CMRO2 and Uncoupling of Oxidative-Phosphorylation in Experimental HIE

CMRO2 和实验 HIE 中氧化磷酸化的解偶联

• 批准号: 10533435
• 负责人: Song Hu
• 金额: $ 62.8万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10533435
• 关键词: ATP Synthesis Pathway; Abate; Address; Adjuvant; Adjuvant Therapy; Adult; Antioxidants; Attenuated; Beds; Biochemical; Biological Markers; Biopsy; Blood; Brain Hypoxia-Ischemia; Brain Injuries; Cerebral Ischemia-Hypoxia; Cerebral Palsy; Cerebrum; Clinical Management; Complex; Contralateral; Data; Detection; Diagnostic; Early Diagnosis; Electron Transport; Epilepsy; Failure; Foundations; Freezing; Glutamates; Glutamine; Histologic; Hyperactivity; Imaging technology; Impaired cognition; Infarction; Interruption; Ipsilateral; Ischemic Stroke; Knowledge; Lead; Live Birth; Magic; Magnetic Resonance Spectroscopy; Measurement; Measures; Membrane Potentials; Metabolism; Methods; Microscopy; Mitochondria; Modeling; Monitor; Mus; N-acetylaspartate; Neonatal Brain Injury; Neonatology; Optics; Outcome; Oxidative Phosphorylation; Oxygen; Oxygen Consumption; Pathologic; Phosphocreatine; Phosphorylation; Prognostic Marker; Reactive Oxygen Species; Recovery; Reperfusion Therapy; Respiration; Side; Speed; Superoxides; System; Testing; Therapeutic; Therapeutic Effect; Time; Tissue Viability; awake; base; behavioral outcome; brain tissue; candidate marker; cranium; exhaustion; experimental study; high risk; improved; insight; ischemic injury; metabolic rate; microscopic imaging; mouse model; natural hypothermia; neonatal brain; neonatal hypoxic-ischemic brain injury; neonate; non-invasive monitor; novel; optical imaging; osteopontin; outcome prediction; phenylmethylpyrazolone; preservation; prevent; prognostic value; prognostication; public health relevance; stroke therapy; therapeutic evaluation

PROJECT SUMMARY (Description) Optical detection of cerebral metabolic rate of oxygen (CMRO2) is a promising non-invasive method to monitor brain injury in neonatal hypoxia-ischemia (HI), but its neuropathological correlates remain partially understood. In this project, we will use photoacoustic microscopy (PAM) to measure CMRO2 in a murine model of HI to test whether HI causes an overshoot of CMRO2 due to uncoupling of the mitochondrial oxidative-phosphorylation (OXPHOS) upon reperfusion/reoxygenation, whether a secondary decline of CMRO2 signifies cerebral energy failure and irreversible brain damage after HI, and whether hypothermia with or without antioxidants interrupts this pathological mechanism. This project has three specific aims. Aim 1: To test whether post-HI overshoot of CMRO2 correlates with uncoupling of the mitochondrial OXPHOS. We will compare the changes of CMRO2, mitochondrial respirations, and cerebral energy after the HI insult in mouse neonates. Aim 2: To test if CMRO2 predicts the outcomes and benefits of hypothermia treatment against neonatal HI. We will compare the changes of CMRO2 and blood levels of three candidate biomarkers (osteopontin/OPN, S100b, UCH-L1) in HI-injured mouse neonates with and without hypothermia treatment. Aim 3: To test whether HIF1a and antioxidants attenuates the post-HI overshoot of CMRO2 and brain damage. We will test the effects of MitoSNO, Edaravone, and GSK360A (a HIF1a-stablizer) either as a stand-alone or adjuvant treatment to hypothermia against neonatal HI brain injury. Successful completion of this project will shed insights into the mechanisms and prognostic value of CMRO2 in neonatal HI brain injury. This new knowledge may lead to better clinical managements in neonatology.

项目摘要（描述） 氧脑代谢率的光学检测（CMRO2）是一种有希望的非侵入性方法 新生儿缺氧 - 缺血性（HI）的脑损伤，但其神经病理学相关性仍然部分理解。 在这个项目中，我们将使用光声显微镜（PAM）在HI的鼠模型中测量CMRO2进行测试 HI是否由于线粒体氧化磷酸化的解偶联而导致CMRO2的过冲。 （OXPHOS）在再灌注/重氧时，CMRO2的继发性下降是否表示脑能量 HI之后的衰竭和不可逆转的脑损伤，以及是否有或没有抗氧化剂的体温过低会中断 这种病理机制。该项目具有三个特定的目标。 目的1：测试hi后cmro2是否与线粒体oxphos的解偶联相关。 我们将比较HI侮辱后CMRO2，线粒体呼吸和大脑能的变化 小鼠新生儿。 目标2：测试CMRO2是否预测了针对新生儿HI的低温治疗的结果和益处。我们 将比较三种候选生物标志物的CMRO2和血液水平的变化（骨桥/OPN，S100B， UCH-L1）在有或没有低温治疗的高伤害小鼠新生儿中。 AIM 3：测试HIF1A和抗氧化剂是否会抑制CMRO2和脑损伤后的过冲。 我们将测试Mitosno，Edaravone和GSK360A（HIF1A-Stablizer）的影响 针对新生儿HI脑损伤的体温过低的辅助治疗。 该项目的成功完成将洞悉CMRO2的机制和预后价值 新生儿HI脑损伤。这种新知识可能会导致新生儿学方面的临床管理更好。