The goal of this proposal is to develop a novel small animal model of neonatal brain injury to describe mechanisms of preterm brain injury and neuroprotection that can translate effectively to humans. Up to 50% of infants born extremely preterm develop poor outcomes involving long-term neurodevelopmental impairments affecting cognition and learning, or motor problems such as cerebral palsy. Poor outcomes arise because the preterm brain is vulnerable both to direct injury (by events such as intracerebral hemorrhage, infection and/or hypoxia), or indirect injury due to disruption of normal development. Developing white matter is particularly vulnerable to inflammation and hypoxia during the third trimester, and white matter injury is prevalent in preterm survivors. The combination of neonatal brain injury and disruption of brain development is called encephalopathy of prematurity. Rodents are the most common species used to model neonatal brain injury. But one shortcoming of using rodents is that they have a much lower proportion of white matter when compared to humans (12.5% vs. 50% white/gray). This species difference in the proportion of white matter has limited translation of rodent neuroprotective strategies to human neonates. Neonatal ferrets (Mustela putorius furo) provide a more promising opportunity to study brain injury and development relevant to preterm humans for a number of reasons. In comparison to rodents, ferrets have a more favorable white to gray matter ratio, greater cortical gyrification and, they undergo prolonged postnatal brain development so postnatal interventions may be performed at relevant stages of brain development. On postnatal day (P) 9, ferret brain development correlates well with human brain development at 25 weeks of gestation, while P21 ferret brains correspond to term gestation in human brains. We propose to create a pathophysiologically relevant ferret model of preterm brain injury that will recreate injuries associated with encephalopathy of prematurity and enable description of the underlying neuropathologic mechanisms and discovery of translatable neuroprotective strategies.
Our Specific Aims are to: 1) use the bacterial endotoxin lipopolysaccharide (LPS) to create and characterize acute and chronic inflammation in P9 ferret brain; 2) evaluate the effects of hypoxia and hypoxia-ischemia on ferret brain growth and development; and 3) identify the interaction effects of acute and chronic LPS-induced inflammation with hypoxia and hypoxia-ischemia in neonatal ferret brain. Inflammatory cytokines, magnetic resonance imaging (MRI) and immunohistochemistry (IHC) will be used to assess inflammation, injury, growth and development. We are confident that completion of these aims will produce a better understanding of the pathologic mechanisms underlying neonatal brain injury, and improve our capacity to validate new therapies for human neuroprotection.

Public Health Relevance

New small animal models of preterm brain injury are needed in order to better understand the interaction between injury (destruction) and interruption of normal brain development that occurs in extremely preterm infants and leads to neurodevelopmental impairment. Postnatal ferret brain development is remarkably similar to prenatal human brain development, and ferret kits may provide a more faithful reproduction of human preterm encephalopathy than rodent models can provide. We aim to develop such a model using a combination of inflammation and hypoxia, 2 factors that are strongly correlated with brain injury in human preterm infants.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Koenig, James I
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University of Washington
Schools of Medicine
United States
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Snyder, Jessica M; Wood, Thomas R; Corry, Kylie et al. (2018) Ontogeny of white matter, toll-like receptor expression, and motor skills in the neonatal ferret. Int J Dev Neurosci 70:25-33
Empie, Kristen; Rangarajan, Vijayeta; Juul, Sandra E (2015) Is the ferret a suitable species for studying perinatal brain injury? Int J Dev Neurosci 45:2-10
Juul, Sandra E; Mayock, Dennis E; Comstock, Bryan A et al. (2015) Neuroprotective potential of erythropoietin in neonates; design of a randomized trial. Matern Health Neonatol Perinatol 1:27