Neonatal brain injury is an important cause of death and disability, with pathways of oxidant stress, inflammation, and excitotoxicity leading to damage that progress over a long period of time. Therapies have classically targeted individual pathways during early phases of injury, but more recent studies indicate that growth factors may also enhance cell proliferation, differentiation and migration of newly born neurons over time. Understanding how the cascade of injury responses occur and the key modulators during each phase will lead to more rationale therapies. Oxidative stress is a critical mediator of the injury response after neonatal hypoxia ischemia. We have shown that hydrogen peroxide toxicity is related to cell death but a paradox exists such that H2O2 may also be a signaling molecule that is involved in neuroprotection. In the previous cycle of this grant, to gain insight into potential new therapies we focused on hypoxic preconditioning to better understand the endogenous protective response that might occur after hypoxic-ischemic (HI) insults. We hypothesized that H2O2 serves as a critical signaling molecule for activation of hypoxia inducible factor 1 (HIF-1) t promote protection in the brain after neonatal ischemia. To address this hypothesis we have been examining the mechanisms by which HIF-1 is regulated by H2O2 to generate a cytoprotective response through the use of HIF conditional knockouts and glutathione peroxidase transgenics and knockouts. We now hypothesize that during mild HI, low levels of H2O2 upregulate HIF-1a and 2a in neurons and astrocytes respectively to enhance cell survival through paracrine signaling. Understanding the exact timing and control of this signaling is essential for translation of Epo dosing in the clinic. Therefore, this work will not only move the field forward in regard to understanding mechanisms, but provide a translatable therapy, Epo, to the bedside of asphyxiated term newborns. We will address this hypothesis in three specific aims. First, we will understand how the temporal and cell-specific regulation of H2O2 levels after HI in vivo leads to HIF upregulation and downstream production of Epo, secondly, we will understand if paracrine signaling is important for Epo production and cell survival after HI in vitro, and finally we will determine whether exogenous Epo will protect the brain from severe injury by overcoming the downregulation of HIF from high H2O2. The synergistic effects of hypothermia and Epo will also be assessed.

Public Health Relevance

Lack of oxygen to the newborn brain is the major cause of lifelong disability in children resulting in mental retardation, epilepsy and cerebral palsy. Understanding pathways for protecting the brain will result in therapeutic avenues for brain recovery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033997-16
Application #
8431345
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Koenig, James I
Project Start
1996-04-01
Project End
2017-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
16
Fiscal Year
2013
Total Cost
$345,460
Indirect Cost
$121,861
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Sheldon, R Ann; Lee, Christina L; Jiang, Xiangning et al. (2014) Hypoxic preconditioning protection is eliminated in HIF-1? knockout mice subjected to neonatal hypoxia-ischemia. Pediatr Res 76:46-53
Knox, Renatta; Brennan-Minnella, Angela M; Lu, Fuxin et al. (2014) NR2B phosphorylation at tyrosine 1472 contributes to brain injury in a rodent model of neonatal hypoxia-ischemia. Stroke 45:3040-7
Liu, Jia; Sheldon, R Ann; Segal, Mark R et al. (2013) 1H nuclear magnetic resonance brain metabolomics in neonatal mice after hypoxia-ischemia distinguished normothermic recovery from mild hypothermia recoveries. Pediatr Res 74:170-9
Fang, Annie Y; Gonzalez, Fernando F; Sheldon, R Ann et al. (2013) Effects of combination therapy using hypothermia and erythropoietin in a rat model of neonatal hypoxia-ischemia. Pediatr Res 73:12-7
Knox, Renatta; Zhao, Chong; Miguel-Perez, Dario et al. (2013) Enhanced NMDA receptor tyrosine phosphorylation and increased brain injury following neonatal hypoxia-ischemia in mice with neuronal Fyn overexpression. Neurobiol Dis 51:113-9
Ortmann, Jana; Veit, Martha; Zingg, Sandra et al. (2011) Estrogen receptor-* but not -* or GPER inhibits high glucose-induced human VSMC proliferation: potential role of ROS and ERK. J Clin Endocrinol Metab 96:220-8
Jiang, Xiangning; Knox, Renatta; Pathipati, Praneeti et al. (2011) Developmental localization of NMDA receptors, Src and MAP kinases in mouse brain. Neurosci Lett 503:215-9
Sury, Matthias D; Vorlet-Fawer, Lorianne; Agarinis, Claudia et al. (2011) Restoration of Akt activity by the bisperoxovanadium compound bpV(pic) attenuates hippocampal apoptosis in experimental neonatal pneumococcal meningitis. Neurobiol Dis 41:201-8
Cilio, Maria Roberta; Ferriero, Donna M (2010) Synergistic neuroprotective therapies with hypothermia. Semin Fetal Neonatal Med 15:293-8
Li, Jinhui; Qu, Yi; Li, Xihong et al. (2010) The role of integrin alpha(v)beta (8) in neonatal hypoxic-ischemic brain injury. Neurotox Res 17:406-17

Showing the most recent 10 out of 47 publications