Human periventricular white matter injury (PWMI) is the predominant form of brain damage and the leading cause of life-long neurological disability from cerebral palsy in survivors of premature birth. In the premature human brain there is a window of vulnerability when hypoxia-ischemia (H-l), maternal-fetal infection and other insults damage cerebral white matter. The spectrum of chronic PWMI includes cystic necrotic lesions (periventricular leukomalacia, PVL) and a diffuse failure of normal myelination associated with reactive astrocytosis. Despite the large number of affected infants, the cellular and molecular basis for chronic PWMI is unknown and has not been studied in a relevant animal model. Although considerable evidence exists that cerebral H-l occurs in critically ill premature neonates who sustain PWMI, the pathophysiologic relationships among H-l, acute white matter damage and chronic myelination disturbances remain poorly understood. Definition of the cellular and molecular events that generate chronic white matter injury is, thus, critically needed to advance preventive therapies. We propose to define novel mechanisms in perinatal rat and human by which acute white matter injury leads to disruptions in the neurovascular unit at the level of the extracellular matrix that disrupt normal myelinogenesis. In a perinatal rat model relevant to human PWMI, we will define mechanisms by which acute degeneration of late OL progenitors (preOLs) after H-l triggers a chronic disruption of normal myelination. We will test the overall hypothesis that the predilection of the preterm white matter to chronic myelination disturbances after H-l is related to the acute degeneration of preOLs that triggers chronic reactive astrocytosis. Our preliminary data suggest that reactive gliosis leads to the accumulation of the glycosaminoglycan hyaluronan (HA) and that HA can block preOL maturation. We hypothesize, therefore, that reactive astrocytosis prevents the normal maturation of the residual pool of susceptible preOLs, arrests normal myelination and results in a persistent state of increased vulnerability of the white matter with delayed preOL death through a mechanism that involves HA accumulation. Our approach is a significant departure from previous studies in that we will employ the full spectrum of OL lineage-specific markers previously characterized by us in developing human white matter to define the mechanisms by which H-l triggers chronic preOL degeneration and myelination failure. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Leblanc, Gabrielle G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Oregon Health and Science University
Schools of Medicine
United States
Zip Code
Srivastava, Taasin; Diba, Parham; Dean, Justin M et al. (2018) A TLR/AKT/FoxO3 immune tolerance-like pathway disrupts the repair capacity of oligodendrocyte progenitors. J Clin Invest 128:2025-2041
Bagi, Zsolt; Brandner, Dieter D; Le, Phuong et al. (2018) Vasodilator dysfunction and oligodendrocyte dysmaturation in aging white matter. Ann Neurol 83:142-152
Bosetti, Francesca; Koenig, James I; Ayata, Cenk et al. (2017) Translational Stroke Research: Vision and Opportunities. Stroke 48:2632-2637
Back, Stephen A (2017) White matter injury in the preterm infant: pathology and mechanisms. Acta Neuropathol 134:331-349
Sherman, Larry S; Back, Stephen A (2017) Comment on: PH20 is not expressed in murine CNS and oligodendrocyte precursor cells. Ann Clin Transl Neurol 4:608-609
McClendon, Evelyn; Shaver, Daniel C; Degener-O'Brien, Kiera et al. (2017) Transient Hypoxemia Chronically Disrupts Maturation of Preterm Fetal Ovine Subplate Neuron Arborization and Activity. J Neurosci 37:11912-11929
Penn, Anna A; Gressens, Pierre; Fleiss, Bobbi et al. (2016) Controversies in preterm brain injury. Neurobiol Dis 92:90-101
McNeal, David W; Brandner, Dieter D; Gong, Xi et al. (2016) Unbiased Stereological Analysis of Reactive Astrogliosis to Estimate Age-Associated Cerebral White Matter Injury. J Neuropathol Exp Neurol 75:539-54
Sherman, Larry S; Matsumoto, Steven; Su, Weiping et al. (2015) Hyaluronan Synthesis, Catabolism, and Signaling in Neurodegenerative Diseases. Int J Cell Biol 2015:368584
Back, Stephen A (2015) Brain Injury in the Preterm Infant: New Horizons for Pathogenesis and Prevention. Pediatr Neurol 53:185-92

Showing the most recent 10 out of 38 publications