Bacterial endotoxin (LPS) stimulates a variety of cell types to release mediators that cause septic shock. Remarkable progress has been made in identifying the most important of these mediators and their sequence of release during septic shock or experimental models of sepsis/ endotoxemia. However, until recently, wide gaps in our knowledge existed regarding the identity of receptors and signalling pathways used by LPS. The discovery that LPS, when complexed to the plasma protein, LPS binding protein (LBP), binds to membrane bound CD14 (mCD14) and that a consequence of this interaction is cell activation, has provided an entirely new basis for determining how LPS stimulates cells. The long range goal of this proposal to understand LPS action at the molecular level so that new treatments for septic shock can be developed. Studies conducted by the applicant have led to the hypothesis that CD14 can serve s a ligand binding subunit of a multimeric LPS receptor and enables rapid intracellular uptake of LPS. The applicant will now utilize biochemical, immunologic or expression cloning approaches to identify additional proteins of the LPS receptor that interact with LPS uptake into cells via CD14 dependent pathways using transfected cell lines expressing GPI anchored or integral membrane forms CD14.
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