The long term goal for our research is to understand bacterial lipopolysaccharide (LPS) action at the molecular level. We will focus our efforts on models that should help us understand how LPS induces cellular injury during endotoxemia resulting from gram-negative bacillary infections. We hypothesize that a significant contribution to the initial host response to LPS is described by three sequential events; FIRST, the formation of a complex between LPS and a plasma protein we discovered, characterized and named LPS-binding protein (LBP). SECOND, the binding of LPS-LBP complexes to monocytes/macrophages via a unique plasma membrane receptor we have identified as CD14. THIRD, stimulation of macrophages by LPS to rapidly release mediators such as TNF. To test this hypothesis we will prepare monoclonal antibodies to LBP and CD14 for initial use in two types of in vitro experiments; (i). to investigate their ability to block binding of LPS to LBP and of LPS-LBP to CD14 on macrophages, (ii). to identify the structures of LBP involved in LPS binding and binding of LPS-LBP complexes to CD14. This latter approach will provide the requisite data for design of polypeptides to be tested as inhibitors of LPS/LBP/CD14 interactions. To further test our hypothesis we will use a rabbit model of endotoxic shock that approximates pathophysiologic changes in man during endotoxemia to test whether antibodies and/or polypeptides shown to inhibit LPS/LBP/CD14 interactions in vitro will modify LPS-induced release of TNF, DIC and lethality. Implicit in these studies is the potential for development of new therapeutic modalities to intervene in endotoxemia in man.
| da Silva Correia, J; Miranda, Y; Leonard, N et al. (2007) Regulation of Nod1-mediated signaling pathways. Cell Death Differ 14:830-9 |
| da Silva Correia, Jean; Miranda, Yvonne; Leonard, Nikki et al. (2007) The subunit CSN6 of the COP9 signalosome is cleaved during apoptosis. J Biol Chem 282:12557-65 |
| da Silva Correia, Jean; Miranda, Yvonne; Leonard, Nikki et al. (2007) SGT1 is essential for Nod1 activation. Proc Natl Acad Sci U S A 104:6764-9 |
| da Silva Correia, Jean; Miranda, Yvonne; Austin-Brown, Nikki et al. (2006) Nod1-dependent control of tumor growth. Proc Natl Acad Sci U S A 103:1840-5 |
| Pan, Qilin; Kravchenko, Vladimir; Katz, Alex et al. (2006) NF-kappa B-inducing kinase regulates selected gene expression in the Nod2 signaling pathway. Infect Immun 74:2121-7 |
| Han, Jiahuai; Ulevitch, Richard J (2005) Limiting inflammatory responses during activation of innate immunity. Nat Immunol 6:1198-205 |
| Chuang, Tsung-Hsien; Ulevitch, Richard J (2004) Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors. Nat Immunol 5:495-502 |
| Ulevitch, Richard J (2003) Regulation of receptor-dependent activation of the innate immune response. J Infect Dis 187 Suppl 2:S351-5 |
| da Silva Correia, Jean; Ulevitch, Richard J (2002) MD-2 and TLR4 N-linked glycosylations are important for a functional lipopolysaccharide receptor. J Biol Chem 277:1845-54 |
| Sanna, M Germana; da Silva Correia, Jean; Luo, Ying et al. (2002) ILPIP, a novel anti-apoptotic protein that enhances XIAP-mediated activation of JNK1 and protection against apoptosis. J Biol Chem 277:30454-62 |
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