Preterm birth results in significant developmental disability, and the incidence of neurodevelopmental handicaps in preterm infants is reported to be unchanged during the past decade. Thus, examination of those factors which may affect developmental outcome is critical. Circulatory disturbances and oxygen deprivation are a major cause of developmental impairments in preterm infants. Although intraventricular hemorrhage is perhaps the most commonly recognized and best studied of these disturbances, hypoxia is particularly prevalent among very low birth weight preterm infants. A developmentally regulated pattern of ingrowth of cortical axonal systems, synaptogenesis, and receptor development is thought to be central to learning and cognition. Although recent data have suggested that the pharmacologic disruption of the genetically programmed onset of synaptogenesis may contribute to cognitive deficits, the effect of hypoxia on the developing brain at different gestational time points are relatively unexplored. These data are of particular importance if one is to both establish an understanding of the mechanisms of injury associated with this insult and provide therapeutic strategies for those who care for these tiny and frequently critically ill subjects. We hypothesize that a dominant factor in the neurodevelopmental handicap resulting from preterm birth is sublethal hypoxic stress. In the previous neonatal exploratory brain research grant funding period, our studies demonstrated that the neonatal rat model of preterm brain responds to chronic sublethal hypoxia with angiogenesis and significant changes in cerebral microvascular permeability. Our preliminary data suggest that this insult alters the profile of developmentally regulated genes in the brain and results in modification of the developmentally regulated pattern of programmed cell death. We hypothesize, therefore, that chronic sublethal hypoxia results in the developmental arrest or delay of many of those cerebral processes critical to learning and cognition, including callosal connectivity, synaptogenesis and programmed cell death.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS035476-04
Application #
6187316
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Spinella, Giovanna M
Project Start
1997-07-01
Project End
2002-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
4
Fiscal Year
2000
Total Cost
$1,041,260
Indirect Cost
Name
Yale University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Silbereis, John; Heintz, Tristan; Taylor, Mary Morgan et al. (2010) Astroglial cells in the external granular layer are precursors of cerebellar granule neurons in neonates. Mol Cell Neurosci 44:362-73
Fagel, Devon M; Ganat, Yosif; Cheng, Elise et al. (2009) Fgfr1 is required for cortical regeneration and repair after perinatal hypoxia. J Neurosci 29:1202-11
Silbereis, John; Cheng, Elise; Ganat, Yosif M et al. (2009) Precursors with glial fibrillary acidic protein promoter activity transiently generate GABA interneurons in the postnatal cerebellum. Stem Cells 27:1152-63
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Chahboune, Halima; Ment, Laura R; Stewart, William B et al. (2009) Hypoxic injury during neonatal development in murine brain: correlation between in vivo DTI findings and behavioral assessment. Cereb Cortex 19:2891-901
Rauch, Millicent Ford; Michaud, Michael; Xu, Hao et al. (2008) Co-culture of primary neural progenitor and endothelial cells in a macroporous gel promotes stable vascular networks in vivo. J Biomater Sci Polym Ed 19:1469-85
Constable, R Todd; Ment, Laura R; Vohr, Betty R et al. (2008) Prematurely born children demonstrate white matter microstructural differences at 12 years of age, relative to term control subjects: an investigation of group and gender effects. Pediatrics 121:306-16
Li, Qi; Michaud, Michael; Stewart, William et al. (2008) Modeling the neurovascular niche: murine strain differences mimic the range of responses to chronic hypoxia in the premature newborn. J Neurosci Res 86:1227-42
Glantz, Susan B; Cianci, Carol D; Iyer, Rathna et al. (2007) Sequential degradation of alphaII and betaII spectrin by calpain in glutamate or maitotoxin-stimulated cells. Biochemistry 46:502-13

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