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  • Therapeutic Targeting of Endoplasmic Reticulum Stress in Inflammatory Bowel Disease

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    Das_2012_02Thesis.pdf (20.21Mb)
    Author(s)
    Das, Indrajit
    Primary Supervisor
    Crane, Denis
    Other Supervisors
    McGuckin, Michael
    Florin, Timothy
    Eri, Rajaraman
    Year published
    2012
    Metadata
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    Abstract
    Endoplasmic reticulum (ER) stress occurs when proteins misfold during biosynthesis in the ER. ER stress in intestinal secretory cells has been implicated in the aetiology of inflammatory bowel diseases (IBD) and intestinal inflammation in mice. Intestinal secretory cells are susceptible to ER stress due to high rates of protein synthesis, and ER stress in these cells results in reduced production of cell surface and secreted proteins leading to thinner mucus with a lower anti-microbial content, allowing penetration by luminal microbes, leading to inflammation. Cells experiencing ER stress attempt to restore homeostasis via ...
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    Endoplasmic reticulum (ER) stress occurs when proteins misfold during biosynthesis in the ER. ER stress in intestinal secretory cells has been implicated in the aetiology of inflammatory bowel diseases (IBD) and intestinal inflammation in mice. Intestinal secretory cells are susceptible to ER stress due to high rates of protein synthesis, and ER stress in these cells results in reduced production of cell surface and secreted proteins leading to thinner mucus with a lower anti-microbial content, allowing penetration by luminal microbes, leading to inflammation. Cells experiencing ER stress attempt to restore homeostasis via the unfolded protein response (UPR), which enables the cells to increase the protein folding capacity of the ER. The primary focus of this thesis is to examine whether the drugs that are efficacious in IBD treatment modulate goblet cell function and ER homeostasis, and whether drugs that modulate ER stress can suppress intestinal inflammation and restore intestinal homeostasis. In order to explore the ER stress-inflammation nexus I utilized well established IBD anti-inflammatory agents, 5-Aminosalicylate (5-ASA), 6-thioguanine (6-TG), the anti-TNF antibody, infliximab, and the glucocorticoid dexamethasone (DEX). Chemical chaperones (TUDCA and sodium 4-PBA) and UPR modulators (guanabenz, salubrinal and 4μ8C) were used to investigate how modulation of ER stress affects goblet cell function and intestinal inflammation. In vivo studies were carried out in Winnie mice, which have ER stress in goblet cells due to a Muc2 misfolding mutation resulting in colitis involving both innate and adaptive immunity. To understand the direct effect of these drugs on ER stress in goblet cells in the absence of confounding inflammatory factors, in vitro experiments were performed using the human colonic adenocarcinoma LS174T cell line, a cell line containing cells with goblet cell differentiation, where ER stress was induced either by inhibition of N-glycosylation by tunicamycin or by depletion of Ca2+ by thapsigargin.
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    Thesis Type
    Thesis (PhD Doctorate)
    Degree Program
    Doctor of Philosophy (PhD)
    School
    School of Biomolecular and Physical Sciences
    DOI
    https://doi.org/10.25904/1912/2904
    Copyright Statement
    The author owns the copyright in this thesis, unless stated otherwise.
    Item Access Status
    Public
    Subject
    Endoplasmic reticulum stress
    Inflammatory bowel diseases
    Chemical chaperones
    Anti-inflammatory agents
    Publication URI
    http://hdl.handle.net/10072/365999
    Collection
    • Theses - Higher Degree by Research

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