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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Synthesis of Lewis X Analogues and Their Use as Inhibitors in Competitive Binding Studies

Moore, Christopher 14 September 2012 (has links)
Four analogues of the Lewis X trisaccharide antigen (β-D-Galp(1→4)[α-L-Fucp(1→3)]-D-GlcNAcp) in which the galactosyl residue is modified at O-4 as a methyloxy, deoxychloro, deoxyfluoro or deoxy were synthesized. The preparation of the modified 4-OMe, 4-Cl, 4-F and 4-H trichloroacetimidate galactosyl donors is described as well as their use in the glycosylation of an N-acetylglucosamine glycosyl acceptor. The resulting disaccharides were deprotected at O-3 of the glucosamine residue and fucosylated giving access to the desired protected Lewis X analogues. One step global deprotection (Na/NH3) of the protected 4”-methoxy and 4”-deoxy analogues, and two step deprotections (removal of a p-methoxybenzyl with DDQ, then Zemplén deacylation) of the 4”-deoxychloro and 4”-deoxyfluoro protected Lex analogues gave the desired compounds in good yields. The relative binding energies of the 4” manipulated Lewis X methyl glycoside analogues for anti-Lewis X mAb SH1 were determined using competitive ELISA procedures. The binding experiments revealed that substitution of the 4” site with a deoxychloro, deoxyfluoro or deoxy function had a large differential change in the free energy of binding; yet they did not completely abolish cross reactivity with native Lewis X. Substitution with a methyloxy function eliminated recognition by anti-Lewis X monoclonal antibody SH1. / NSERC
2

Helicobacter pylori adhesion and patho-adaptation : the role of BabA and SabA adhesins in persistent infection and chronic inflammation

Mahdavi, Jafar January 2004 (has links)
Helicobacter pylori (H. pylori) is a human-specific gastric pathogen which is responsible for a spectrum of diseases ranging from superficial gastritis to gastric and duodenal ulceration, and which is also highly associated with gastric cancer. The pathogenesis of severe gastric disorders caused by H. pylori is multifactorial and involves complex interactions between the microbe and the gastric mucosa. H. pylori expresses several adhesion proteins. These molecules have important roles in the establishment of persistent infection and chronic inflammation, which cause tissue damage. The aim of this thesis was to study the attachment of this bacterium to human gastric epithelium, mediated by blood group antigens in both health and disease. One of the bestcharacterized H. pylori adhesins is the histo-blood group antigen binding adhesin (BabA), which binds specifically to the Lewis b antigen (Leb) in the gastric mucosa. A protective mucus layer lines the stomach. The mucosal glycosylation patterns (GPs) vary between different cell lineages, different locations along the gastrointestinal (GI) tract and different developmental stages. In addition, GPs undergo changes during malignant transformation. MUC5AC is a mucin molecule produced by the surface epithelium. Three distinctly different types of human gastrointestinal tissue were studied by bacterial adherence analysis in situ. MUC5AC is the most important carrier of Leb and the new results demonstrate that it forms major receptors for H. pylori adherence. By analysing an H. pylori babA-deletion mutant, a novel adhesin-receptor binding mode was found. Surprisingly, the mutant bound efficiently to both human gastric mucosa and to gastric mucosa of Leb transgenic mice. The sialylated and fucosylated blood group antigen, sialyl-dimeric-Lewis x (sdiLex), was structurally identified as the new receptor. A positive correlation was found between adherence of H. pylori to sialyl-Lewis x (sLex) and elevated levels of inflammation response in the human gastric mucosa. These results were supported by detailed analysis of sialylated and fucosylated blood group antigen glycosylation patterns and, in addition, in situ bacterial adherence to gastric mucosa of experimentally challenged Rhesus monkey. The cognate sialic acid-binding adhesin (SabA) was purified by the retagging technique, and the corresponding sabA-gene was identified. H. pylori lipopolysaccharide (LPS) contains various Lewis blood group antigens such as Lewis x (Lex) and Lewis y (Ley). Additional bacterial adherence modes, which are independent of the BabA and/or SabA adhesins, could possibly be mediated by Lex interactions. Adherence of a clinical isolate and its corresponding Lex mutant to human gastric mucosa with various gastric pathologies was studied in situ. The results suggest that H. pylori LPS plays a distinct but minor role in promotion of bacterial adhesion. Taken together, the results suggest mechanisms for continuous selection of H. pylori strains, involving capacity to adapt to changes in the local environment such as shifts in cell differentiation and associated glycosylation patterns. Adherence of H. pylori is dependent on both the BabA and the SabA adhesin. Multi-step dependent attachment mechanisms may direct the microbes to distinct ecological niches during persistent infections, driving the chronic inflammation processes further toward the development of peptic ulcer disease and/or malignant transformation. Key words: H. pylori, BabA, adhesin, Lewis b, MUC5AC, sialyl-dimeric-Lewis x, chronic inflammation, SabA, Lewis x, LPS.

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