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.

项目总结(说明) 光学检测脑氧代谢率(CMRO2)是一种很有前途的无创监测方法 新生儿缺氧缺血(HI)时的脑损伤，但其神经病理关系尚不完全清楚。 在这个项目中，我们将使用光声显微镜(PAM)测量CMRO2在HI小鼠模型中进行测试 缺氧缺血是否导致线粒体氧化-磷酸化解偶联导致CMRO2超调 (OXPHOS)在再灌注/复氧时，CMRO2的继发性下降是否意味着大脑能量 缺氧缺血性脑损伤后的衰竭和不可逆脑损伤，以及低温加或不加抗氧化剂是否中断 这种病理机制。这个项目有三个具体目标。 目的1：检测缺氧缺血后CMRO2超调是否与线粒体OXPHOS解偶联有关。 我们将比较缺氧损伤后CMRO2、线粒体呼吸和脑能量的变化。 小鼠新生的。 目的2：检验CMRO2是否能预测新生儿缺氧缺血性脑病亚低温治疗的结果和益处。我们 将比较CMRO2和三种候选生物标志物(骨桥蛋白/OPN，S100B， UCH-L1)在接受和不接受低温治疗的缺氧损伤小鼠新生仔鼠中的作用。 目的3：检测HIF1a和抗氧化剂是否能减轻缺氧缺血后CMRO2超调和脑损伤。 我们将测试MitoSno，Edaravone和GSK360A(HIF1a稳定剂)的效果，无论是作为独立的还是 新生儿缺氧缺血性脑损伤的亚低温辅助治疗。 该项目的成功完成将有助于深入了解CMRO2的机制和预后价值。 新生儿缺氧缺血性脑损伤。这一新的知识可能会导致更好的新生儿临床管理。