The proposed studies will investigate specific cellular and molecular mechanisms of hypoxic neuronal injury in the newborn by relating the degree of hypoxia to alterations in neuronal nuclear membrane and intranuclear Ca/++, as well as the expression of apoptotic and anti- apoptotic genes. We propose that the severity of hypoxia will have a specific impact on the function of the neuronal nuclear membrane calcium influx mechanisms and critical nuclear functions. The monitoring of the degree of brain tissue hypoxia in vivo will be achieved by the continuous measurement of brain high energy compounds with 31P nuclear magnetic resonance spectroscopy and confirmed biochemically by ATP and phosphocreatine. Histochemical methods will be performed to assess histopathologic changes. Experimental protocols will be carried out on newborn piglets investigating: (1) The relationship of quantitative tissue hypoxia to changes in neuronal calcium influx mechanisms: high affinity Ca/++-ATPase, inositol 1, 3, 4, 5 tetrakisphosphate (IP/4) receptor and inositol 1, 4, 5 triphosphate (IP/3) receptor; (2) The effect of hypoxia on increased intranuclear calcium concentration; (3) The relationship of increased neuronal intranuclear Ca/++ to transcription of bax (apoptotic) and bcl-2 (anti-apoptotic) genes, endonuclease activity, and the pattern of DNA fragmentation in response to graded tissue hypoxia; (4) Morphological changes indicative of neuronal death, particularly programmed cell death following hypoxia; and (5) The effect of inhibition of the NMDA receptor or pathways of free radical generation or hypoxia- induced changes in neuronal nuclei and programmed cell death. The proposed experiments will be performed by utilizing well established techniques. These studies will provide new insights into neuronal nuclear functions and will lead to a better understanding of the mechanisms of hypoxic brain injury. The elucidation of basic cellular mechanisms in response to hypoxic brain injury. The elucidation of basic cellular mechanisms in response to hypoxia will enable the development of novel strategies of preventing or attenuating the deleterious effects of hypoxia in the newborn.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD020337-15
Application #
2751711
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Wright, Linda
Project Start
1985-09-01
Project End
2003-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
15
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Mcp Hahnemann University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19102
Kratimenos, Panagiotis; Koutroulis, Ioannis; Jain, Amit et al. (2018) Effect of Concurrent Src Kinase Inhibition with Short-Duration Hypothermia on Ca2+/Calmodulin Kinase IV Activity and Neuropathology after Hypoxia-Ischemia in the Newborn Swine Brain. Neonatology 113:37-43
Delivoria-Papadopoulos, Maria (2012) Mechanism of caspase-9 activation during hypoxia in the cerebral cortex of newborn piglets: the role of Src kinase. Neurosci Lett 523:19-23
Delivoria-Papadopoulos, Maria; Ashraf, Qazi M; Mishra, Om Prakash (2011) Mechanism of CaM kinase IV activation during hypoxia in neuronal nuclei of the cerebral cortex of newborn piglets: the role of Src kinase. Neurochem Res 36:1512-9
Delivoria-Papadopoulos, Maria; Ashraf, Qazi M; Mishra, Om Prakash (2011) Brain tissue energy dependence of CaM kinase IV cascade activation during hypoxia in the cerebral cortex of newborn piglets. Neurosci Lett 491:113-7
Delivoria-Papadopoulos, Maria; Mishra, Om Prakash (2010) Mechanism of post-translational modification by tyrosine phosphorylation of apoptotic proteins during hypoxia in the cerebral cortex of newborn piglets. Neurochem Res 35:76-84
Mishra, Om Prakash; Ashraf, Qazi M; Delivoria-Papadopoulos, Maria (2010) Hypoxia-induced activation of epidermal growth factor receptor (EGFR) kinase in the cerebral cortex of newborn piglets: the role of nitric oxide. Neurochem Res 35:1471-7
Mishra, Om P; Delivoria-Papadopoulos, Maria (2010) Mechanism of tyrosine phosphorylation of procaspase-9 and Apaf-1 in cytosolic fractions of the cerebral cortex of newborn piglets during hypoxia. Neurosci Lett 480:35-9
Mudduluru, Manjula; Zubrow, Alan B; Ashraf, Q M et al. (2010) Tyrosine phosphorylation of apoptotic proteins during hyperoxia in mitochondria of the cerebral cortex of newborn piglets. Neurochem Res 35:1003-9
Mishra, Om Prakash; Ashraf, Qazi M; Delivoria-Papadopoulos, Maria (2010) Mechanism of increased tyrosine (Tyr(99)) phosphorylation of calmodulin during hypoxia in the cerebral cortex of newborn piglets: the role of nNOS-derived nitric oxide. Neurochem Res 35:67-75
Mishra, Om Prakash; Ashraf, Qazi M; Delivoria-Papadopoulos, Maria (2009) NO-mediated activation of Src kinase during hypoxia in the cerebral cortex of newborn piglets. Neurosci Lett 460:61-5

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