Targeting IL-33 to treat Crohn’s Disease-associated fibrosis
department or school: Medicine, Department of
department or school: Obstetrics and Gynaecology, Department of
data provider: DSpace
degree campus: UBCV
creator: Sekhon, Prabhreet
issued: 2025-01-13T18:02:24Z
issued: 2024
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: Crohn’s disease (CD) is one form of inflammatory bowel disease (IBD) in which inflammation penetrates all gut layers, and occurs discontinuously anywhere from the lips to the anus. One in 3 people with CD will develop a life-threatening complication called fibrosis. Fibrosis is driven by excessive deposition of extracellular matrix components and thickening of the bowel wall due to fibroblast activation and smooth muscle cell hyperplasia, respectively. There are currently no therapies to directly treat intestinal fibrosis, and surgery is the only available intervention. The Sly laboratory has previously characterized the src homology 2 (SH2) domain-containing inositol polyphosphate 5′-phosphatase deficient (SHIP-/-) mouse model of CD-like intestinal inflammation and fibrosis. They have shown a critical role of phosphatidylinositol 3-kinase (PI3K) p110δ-mediated upregulation of arginase I (ArgI) in intestinal fibrosis. ArgI is an enzyme that uses L-arginine to produce L-ornithine, which ultimately gets broken down into precursors used for collagen biosynthesis and cell proliferation. Previous studies have implicated a pro-fibrotic role of interleukin (IL)-33 by promoting ArgI expression in the context of lung fibrosis. Based on this, I hypothesized that IL-33 promotes fibrosis in the SHIP-/- model of CD by inducing ArgI activity. I found that IL-33 concentrations and relative gene expression were higher in the fibrotic sections of SHIP-/- mice compared to SHIP+/+ controls, specifically the 30 kDa isoform. IL-33 may synergize with IL-13 to induce ArgI expression and activity in SHIP-/- bone marrow derived macrophages (BMDMs). IL-33 neutralization and genetic ablation in vivo reduced mean ArgI activity in SHIP-/- non-fibrotic and fibrotic sections, however, did not improve disease. Because high IL-1β concentrations persisted upon IL-33 neutralization and genetic ablation in SHIP deficiency, I speculate that targeting both the pro- and anti-inflammatory responses are re…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/90107
note: Targeting IL-33 to treat Crohn’s Disease-associated fibrosis by Prabhreet Sekhon BSc., The University of British Columbia, 2020 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Women+ and Children’s Health Sciences) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) December 2024 © Prabhreet Sekhon, 2024 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the thesis entitled: Targeting IL-33 to treat Crohn’s Disease-associated fibrosis submitted by Prabhreet Sekhon in partial fulfilment of the requirements for the degree of Master of Science in Women+ and Children’s Health Sciences Examining Committee: Dr. Laura Sly, Professor, Department of Pediatrics, UBC Supervisor Dr. Kelly Brown, Associate Professor, Department of Pediatrics, UBC Supervisory Committee Member Dr. Alice Mui, Associate Professor, Departments of Surgery and Biochemistry & Molecular Biology, UBC Additional Examiner Additional Supervisory Committee Members: Dr. Wilfred Jefferies, Professor, Department of Medical Genetics, UBC Supervisory Committee Member iii Abstract Crohn’s disease (CD) is one form of inflammatory bowel disease (IBD) in which inflammation penetrates all gut layers, and occurs discontinuously anywhere from the lips to the anus. One in 3 people with CD will develop a life-threatening complication called fibrosis. Fibrosis is driven by excessive deposition of extracellular matrix components and thickening of the bowel wall due to fibroblast activation and smooth muscle cell hyperplasia, respectively. There are currently no therapies to directly treat intestinal fibrosis, and surgery is the only available intervention. The Sly laboratory has previously characterized the src homology 2 (SH2) domain-containing inositol polyphosphate 5′-phosphatase deficient (SHIP-/-) mouse model of CD-like intestinal inflam…
has type: Thesis/Dissertation
date issued: 2025-05
is shown at: 10.14288/1.0447742
language: eng
degree discipline: Women+ and Children’s Health Sciences
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Sly, Laura
type: Text
identifier URI: http://hdl.handle.net/2429/90107