Cerebral hypoxia-ischemia remains a major cause of acute perinatal brain injury initiated when either placental or pulmonary gas exchange is compromised. This leads to neuronal death and neurologic dysfunction such as cerebral palsy, mental retardation or epilepsy. This clinical problem is the most common cause of static encephalopathies in infants and children. Our objective is to understand the pathophysiology of this process. Excessive NO appears to play a critical role in the pathologic sequelae associated with perinatal asphyxia. Our in vivo work has demonstrated that nitric oxide (NO) plays an important role in modulating the neurotoxic effects associated with perinatal asphyxia. NO is formed, from L-arginine, by the action of the enzyme nitric oxide synthase (NOS). We have demonstrated that the predominant NOS isoform expressed in the neurons involved in hypoxic-ischemic brain injury is neuronal NOS (nNOS). One strategy that could ameliorate the neuronal damage produced by global hypoxia could be based on the ability to regulate the activity of nNOS, thereby reducing the production of NO. Thus, if we could specifically, and effectively, block nNOS dimerization we would have developed a treatment that could reduce the neurotoxic effects of NO without the non-selective effects associated with other protocols. Dimerization is an absolute requirement for nNOS activity. Therefore, an understanding how nNOS dimerization is controlled could lead to the development of pharmacologic agents that could regulate nNOS dimerization in vivo and hence nNOS activity. This would produce a reduction in the levels of NO released during perinatal asphyxia with potential neuroprotective effects. At least four factors are involved in the regulation of nNOS activity and potentially dimer formation: Co-factor and substrate binding, the phosphorylation state of the protein, sequences within the monomeric protein structure, and the action of the PIN (protein inhibitor of nNOS) protein. We will identify how these factors interact to regulate nNOS dimer formation and hence nNOS activity.
|Effective start/end date||9/24/99 → 8/31/12|
- National Institutes of Health: $191,487.00
- National Institutes of Health: $63,692.00
- National Institutes of Health: $122,879.00
- National Institutes of Health: $270,686.00
- National Institutes of Health: $175,860.00
- National Institutes of Health: $181,137.00
- National Institutes of Health: $292,548.00
- National Institutes of Health: $297,215.00
- National Institutes of Health: $297,081.00
- National Institutes of Health: $283,348.00
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