Novel Therapeutic Approaches for Inflammatory Bowel disease

• Author / Creator

  Fiteih,Yahya M

• 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.

• Subjects / Keywords

  • IBD

• Graduation date

  Fall 2014

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R34H4S

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.