Nitric oxide is an important biological mediator produced by neurons, glial cells, and blood vessels in the brain. It mediates cerebral blood flow and neuronal communication, but is also contributes to neuronal toxicity following cerebral ischemia. The principal investigators have studied the role of the various NOS isoforms in cerebral blood flow and response to ischemia using nNOS mutant mice and eNOS mutant mice. Their studies reveal that in the absence of the nNOS and eNOS genes, alternative physiologic mechanisms compensate in some cases, and in other cases, one NOS isoform is able to substitute for another. In addition, the genetic background of the mutant mice has large effects on certain phenotypes. These effects may confound the interpretation of experiments using these mice. They plan to continue our studies on the role of NOS isoforms in regulation of cerebral blood flow. First, we will examine potential mechanisms for the toxicity of nNOS-derived NO following cerebral ischemia, including the formation of peroxynitrite anion and the stimulation of programmed cell death. Next, we plan to extend the power of our genetic approach by using the Cre-recombinase loxP system to generate inducible and tissue-specific nNOS and eNOS knockout mice. Finally, the principal investigators plan to use these inducible knockout animals to address the development of compensatory mechanisms, define developmental effects of gene knockout, and control for the effects of genetic background. While their goal is to address biological questions raised by our previous studies, we hope that the development of inducible knockout technology and strains of Cre recombinase mice will be useful to study other systems and molecules important to cerebral flow and ischemia.
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