Therapeutic hypothermia, although profoundly neuroprotective, is only effective in 60% of infants affected by neonatal hypoxic-ischemic encephalopathy (HIE). The initial insult in neonatal HIE produces a reduction in the supply of glucose and oxygen to the brain, to levels insufficient to meet the developing brains energetic demands. Thus, we are investigating the metabolic signatures that might distinguish the non-responders from the responders to the hypothermia treatment. While hypothermia appears to ameliorate cell death, the precise molecular events of how and where hypothermia acts on the hypoxic-ischemic biochemical cascade are poorly understood. The cold-inducible RNA binding protein (CIRP) and the RNA binding motif protein 3 (RBM3) and their inducibility in hypothermia have recently generated new interest in the field of neonatal brain injury. While most protein synthesis is suppressed during hypothermia, these are induced, and they mediate a neuroprotective effect. Neuronal hypoxia-inducible factor (HIF) signaling also plays a substantial role in the endogenous protective responses following HI and there is documented evidence of a crosstalk between CIRP and its subunit HIF1α. Using an established murine model of hypoxia-ischemia, we hypothesize that the upregulation of these RNA binding proteins occurs in animals identified as responders to therapeutic hypothermia. We will use hyperpolarized 13-labeled carbon (HP-13C) magnetic resonance spectroscopy (MRS) to determine in real-time the conversion of intravenously administered 13C-labeled pyruvate to lactate in the brain of neonatal mice that have undergone hypoxic-ischemic injury and hypothermia treatment. The acquired metabolomics data will aid in distinguishing between responders and non-responders to the treatment. We will prove our hypothesis in two specific aims: First, by measuring CIRP and RBM3 within 24 h after hypothermia and showing that these proteins are upregulated in the responders as determined by the HP-13C MRS pyruvate to lactate conversion rates and second, by associating the induction of CIRP and RBM3 with the upregulation of HIF1α and the stabilization of its transcript. Elucidation of these novel cold-responsive pathways will lead to new frontiers in the research of therapeutic hypothermia and the treatment of acute brain injury.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|