Human periventricular white matter injury (PWMI) is the major form of brain injury and the leading cause of cerebral palsy in survivors of premature birth. With advances in neonatal care, diffuse myelination disturbances and cerebral gray matter atrophy are emerging as the major lesions associated with PWMI. We developed in preterm fetal sheep an in utero model of cerebral ischemia that preserves the maternal- fetal unit and generates a spectrum of acute and chronic cerebral injury that closely resembles that seen in preterm survivors. The predilection for acute white matter injury was defined by the regional distribution of late oligdendrocyte (OL) progenitors (preOLs) that were found to be selectively vulnerable to ischemia. We, thus, hypothesized that the acute degeneration of preOLs depletes the white matter of mature OLs required for myelination. However, as white matter injury evolves, myelination failure coincides with diffuse astrogliosis and an expanding population of preOLs that re-populate the lesions but fail to differentiate and myelinate despite the presence of numerous intact axons. These unexpected findings suggest the alternative overall hypothesis that myelination failure is related to diffuse gliosis and an arrest of OL maturation at pre-myelinating stages. We further hypothesize that arrest of preOL maturation at this OL stage, that is highly susceptible to ischemia, predisposes the white matter to persistent susceptibility to recurrent ischemia. Our approach is a significant departure from previous studies in that we will employ the full spectrum of developmental markers of the OL lineage and other neural cell types previously characterized by us in developing human white matter to define cellular mechanisms of chronic myelination failure. We will develop the first large animal model that permits an integrated quantitative regional and temporal histopathological analysis of the progression of white and gray matter injury with the application of EEG, MRI and quantitative cerebral blood flow studies. Upon completion of this project, we expect to gain fundamental new insights into pathogenetic mechanisms that trigger a failure of normal myelination in chronic PWMI. Our long-term objectives are to utilize this pre-clinical model to test new translational strategies to restore normal myelination and, potentially, neurological function in survivors of premature birth.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS045737-11
Application #
8525461
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Morris, Jill A
Project Start
2007-08-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
11
Fiscal Year
2013
Total Cost
$364,095
Indirect Cost
$127,670
Name
Oregon Health and Science University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Dean, Justin M; Bennet, Laura; Back, Stephen A et al. (2014) What brakes the preterm brain? An arresting story. Pediatr Res 75:227-33
McClendon, Evelyn; Chen, Kevin; Gong, Xi et al. (2014) Prenatal cerebral ischemia triggers dysmaturation of caudate projection neurons. Ann Neurol 75:508-24
Back, Stephen A (2014) Cerebral white and gray matter injury in newborns: new insights into pathophysiology and management. Clin Perinatol 41:1-24
Chattergoon, N N; Louey, S; Stork, P J et al. (2014) Unexpected maturation of PI3K and MAPK-ERK signaling in fetal ovine cardiomyocytes. Am J Physiol Heart Circ Physiol 307:H1216-25
Drobyshevsky, Alexander; Jiang, Rugang; Lin, Laixiang et al. (2014) Unmyelinated axon loss with postnatal hypertonia after fetal hypoxia. Ann Neurol 75:533-41
Back, Stephen A; Rosenberg, Paul A (2014) Pathophysiology of glia in perinatal white matter injury. Glia 62:1790-815
Back, Stephen A; Miller, Steven P (2014) Brain injury in premature neonates: A primary cerebral dysmaturation disorder? Ann Neurol 75:469-86
Dean, Justin M; McClendon, Evelyn; Hansen, Kelly et al. (2013) Prenatal cerebral ischemia disrupts MRI-defined cortical microstructure through disturbances in neuronal arborization. Sci Transl Med 5:168ra7
Back, Stephen A; Riddle, Art; Dean, Justin et al. (2012) The instrumented fetal sheep as a model of cerebral white matter injury in the premature infant. Neurotherapeutics 9:359-70
Riddle, Art; Maire, Jennifer; Gong, Xi et al. (2012) Differential susceptibility to axonopathy in necrotic and non-necrotic perinatal white matter injury. Stroke 43:178-84

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