A specific focus of the studies planned will be to define the role of lipid raft membrane microdomains in transduction of the LPS signal in human leukocytes. Lipid rafts are cholesterol-rich microdomains in the plasma membrane, within which the LPS receptor, Toll-like Receptor 4 (TLR4), has been described to reside. LPS signaling has been reported to be sensitive to raft cholesterol content, presumably because the specific repertoire of proteins in rafts is sensitive to raft cholesterol content. Rafts are thought to act as dynamic signaling platforms for co-segregation of proximal adaptor proteins, kinases, and other signaling proteins. Of interest, while LPS has been described to modulate the activity of proteins that determine raft cholesterol content (eg, Liver X Receptor, ABCA1), virtually no work has been done to clarify: 1) the mechanisms underlying LPS-induced intracellular cholesterol redistribution, and, more importantly, 2) whether such intracellular redistribution of cholesterol is causal to the signaling events triggered by LPS, or 3) whether innate immunity signaling is dependent upon inter-subject variations in raft cholesterol content.