The role of RASSF1A in the regulation of NOD2/RIPK2 Pathogen Recognition Pathway

  • Author / Creator
    Said, Ahmed
  • Inflammatory bowel disease (IBD) is a chronic relapsing and remitting disease of the gastrointestinal tract. There are several risk factors involved in IBD pathogenesis which are environmental, microbial and genetic factors. More than 200 susceptible genes are linked to IBD and many are involved in the innate immune response towards intestinal microbes. Three of these susceptible genes are: 1) nucleotide-binding oligomerization domain-containing protein 2 (NOD2); 2) Autophagy Related 16-Like 1 (ATG16L1) and 3) Ras association domain family one isoform A (RASSF1A). RASSF1A is a tumor suppressor protein epigenetically silenced in colorectal cancer and diseases with robust inflammation such as IBD. In a recently published manuscript, we have demonstrated the importance of RASSF1A in modulating the activation of the pathogen receptor, TLR, such that it interferes with NFκB-directed inflammation. Utilizing the dextran sodium sulfate (DSS) model of acute colitis, we demonstrated enhanced inflammation and poor recovery from DSS-induced inflammation injury in DSS-treated Rassf1a-/- mice. These mice had most of the symptoms of human ulcerative colitis. Thus, the Rassf1a-/- genetic knockout model will aid in understanding the molecular drivers of colitis and in the design of new therapeutics to treat IBD. Our hypothesis is that RASSF1A can also restrict the NOD2/RIPK2 pathogen recognition pathway by restricting how RIPK2 and NOD2 associate thus interfering with NFκB and autophagic activation. Using Rassf1a-/- single and the Rassf1a-/-Nod2-/- double knockout mice we observed that NOD2 is responsible of inducing inflammation in these mice. RASSF1A physical associates with NOD2 and regulates RIPK2 and ATG16L1 which are the downstream signalling pathway for NOD2. The use of autophagy inhibitors and RIPK2 inhibitor-1 effectively induced recovery from DSS-induced inflammation injury in both the Rassf1a-/- mice and in the il10-/- mice. RIPK2 may be novel therapeutic approaches to enhance recovery from injury caused by induced inflammation and they would be useful in treating and protecting IBD patients from increased risk of cancer later in life.

  • Subjects / Keywords
  • Graduation date
    Spring 2018
  • Type of Item
  • Degree
    Master of Science
  • DOI
  • 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.