Neonatal hypoxic-ischemic (HI) brain injury results in devastating, life-long disability for the affected children. At present, hypothermia is the only treatment for neonatal HI and it is incompletely effective. 45% of treated infants still die or sustain severe neurodevelopmental disability following HI. Designing safe, effective, mechanistically novel adjuvant therapies is the highest priority in this field of research. In concert, there is a need to develop mechanistically-based, reliable biomarkers to track novel therapies and measure their efficacy. Our identification of programmed necrosis as a mechanism of injury in neonatal HI provides an opportunity to identify novel therapies. That programmed necrosis may be operative in neonatal HI is clinically compelling. Programmed necrosis, unlike classical necrosis, is regulated, treatable, and is well understood in vitro. How and whether hypothermia acts to inhibit programmed necrosis is unknown and very important to the successful development of adjuvant therapies for neonatal HI. The in vivo neural target of hypothermia and programmed necrosis inhibitors is also a gap in our knowledge. Effects of hypothermia on neurons are best known. Little is known about the effects of hypothermia on glia and nothing is known about the effects of programmed necrosis inhibitors. Glia, oligodendroglia and astrocytes, clearly contribute to the overall """"""""encephalopathy"""""""" resulting from neonatal HI. Astrocytes, in particular, may play a pivotal role in initiation of and protection from HI by both hypothermia and programmed necrosis inhibitors. Because of their possible involvement in the initiation and response to HI injury and treatment, astrocytic release of glial fibrillary acid proein (GFAP) may be the reliable, regionally specific, mechanistically-based biomarker that we seek for neonatal HI brain injury. In this proposal, we will use an established model of neonatal HI and hypothermia address each of these research priorities and areas of knowledge gap. We will test the hypothesis that hypothermia provides neuroprotection following neonatal HI by interrupting programmed necrosis. Subsequently, using data from these experiments we will test combinations of hypothermia, anti-programmed necrosis and anti-apoptosis treatments for treatment of neonatal HI and GFAP as an experimental biomarker. In doing so we will forge new pathways in neonatal brain injury research These experiments address critical, timely, and highly relevant issues in neonatal brain injury.

Public Health Relevance

These studies address one of the highest priorities in neonatal brain injury;finding novel therapies to combine with our current treatment for neonatal hypoxic ischemic brain injury. Additionally, we will be applying a promising clinical biomarker to an experimental model, to test its ability to predict severity of injury and response to treatment. Results from these studies have the potential to fundamentally alter our understanding of how hypoxic ischemic injury causes brain damage and how to significantly improve treatment for this devastating injury.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Urv, Tiina K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Lee, J K; Perin, J; Parkinson, C et al. (2017) Relationships between cerebral autoregulation and markers of kidney and liver injury in neonatal encephalopathy and therapeutic hypothermia. J Perinatol 37:938-942
Chavez-Valdez, Raul; O'Connor, Matthew; Perin, Jamie et al. (2017) Sex-specific associations between cerebrovascular blood pressure autoregulation and cardiopulmonary injury in neonatal encephalopathy and therapeutic hypothermia. Pediatr Res 81:759-766
Lee, Jennifer K; Poretti, Andrea; Perin, Jamie et al. (2017) Optimizing Cerebral Autoregulation May Decrease Neonatal Regional Hypoxic-Ischemic Brain Injury. Dev Neurosci 39:248-256
Jan, Saber; Northington, Frances J; Parkinson, Charlamaine M et al. (2017) EEG Monitoring Technique Influences the Management of Hypoxic-Ischemic Seizures in Neonates Undergoing Therapeutic Hypothermia. Dev Neurosci 39:82-88
Lei, Jun; Paules, Cristina; Nigrini, Elisabeth et al. (2017) Umbilical Cord Blood NOS1 as a Potential Biomarker of Neonatal Encephalopathy. Front Pediatr 5:112
Lemmon, Monica E; Wagner, Matthias W; Bosemani, Thangamadhan et al. (2017) Diffusion Tensor Imaging Detects Occult Cerebellar Injury in Severe Neonatal Hypoxic-Ischemic Encephalopathy. Dev Neurosci 39:207-214
Lemmon, Monica E; Donohue, Pamela K; Parkinson, Charlamaine et al. (2017) Parent Experience of Neonatal Encephalopathy. J Child Neurol 32:286-292
Diaz, Johana; Abiola, Suleiman; Kim, Nancy et al. (2017) Therapeutic Hypothermia Provides Variable Protection against Behavioral Deficits after Neonatal Hypoxia-Ischemia: A Potential Role for Brain-Derived Neurotrophic Factor. Dev Neurosci 39:257-272
Johnson, C T; Burd, I; Raghunathan, R et al. (2016) Perinatal inflammation/infection and its association with correction of metabolic acidosis in hypoxic-ischemic encephalopathy. J Perinatol 36:448-52
Lemmon, Monica E; Donohue, Pamela K; Parkinson, Charlamaine et al. (2016) Communication Challenges in Neonatal Encephalopathy. Pediatrics 138:

Showing the most recent 10 out of 57 publications