The proposed studies investigate the cerebral metabolic responses of newborn animals induced by ischemia and hypoxia of varying intensity and duration. Cerebral metabolism will be assessed by in-vivo measurements of phosphorus cellular metabolites and intracellular pH with nuclear magnetic resonance of 31-Phosphorus and simultaneous measurements of cerebral metabolic rate for oxygen, glucose, and lactate. 31-P NMR spectroscopy allows repetitive and quantitative measurements of the dynamic aspects of metabolism of organophosphates and intracellular pH in the intact animal. Hemodynamic events occurring as a result of general or regional changes in oxygen content will be related to metabolic alterations reflecting the onset of transient or permanent tissue damage in newborn animals. Experimental protocols will be carried out on newborn piglets and lambs, investigating limits in brain energy reserves as identified by 31-Phosphorus NMR spectroscopy in-vivo in acute hypoxia and ischemia, identifying the critical level of oxygen delivery to brain (depending on the prevailing metabolic demand). Physiologic measurements of oxygen and glucose availability and uptake, acid-base balance, and hemodynamic measurements will be correlated with metabolic phosphorus containing compounds. These projects will test the overall hypotheses that single or repeated episodes of hypoxic and metabolic stress, as well as long-lasting states of hypoxia, may result in subtle alterations of metabolic function. Specific studies will investigate the efficiency of compensatory mechanisms maintaining cellular brain metabolism in newborn animals under conditions of impaired oxygenation and will establish the limits of this efficiency by comparing the microcirculatory and metabolic responses during various insults identified by NMR and CBF measurements.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD020337-04
Application #
3318329
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1985-09-01
Project End
1994-04-30
Budget Start
1989-08-01
Budget End
1990-04-30
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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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