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Novel Therapeutic Approaches for Inflammatory Bowel disease Open Access


Other title
Type of item
Degree grantor
University of Alberta
Author or creator
Fiteih,Yahya M
Supervisor and department
Baksh, Shairaz (Paediatrics)
Examining committee member and department
Huynh, Hien (Paediatrics)
Velazquez, Carlos (Pharmacy)
Madsen, Karen (Medicine)
Medical Sciences-Paediatrics

Date accepted
Graduation date
Master of Science
Degree level
Inflammatory bowel disease (IBD) is chronic relapsing and remitting inflammation of the gastrointestinal tract resulting in abdominal pain, diarrhoea and weight loss. The two major types of IBD are Crohn’s disease (CD) and ulcerative colitis (UC). Genetic analysis has implicated several genomic regions containing IBD susceptibility genes including genes on 3p21 such as macrophage stimulating1 gene (MST1) and Ras-association domain family member 1A gene (RASSF1A or 1A). In this thesis project, we explored the molecular mechanisms by which the loss of RASSF1A can modulate the appearance of IBD in a rodent model. It has been established that RASSF1A is frequently epigenetically silenced by promoter specific methylation in numerous cancers (including colorectal cancer) and in IBD (specifically in ulcerative colitis patients), suggesting its importance for both. The genetic loss of 1A in our Rassf1a-/- and Rassf1a+/- mice resulted in clinical symptoms of colitis including increased intestinal permeability, increased DNA and oxidative damage enhanced cytokine/chemokine production, elevated NF-κB activity, severe colonic epithelial cell injury and poor recovery following dextran sulphate sodium (DSS)-induced inflammation injury, suggesting importance of RASSF1A and haploinsufficiency in the Rassf1a locus for DSS inflammation injury. DSS is a chemical inducer of colitis in mice and a potent activator of innate immunity. The absence of Rassf1a also resulted in decreased epithelial repair with reduction of several markers of proliferation including Yes-associated protein (YAP)-driven proliferation, an important proliferation regulator within the Hippo pathway. Surprisingly, tyrosine phosphorylation of YAP appeared versus serine phosphorylation in the absence of Rassf1a that resulted in enhanced p73 transcriptional upregulation of pro-apoptotoic genes including Bax. These aforementioned events resulted in increased epithelial cell death and poor survival of DSS-treated mice in the absence of RASSF1A. More importantly to the aims of this thesis, the genetic loss of Rassf1a also resulted in increased autophagic signalling linked to the NOD2 pathway. The use of PTK inhibitors and autophagy inhibitors effectively increased recovery from DSS-induced inflammation injury in both the Rassf1a-/- mice and in the IL-10-/- mice. In this thesis, I have demonstrated that tyrosine kinase inhibitors and anti-autophagy drugs may be novel therapeutic approaches to enhance recovery from inflammation-induced injury and be useful to treat and protect IBD patients from increased risk of developing cancer later in life.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Gordon, M., et al., The tumor suppressor gene, RASSF1A, is essential for protection against inflammation -induced injury. PLoS One, 2013. 8(10): p. e75483.

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