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.Based on conservative estimates, septicemia is associated with 200,000 human deaths annually in the United States. Morbidity and mortality rates are linked to the presence of endotoxin (lipopolysaccharide; LPS) in the blood of affected patients, strongly implicating endotoxemia as a critical factor in pathogenesis. LPS, a component of Gram-negative bacteria, is among the most potent proinflammatory substances known and initiates the production of multiple host-derived inflammatory mediators including cytokines (e.g., TNF ), arachidonic acid metabolites, and tissue factor. Data from our center indicate that structurally novel LPS from rhizobial nitrogen-fixing symbionts do not stimulate human monocytes and can significantly inhibit LPS-dependent TNF secretion by these cells. Due to its inherent variations in fatty acid acylation patterns, purified R. sin-1 lipid A cannot be developed as a therapeutic agent for Gram-negative septicemia. Furthermore, the microheterogeneity of rhizobial lipid A limits the identification of specific structural features that make it an antagonist rather than an agonist. To address this problem, we are developing flexible approaches for the facile synthesis of a wide range of well-defined lipid A derivatives based on the structure of R. sin-1 LPS. The potential of the synthetic compounds to inhibit cytokine production induced by E. coli LPS is being studied in cell culture.
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