CMRO2 and Uncoupling of Oxidative-Phosphorylation in Experimental HIE

项目概要（说明） 脑氧代谢率（CMRO 2）的光学检测是一种很有前途的无创监测方法 新生儿缺氧缺血性脑损伤（HI），但其神经病理学相关性仍部分了解。 在这个项目中，我们将使用光声显微镜（PAM）来测量HI小鼠模型中的CMRO 2，以测试 HI是否由于线粒体氧化磷酸化解偶联而导致CMRO 2过冲 （OXPHOS）再灌注/复氧后，CMRO 2的继发性下降是否意味着脑能量 HI后失败和不可逆的脑损伤，以及是否有抗氧化剂的低体温中断 这种病理机制。该项目有三个具体目标。 目的1：测试CMRO 2的HI后过冲是否与线粒体OXPHOS的解偶联相关。 我们将比较HI损伤后CMRO 2、线粒体呼吸和脑能量的变化。 小鼠新生儿。 目的2：测试CMRO 2是否预测新生儿HI的低温治疗的结果和益处。我们 将比较CMRO 2的变化和三种候选生物标志物（骨桥蛋白/OPN，S100 b， UCH-L1）在HI损伤的小鼠新生儿中进行和不进行低温治疗。 目的3：测试HIF 1a和抗氧化剂是否减弱CMRO 2的HI后过冲和脑损伤。 我们将测试MitoSNO、依达拉奉和GSK 360 A（一种HIF 1a稳定剂）单独或联合使用的效果。 低温辅助治疗新生儿HI脑损伤。 该项目的成功完成将有助于深入了解CMRO 2的机制和预后价值， 新生儿HI脑损伤。这一新的知识可能会导致更好的临床管理在泌尿外科。

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.