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.

项目概要（描述） 光学检测脑氧代谢率（CMRO2）是一种有前途的非侵入性监测方法 新生儿缺氧缺血（HI）中的脑损伤，但其神经病理学相关性仍然部分不为人所知。 在本项目中，我们将使用光声显微镜 (PAM) 测量 HI 小鼠模型中的 CMRO2，以进行测试 HI 是否会因线粒体氧化磷酸化解偶联而导致 CMRO2 过度调节 (OXPHOS) 再灌注/再氧合时，CMRO2 的继发性下降是否意味着脑能量 HI 后的衰竭和不可逆的脑损伤，以及有或没有抗氧化剂的低温是否会中断 这种病理机制。该项目有三个具体目标。 目标 1：测试 HI 后 CMRO2 的过冲是否与线粒体 OXPHOS 解偶联相关。 我们将比较 HI 损伤后 CMRO2、线粒体呼吸和脑能量的变化。 小鼠新生儿。 目标 2：测试 CMRO2 是否可以预测低温治疗新生儿 HI 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 HI 损伤的小鼠新生儿中进行和不进行低温治疗。 目标 3：测试 HIF1a 和抗氧化剂是否可以减轻 HI 后 CMRO2 的过度调节和脑损伤。 我们将测试 MitoSNO、Edaravone 和 GSK360A（HIF1a 稳定剂）的效果，无论是单独使用还是 低温辅助治疗新生儿HI脑损伤。 该项目的成功完成将深入了解 CMRO2 的机制和预后价值 新生儿 HI 脑损伤。这些新知识可能会带来更好的新生儿临床管理。