]: Brain hypoxia is a component of perinatal ischemia that is increasingly common among low birth weight infants and those suffering ischemia in utero with 100% oxygen (hyperoxia) treatment being a common clinical practice. In addition to resultant child morbidity and mortality, there are delayed cognitive impairments persisting up to eight years later. The overall hypothesis of this program project is that hypoxia/ischemia-associated oxidative stress in postnatal day 7 (P7) rat results in DNA damage, delayed cell death, and inflammation; all risk factors to neuronal development and function. The characterization of the signal transduction pathways that regulate cell death processes and determine outcomes will allow for rational design of interventions to decrease cell death and reduce inflammatory cascades. Specific hypotheses to be tested are that there is DNA damage after hypoxia/ischemia that triggers DNA repair (Project I); that neuronal sparing after hypoxia/ischemia is due in part to Bcl-xL expression (Project II); and that cytokine expression and vascular responses are part of the inflammatory activation of NF-kappaB transcription factors that determine cell death (Project III). Intervention paradigms will be via inhibition of DNA repair processes, injection of Bcl-xL, and modulation of NF-kappaB activation by a """"""""decoy"""""""" elements. Characterizations will rely on electrophoretic mobility shift and footprinting assays, Westerns and microaffinity isolation, immunoblot assays, as well as various in situ histochemical and immunocytochemical assays. Transcription factor inhibition and overexpression will be assessed in vitro and in vivo. Lesion damage in the three projects will be determined by immunohistochemistry and MRI techniques sensitive to local edema and blood flow changes. Confounds and integration of observations will also rely on longitudinal MRI studies together with Affymetrix DNA microarray analyses. An understanding of risk factor outcomes may provide therapeutic strategies for children affected by perinatal/ischemia.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD039833-05
Application #
7276055
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Vitkovic, Ljubisa
Project Start
2003-09-01
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2010-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$908,655
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
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Woodworth, K Nina; Palmateer, Julie; Swide, Joseph et al. (2011) Short- and long-term behavioral effects of exposure to 21%, 40% and 100% oxygen after perinatal hypoxia-ischemia in the rat. Int J Dev Neurosci 29:629-38
Wiktorowicz, John E; Stafford, Susan; Rea, Harriet et al. (2011) Quantification of cysteinyl S-nitrosylation by fluorescence in unbiased proteomic studies. Biochemistry 50:5601-14
Bockhorst, K H; Narayana, P A; Dulin, J et al. (2010) Normobaric hyperoximia increases hypoxia-induced cerebral injury: DTI study in rats. J Neurosci Res 88:1146-56
Gill, Martin B; Perez-Polo, J Regino (2009) Bax shuttling after rotenone treatment of neuronal primary cultures: effects on cell death phenotypes. J Neurosci Res 87:2047-65
Fabian, Roderic H; Perez-Polo, J Regino; Kent, Thomas A (2008) Perivascular nitric oxide and superoxide in neonatal cerebral hypoxia-ischemia. Am J Physiol Heart Circ Physiol 295:H1809-14
Gill, Martin B; Bockhorst, Kurt; Narayana, Ponnada et al. (2008) Bax shuttling after neonatal hypoxia-ischemia: hyperoxia effects. J Neurosci Res 86:3584-604
Smith, Karen E; Keeney, Susan; Zhang, Lifang et al. (2008) The association of early blood oxygenation with child development in preterm infants with acute respiratory disorders. Int J Dev Neurosci 26:125-31
Dong, Jing-fei; Cruz, Miguel A; Aboulfatova, Khatira et al. (2008) Magnesium maintains endothelial integrity, up-regulates proteolysis of ultra-large von Willebrand factor, and reduces platelet aggregation under flow conditions. Thromb Haemost 99:586-93
Grafe, Marjorie R; Woodworth, K Nina; Noppens, Kristin et al. (2008) Long-term histological outcome after post-hypoxic treatment with 100% or 40% oxygen in a model of perinatal hypoxic-ischemic brain injury. Int J Dev Neurosci 26:119-24

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