Abstract

This is a proposal to further examine the biochemistry, cell biology and pathogenesis of lipopolysaccharide binding protein (LBP) Dr. Tobias' thesis is that LBP assists in the clearance and detoxification of LPS and other microbial products. The following specific aims are listed.
Specific Aim 1 : to characterize the mechanism by which LBP enhances cellular uptake of LPS. This will be done by determining which pathways and molecules mediate cellular internalization of LPS.
Specific Aim 2 : to reinvestigate the role of LPB in the association of LPS with lipoproteins in normal and acute phase sera. This will be done by identifying and quantitating the interactions of LPS with the proteins of normal and LBP deficient sera and by studying the binding of LBP to normal and acute phase lipoproteins.
Specific Aim 3 : To characterize the role of LBP in clearance of LPS from the circulation of intact animals. This will be done by assessing the role of LBP in tissue and cellular targeting of LPS in normal and LBP knockout mice.
Specific Aim 4 : To establish the structural features of LBP important for formation of complexes with LPS and CD14. This will be done using LBP mutants, peptides derived from LPS, and anti-peptide antibodies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI032021-08
Application #
2886727
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Heyse, Stephen P
Project Start
1992-07-02
Project End
2002-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
8
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Thompson, Patricia A; Tobias, Peter S; Viriyakosol, Suganya et al. (2003) Lipopolysaccharide (LPS)-binding protein inhibits responses to cell-bound LPS. J Biol Chem 278:28367-71
Tapping, Richard I; Tobias, Peter S (2003) Mycobacterial lipoarabinomannan mediates physical interactions between TLR1 and TLR2 to induce signaling. J Endotoxin Res 9:264-8
Bussolati, Benedetta; David, Salvatore; Cambi, Vincenzo et al. (2002) Urinary soluble CD14 mediates human proximal tubular epithelial cell injury induced by LPS. Int J Mol Med 10:441-9
Lee, Hyun-Ku; Lee, Jongdae; Tobias, Peter S (2002) Two lipoproteins extracted from Escherichia coli K-12 LCD25 lipopolysaccharide are the major components responsible for Toll-like receptor 2-mediated signaling. J Immunol 168:4012-7
da Silva Correia, J; Soldau, K; Christen, U et al. (2001) Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex. transfer from CD14 to TLR4 and MD-2. J Biol Chem 276:21129-35
Viriyakosol, S; Tobias, P S; Kitchens, R L et al. (2001) MD-2 binds to bacterial lipopolysaccharide. J Biol Chem 276:38044-51
Tapping, R I; Tobias, P S (2000) Soluble CD14-mediated cellular responses to lipopolysaccharide. Chem Immunol 74:108-21
Haudek, S B; Natmessnig, B E; Redl, H et al. (2000) Isolation, partial characterization, and concentration in experimental sepsis of baboon lipopolysaccharide-binding protein. J Lab Clin Med 136:363-70
Tapping, R I; Akashi, S; Miyake, K et al. (2000) Toll-like receptor 4, but not toll-like receptor 2, is a signaling receptor for Escherichia and Salmonella lipopolysaccharides. J Immunol 165:5780-7
Grunfeld, C; Marshall, M; Shigenaga, J K et al. (1999) Lipoproteins inhibit macrophage activation by lipoteichoic acid. J Lipid Res 40:245-52

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