Septic shock is the major cause of morbidity and mortality among the patients receiving an intensive regimen of chemo-radiotherapy. The majority of septic shock is caused by gram-negative bacteria, and gram- negative lipopolysaccharide (LPS) has been shown to be responsible for most of the host responses. Our laboratory showed that the glycoprotein CD 14 initiates these cellular responses by recognizing LPS and that lipopolysaccharide binding protein (LBP enhances responses to LPS by catalyzing binding of LPS to CD 14. Candidate has isolated a plasma protein factor that mediates responses of human PMN to endotoxin in a CD 14-dependent fashion. Preliminary studies showed that this factor is a novel lipoprotein particle containing facto? H related proteins (FHRPs), as well as apolipoprotein A-I, LBP and other species. FHRPs are abundant plasma proteins with unknown function but with homology to serum complement factor H. Additional study showed that polyclonal and monoclonal antibodies against FHRPs blocked the ability of plasma to mediate responses of neutrophils to LPS. Candidate proposes to confirm these findings and to characterize further this novel lipoprotein particle that mediates cellular responses to LPS. These studies will purify the particles to homogeneity and analyze their lipid composition. We will identify all the protein components of the particle by sequence analysis and immunological means, and study the function of individual proteins in mediating responses to LPS using antibodies raised against individual proteins. If a novel protein is identified, candidate will try to clone the cDNA and to prepare the recombinant protein as time permits. These studies will characterize a novel lipoprotein that may regulate host responses to LPS. Furthermore, they may provide new approaches for early detection and control of gram- negative septic shock.
| Park, C T; Wright, S D (2000) Fibrinogen is a component of a novel lipoprotein particle: factor H-related protein (FHRP)-associated lipoprotein particle (FALP). Blood 95:198-204 |
| Park, C T; Creasey, A A; Wright, S D (1997) Tissue factor pathway inhibitor blocks cellular effects of endotoxin by binding to endotoxin and interfering with transfer to CD14. Blood 89:4268-74 |
| Park, C T; Wright, S D (1996) Plasma lipopolysaccharide-binding protein is found associated with a particle containing apolipoprotein A-I, phospholipid, and factor H-related proteins. J Biol Chem 271:18054-60 |
