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NITRIC OXIDE SIGNALING IN MAMMALIAN CELLS
Nitric oxide (NO) is a fascinating inter-and intra-cellular signaling molecule
which had gone unrecognized until 1987. We now appreciate that NO mediates
critical roles in key processes as diverse as the regulation of vascular tone
and blood pressure, neuronal signaling, host-defense, and stimulation-secretion
coupling. Work is underway to identify novel molecular mechanisms and targets
for NO in physiological and pathopyhsiological settings. Our research uses
molecular approaches to explore NO synthesis and action in cells. A major
emphasis is on utilizing our emerging knowledge of NO synthesis and action in
cells. A major emphasis is on utilizing our emerging knowledge of NO biology for
therapeutic benefit. NO is produced by NO synthases (NOSs), a family of 3
related proteins that differ in structure, function, distribution, and
regulation. Although NOS isoforms are products of discrete genes, all catalyze
an identical reaction in which L-arg yields NO and L-citrulline, at the expense
of NADPH, O2, and water.
We are interested in synthetic mechanisms involved in this reaction and
molecular events which regulate the expression on NOS mRNAs, proteins, and
enzymatic activities. Additionally, we are exploring how ancillary genes
influence the capacity of a cell to produce NO. These genes include those
encoding enzymes involved in arginine metabolism and production of NO synthase
cofactors.
Septic shock is the leading cause of death in ICU's in the U.S., afflicting
250,000-350,000 people annually with mortality estimates ranging from 40%-60%.
Our research has led to the concept that a key step in sepsis is the induction
by LPS and cytokines of the gene encoding a specific isoform of NOS that
produces unregulated and toxic quantities of NO. Since NO is a potent
vasodilator, its overproduction can lead to profound vasodilation, vascular
collapse, and death. Accordingly, a variety of approaches have been
developed to downregulate NO overproduction in septic patients; some are
currently under clinical investigation.