CMRO2 and Uncoupling of Oxidative-Phosphorylation in Experimental HIE

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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.