자료유형  

 학위논문

Control Number  

0016934399

International Standard Book Number  

9798380274500

Dewey Decimal Classification Number  

574

Main Entry-Personal Name  

Melkonian, Arek Viken.

Publication, Distribution, etc. (Imprint  

[S.l.] : Stanford University., 2021

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2021

Physical Description  

1 online resource(108 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 85-03, Section: A.

General Note  

Advisor: Khosla, Chaitan.

Dissertation Note  

Thesis (Ph.D.)--Stanford University, 2021.

Restrictions on Access Note  

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

Summary, Etc.  

요약Coeliac disease (CeD) is an inflammatory autoimmune disease triggered by the ingestion of gluten that classically presents with abdominal pain, malabsorption, and diarrhea. Virtually all coeliac patients carry human leukocyte antigen (HLA) DQ2 or DQ8 alleles; gluten peptides bind to HLA-DQ2 or HLA-DQ8, and in coeliac patients, this event results in a T-cell response. Gluten peptides contain many glutamine residues which are deamidated in the small intestine by the ubiquitous protein transglutaminase 2 (TG2), and while native gluten peptides are antigenic to coeliac patients, deamidated gluten peptides are considerably more antigenic. However, TG2 is normally inactive in this environment. Being an abundant protein, TG2 possesses an intricate set of allosteric regulatory mechanisms that governs its activity in its many environments. Careful study of TG2 allosteric regulation is integral for a more complete understanding of CeD pathogenesis, and can thus inform the development of more effective therapies or a cure. Additionally, CeD serves as a model autoimmune disease for our study of other autoimmune diseases, as its disease state can be induced with the introduction of an exogenous protein.This work outlines the allosteric mechanisms of TG2 and their implications for CeD. In Chapter 1, I present a brief treatise on TG2 activity, regulation, and function, and discuss the role of TG2 in the pathogenesis of CeD. In Chapter 2, I present the kinetics of a new model of TG2 activity with various substrates in response to its allosteric activator, calcium. In Chapter 3, I present the discovery of an unusual "OR" gate that governs the fate of TG2's activity state; this phenomenon involves direct competition between two allosteric regulators of TG2: calcium binding and oxidative inactivation. In Chapter 4, I present the role of protein-protein interactions in the regulation of TG2 activity through the lens of a curious homozygous TG2 mutation found in humans. In Chapter 5, I present a protocol for the detection of redox-regulated TG2 activity in vivo; my colleagues and I formalized the protocol based on procedures we developed in our laboratory and have used to publish a number of peer-reviewed works.Overall, this corpus seeks to elucidate some of the crucial regulatory mechanisms that link TG2 chemistry to TG2 biology. There is still a significant amount of work needed to fully understand the role and regulation of TG2 in the context of CeD (and many other disease states for that matter), but I hope that I am able to inform future researchers on some of the intricacies and peculiarities of TG2.

Subject Added Entry-Topical Term  

Molecular biology.

Subject Added Entry-Topical Term  

Biochemistry.

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Biosynthesis.

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Immunology.

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Chemistry.

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Colleges & universities.

Subject Added Entry-Topical Term  

Lipids.

Subject Added Entry-Topical Term  

Celiac disease.

Subject Added Entry-Topical Term  

Plasmids.

Subject Added Entry-Topical Term  

Mass spectrometry.

Subject Added Entry-Topical Term  

Medicine.

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Materials science.

Subject Added Entry-Topical Term  

Antigen presentation.

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Cloning.

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Chemical engineering.

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Hydrogels.

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Analytical chemistry.

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Biology.

Subject Added Entry-Topical Term  

Higher education.

Added Entry-Corporate Name  

Stanford University.

Host Item Entry  

Dissertations Abstracts International. 85-03A.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

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Control Number  

joongbu:642059