Nitric Oxide Signaling in Mammilian 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.