Part 1, development towards a potential anti-pertussis glycoconjugate vaccine. Part 2, binding and mitigation of cytotoxicity of amyloid beta and tau oligomers by heparin
Despite massive vaccination, the world has been experiencing a resurgence of pertussis, a highly contagious respiratory disease. Current acellular vaccines lack sufficient bactericidal activity and there is an urgent need of better vaccines aiming at clearing the pathogen, Bordetella pertussis. Oligosaccharide on the surface of the bacteria has been proven to be a promising protective antigen that elicits antibody-mediated complement-dependent cytotoxicity against Bordetella pertussis. However, obtaining the saccharide on a large scale with high purify remains one of the main obstacles. Herein, we report the first total synthesis of a pentasaccharide antigenic determinant from Bordetella pertussis. Immunization of mice with a conjugate of the pentasaccharide with a carrier protein, bacteriophage Qβ, elicited high titers of IgG antibodies. An IgG subclass study showed that it induced Th1-weighted immune response. The antibodies were able to bind Bordetella pertussis in flow cytometry and induced complement-dependent cytotoxicity. Further study will be focused on the epitope mapping on the pentasaccharide and optimization of the antigen structure.Accumulation of amyloid β in the brain is believed to play a key role in the pathology of Alzheimer’s disease and it is one of the most important biomarkers in the early diagnosis of AD. Glycosaminoglycans have been found to participate in the process of Aβ aggregation. Herein, we report the study on the interaction between Aβ and superparamagnetic iron oxide nanoparticles coated with heparin, a member of the GAG family. The interaction between Aβ and nanoparticle was studied through enzyme-linked immunosorbent assay, gel electrophoresis and thioflavin T assay. Furthermore, the nanoparticle showed no toxicity against neurons and effectively protected neurons from Aβ, which made it a potential tool in the detection of Aβ in vivo.Neurofibrillary tangles formed by intracellular aggregation of tau proteins are another important hallmark of Alzheimer’s disease. However, recent studies have suggested that tau oligomers, rather than neurofibrillary tangles, are playing a key role in the progression of the disease. Glycosaminoglycans can mediate the intercellular propagation of tau proteins. Herein, we report the synthesis of heparin-like oligosaccharides with different lengths and sulfation patterns. Binding assays with tau oligomers revealed that longer backbones and higher sulfation degrees resulted in stronger binding affinity. The oligosaccharides promoted aggregation of tau oligomers and effectively protected SH-SY5Y cells against tau oligomers.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- In Copyright
- Material Type
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Theses
- Thesis Advisors
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Huang, Xuefei
- Committee Members
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Walker, Kevin D.
Wulff, William D.
Kaminski, Norbert E.
- Date Published
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2018
- Program of Study
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Chemistry - Doctor of Philosophy
- Degree Level
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Doctoral
- Language
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English
- Pages
- xxxiv, 334 pages
- ISBN
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9780355922578
0355922576
- Permalink
- https://doi.org/doi:10.25335/0q97-xw48