자료유형  

 학위논문

Control Number  

0016931983

International Standard Book Number  

9798379652883

Dewey Decimal Classification Number  

612

Main Entry-Personal Name  

Shon, Dayeon Judy.

Publication, Distribution, etc. (Imprint  

[S.l.] : Stanford University., 2023

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2023

Physical Description  

1 online resource(162 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 84-12, Section: A.

General Note  

Advisor: Barnes, Christopher O.;Cui, Bianxiao;Bertozzi, Carolyn.

Dissertation Note  

Thesis (Ph.D.)--Stanford University, 2023.

Restrictions on Access Note  

This item must not be sold to any third party vendors.

Summary, Etc.  

요약Every cell in the human body harbors a dense outer layer of carbohydrates, or glycans, that serves as an interface for cell surface communication. This peripheral structure, known as the glycocalyx, influences cell-cell and cell-matrix interactions through a dense network of glycoproteins, glycolipids, and proteoglycans. These glycans are essential for a wide range of physiological processes, and defects in glycosylation often contribute to human disease. In this work, we focus on mucins, which carry densely O-glycosylated domains found in many cell surface and secreted proteins. As introduced in Chapter 1, alterations in mucin expression and glycosylation are common in a variety of diseases such as cancer and cystic fibrosis. These correlations have motivated efforts towards the therapeutic targeting of disease-associated mucins and their aberrant glycoforms. However, the precise contexts in which mucins and their glycans contribute to disease progression remain unclear, due to difficulties associated with their detection and a lack of tools that specifically probe mucin domains. In Chapter 2, we address this limitation by characterizing a panel of bacterial proteases that cleave mucin domains via distinct peptide- and glycan-based motifs, generating a diverse enzymatic toolkit for mucin-selective proteolysis. We further develop catalytically inactive mutants and demonstrate robust detection of mucin-domain glycoproteins by flow cytometry, Western blot, and immunohistochemistry, enabling a new depth in the analysis of mucins on cells and patient tissues. In Chapter 3, we characterize a mucin-selective metalloprotease from Akkermansia muciniphila via X-ray crystallography and molecular modeling to gain insight into the structural determinants of O-glycan recognition. Finally, in Chapter 4, we develop a targeted degradation strategy to selectively remove cancer-associated mucins by fusing an engineered mucin-selective protease to a cancer antigen-binding nanobody. We show that these targeted proteases reduce cancer cell viability in vitro and blunt primary tumor burden and metastatic outgrowth in murine breast cancer models. As nearly all extracellular proteins are glycosylated and glycosylation status is commonly altered in disease, glycoform-dependent and cell type-selective targeted protein degradation presents a general opportunity for increasing on-target specificity for disease-driving extracellular proteins.

Subject Added Entry-Topical Term  

Physiology.

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Glycoproteins.

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Metastasis.

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Disease.

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Families & family life.

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E coli.

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Flow cytometry.

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Lipids.

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Visualization.

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Breast cancer.

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Ovarian cancer.

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Patients.

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Mass spectrometry.

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Cloning.

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Medical research.

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Engineering.

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Surveillance.

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Enzymes.

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Polypeptides.

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Crystallography.

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Interfaces.

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Analytical chemistry.

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Cellular biology.

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Chemistry.

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Individual & family studies.

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Medicine.

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Oncology.

Added Entry-Corporate Name  

Stanford University.

Host Item Entry  

Dissertations Abstracts International. 84-12A.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

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Control Number  

joongbu:640674