This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Endotoxins such as LPS and PGN, components of outer cell walls from Gram-negative and Gram-positive bacteria are potent immunostimulators of monocytes and macrophages in humans and have been implicated in the pathogenesis of sepsis and septic shock, a clinical progression that results in 250,000 deaths annually in the United States alone. Inflammatory responses as part of innate immunity are initiated via high-affinity binding of these endotoxins to a key host cell receptor CD 14, triggering release of a variety of pro inflammatory mediators, including cytokines, through a signal transduction pathway involving Toll-like receptors. An overactivation of this cellular response may, however, result in excessive release of the proinflammatory mediators, inducing septic shock and death. CD 14 is known to play a central role in the innate system, by modulating the inflammatory response and enhancing the sensitivity of endotoxininduced activation. However, the molecular mechanisms by which it accomplishes this are not clear. The proposed studies are focused on understanding the molecular details of CD 14-endotoxin interactions with all atom molecular dynamics simulations. Specific simulations will be applied to identify key CD14 residues involved in interaction with different endotoxins according to our high resolution NMR spectroscopy results which indicated the potential binding interfaces between human CD14 and various endotoxins and ligands. Simulation results will be further tested by mutagenesis and biophysical studies. Completion of these studies will provide the structural basis for the deleterious effects of LPS, PGN and rational design of potentially novel LPS, PGN antagonists for treatment of sepsis.
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