The major causes of periventricular leukomalacia (PVL) in the premature infant are: 1) cerebral ischemia/reperfusion compounded by cerebral vascular immaturity and impaired autoregulation; and/or 2) maternofetal bacterial infection that triggers an inflammatory/cytokine response in the fetal brain. In the first grant cycle, our neuropathologic studies in human PVL demonstrated evidence for extensive free radical injury to premyelinating oligodendrocytes (pre-OLs) that is presumably triggered by cerebral ischemia and infection acting in concert. These studies also implicated critical roles for activated microglia and reactive astrocytes in contributing to or ameliorating this injury. Moreover, we found that PVL is associated with injury to gray matter sites critical to cognitive function, thus suggesting that this injury contributes to the long-term neurological handicaps in premature infants. The overall hypothesis of this Project is that nitrative and oxidative injury plays a major role in the pathogenesis of PVL and its associated injury in vulnerable gray matter sites. In six specific aims, we will examine in depth cellular features of nitrative and oxidative injury in PVL to vulnerable pre-OLs and now neurons, including subplate neurons. We also will determine factors in oligodendrocyte, astrocytic, microglial, and neuronal development that potentially place the immature white matter at risk. Under the auspices of our PVL Tissue Bank, we will accrue and analyze tissue samples with single- and double-labeled immunocytochemistry, in situ hybridization for mRNA, and western blot analysis for selected parameters related to free radical biology and injury, as well as the inflammatory response. The proposed specific aims, hypotheses, and approaches build upon the first cycle's findings in PVL, yet are novel and have the potential to lead to new insights into its pathogenesis. A full understanding of the cellular basis of PVL in the human brain is essential for establishing basic underlying mechanisms in directly relevant experimental models, in turn ultimately resulting in therapeutic interventions for testing in clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
2P01NS038475-06A1
Application #
7006500
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
6
Fiscal Year
2005
Total Cost
$347,403
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Jantzie, Lauren L; Talos, Delia M; Jackson, Michele C et al. (2015) Developmental expression of N-methyl-D-aspartate (NMDA) receptor subunits in human white and gray matter: potential mechanism of increased vulnerability in the immature brain. Cereb Cortex 25:482-95
Elitt, C M; Rosenberg, P A (2014) The challenge of understanding cerebral white matter injury in the premature infant. Neuroscience 276:216-38
Xu, Gang; Takahashi, Emi; Folkerth, Rebecca D et al. (2014) Radial coherence of diffusion tractography in the cerebral white matter of the human fetus: neuroanatomic insights. Cereb Cortex 24:579-92
Haynes, Robin L; van Leyen, Klaus (2013) 12/15-lipoxygenase expression is increased in oligodendrocytes and microglia of periventricular leukomalacia. Dev Neurosci 35:140-54
Lippman-Bell, Jocelyn J; Rakhade, Sanjay N; Klein, Peter M et al. (2013) AMPA receptor antagonist NBQX attenuates later-life epileptic seizures and autistic-like social deficits following neonatal seizures. Epilepsia 54:1922-32
Haynes, Robin L; Sleeper, Lynn A; Volpe, Joseph J et al. (2013) Neuropathologic studies of the encephalopathy of prematurity in the late preterm infant. Clin Perinatol 40:707-22
Selip, D B; Jantzie, L L; Chang, M et al. (2012) Regional differences in susceptibility to hypoxic-ischemic injury in the preterm brain: exploring the spectrum from white matter loss to selective grey matter injury in a rat model. Neurol Res Int 2012:725184
Kinney, Hannah C; Haynes, Robin L; Xu, Gang et al. (2012) Neuron deficit in the white matter and subplate in periventricular leukomalacia. Ann Neurol 71:397-406
Haynes, Robin L; Xu, Gang; Folkerth, Rebecca D et al. (2011) Potential neuronal repair in cerebral white matter injury in the human neonate. Pediatr Res 69:62-7
Volpe, Joseph J; Kinney, Hannah C; Jensen, Frances E et al. (2011) Reprint of ""The developing oligodendrocyte: key cellular target in brain injury in the premature infant"". Int J Dev Neurosci 29:565-82

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