The purpose of this bridging grant is to generate a complete register of all the signaling molecules associated with Toll-like receptors (TLRs) before and after stimulation with ligands, and a full description of the downstream signaling complexes that form within the cytoplasm of the activated cell. Only with a complete understanding of the molecular switching mechanisms controlling inflammatory signaling can we intelligently identify molecules that may control susceptibility to disease or prove to be important candidates for therapeutic intervention. Ongoing projects supported in the lab include the analysis of Toll-like receptors domains that mediate signal activation and association with known signaling molecules such as MyD88 and IRAK. While the importance of these molecules in macrophage activation by pathogens is clear, it is also clear that we have not yet identified many more equally important proteins that function in signaling initiated by TLRs. Present constraints on project definition and scope require individual laboratories to study TLR signaling by standard incremental hypothesis-driven approaches, while the resources and collaborative environment of the GLUE consortium make the full, unbiased analysis of the TLR-initiated signaling cascade possible. By identifying the full set of proteins that mediate LPS-induced (TLR4-mediated) signaling in macrophages, and mapping the organization structure of these components, we will produce a novel foundation for further studies on the regulation of inflammatory responses during sepsis.
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