dictates a need for therapeutic strategies based on a better understanding of the mechanisms of HI injury. HI-reperfusion-associated disruption in glycolysis, the Krebs cycle, mitochondrial energy production, nitrogen metabolism, and oxidative stress negatively affect the survival of cerebral brain cells. These are the major factors contributing to brain tissue damage in HI. However, neither the exact mechanisms of the so-called secondary energy failure nor the origin of oxidative stress in ischemia/reperfusion are known. We propose that brain oxygen deprivation leads to degradation of amino acids and purine nucleotides resulting in the accumulation of ammonia (NH4+). This, in turn, activates reactive oxygen species (ROS) production by the mitochondrial enzyme -ketoglutarate dehydrogenase during reperfusion causing oxidative injury. Our preliminary data identify the presence of this metabolic cascade in the HI brain prompting further study. In the proposed study, we will pursue the novel hypothesis that increased ROS generation and mitochondrial bioenergetics failure correlated with ischemic NH4+ accumulation. This is consistent with all experimental data observed in HI and stroke models. This is a new, insofar unrecognized, and unexplored mechanism of injury, which explains the published experimental data showing the transient burst of ROS during brain ischemia/reperfusion. The data obtained in this study will significantly alter the current paradigm of the origin of neuronal ischemia/reperfusion damage. We aim to define the major role of NH4+ in stimulation of mitochondria ROS production during bioenergetics failure in neonatal HI. The preclinical impact of this project is to provide a rationale for further clinical studies aimed at the reduction of post- HI brain injury.

概括：围产期低氧缺血性（HI）的年度全球死亡率约为120万。在美国，围产期高脑损伤仍然是脑瘫和生命的主要原因之一长神经障碍。据估计，脑瘫患者的寿命成本为每个受影响个人的115亿美元。这决定了基于更好地了解HI损伤机制。糖酵解，克雷布斯循环，线粒体能量中的高灌注相关破坏产生，氮代谢和氧化应激对脑的存活产生负面影响脑细胞。这些是导致HI中脑组织损伤的主要因素。然而，所谓的二次能量故障的确切机制也不是已知缺血/再灌注中的氧化应激。我们提出脑氧剥夺导致氨基酸和嘌呤核苷的降解，导致积累氨（NH4+）。反过来，这激活了活性氧（ROS）的产生线粒体酶-酮戊二酸脱氢酶在再灌注过程中引起氧化性受伤。我们的初步数据确定了这种代谢级联在HI大脑中的存在促使进一步学习。在拟议的研究中，我们将追求新的假设，即增加ROS的产生线粒体生物能力衰竭与缺血性NH4+积累相关。这是与HI和中风模型中观察到的所有实验数据一致。这是一个新的无法识别的损伤机制，这解释了已发表的实验数据显示了在脑缺血/再灌注过程中ROS的瞬态爆发。以这项研究将显着改变神经元起源的当前范式缺血/再灌注损害。我们旨在定义NH4+在刺激中的主要作用新生儿HI中生物能衰竭期间的线粒体ROS产生。临床前的影响该项目的旨在为进一步的临床研究提供基本原理，以减少后嗨，脑损伤。