Thesis Format
Monograph
Degree
Master of Science
Program
Pathology and Laboratory Medicine
Supervisor
Asfaha, Samuel
Abstract
Patients with prolonged ulcerative colitis (UC) exposure are 20% more likely to develop colorectal cancer (CRC). Tuft cells, a rare epithelial cell type within the intestinal crypt, may be the origin of colitis-associated cancer (CAC). Furthermore, myeloid cells have been shown to impact CAC initiation. Currently, there are no models that enable the simultaneous study of intestinal tuft cells and myeloid cells. Therefore, we generated a new transgenic mouse model 5-LO-GFP-DTR-CreERT2, wherein tuft cells and bone marrow cells are marked by 5-lipoxygenase (5-LO) expression. At baseline, immunofluorescent staining of the colon, small intestine, and bone marrow show frequent transgene expression with up to 7 GFP+ cells/100 crypts, 3 GFP+ cells/100 crypts, and 30% of total bone marrow cells, respectively. During colitis, there is a loss of 5-LO+ tuft cells. In highly inflamed regions of colitis, 5-LO+ immune cells can infiltrate the colonic stroma. In rare occurrences, APC mutant 5-LO+ cells can give rise to CAC adenomas. Overall, the 5-GDC model is a complex model that can be used to gain insight into the specific role of myeloid cells and intestinal tuft cells in colitis and CAC.
Summary for Lay Audience
Patients with long-term exposure to ulcerative colitis (UC) face a 20% higher risk of developing colorectal cancer (CRC). Understanding the origins and mechanisms of how colitis-associated cancer (CAC) occurs can help us develop new therapies. Recent research suggests that tuft cells, a rare type of cell in the gut, could be the source of CAC. In my study, I used a mouse model with modified genetics that enables us to study tuft cells, which are marked by the expression of 5-lipoxygenase (5-LO). In the context of CAC, we discovered that deletion of the gene, APC, in 5-LO expressing tuft cells, followed by acute colitis, can result in tuft cell-derived tumor formation. By establishing this mouse model, I laid the groundwork for future experiments on CRC. With this model, further studies will be conducted to unravel the mechanisms behind how tuft cells contribute to the formation of tumors.
Recommended Citation
Mani Murugan, Venkat Vaibhav, "The role of 5-lipooxygenase expressing cells in homeostasis, injury, and colitis-associated cancer" (2024). Electronic Thesis and Dissertation Repository. 10150.
https://ir.lib.uwo.ca/etd/10150