Granzyme B : a novel therapeutic target for radiation dermatitis
department or school: Medicine, Faculty of
department or school: Pathology and Laboratory Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Pawluk, Megan
issued: 2023-06-28T08:05:22Z
issued: 2023
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: Radiation dermatitis (RD) is observed in up to 90% of patients receiving radiation therapy. Symptoms of RD include redness, scaling, and crusted wounds. Severe symptoms can prevent future radiation treatments. Current treatments are not effective and may cause severe side effects. Granzyme B (GzmB) was originally characterized as a serine protease secreted by cytotoxic lymphocytes to promote target cell apoptosis. It is now recognized that GzmB can be secreted by other immune cell and non-immune cell populations. GzmB is elevated in a number of inflammatory skin disorders, such as atopic dermatitis, autoimmune blistering, impaired wound healing and scarring. Previous studies suggest that extracellular GzmB cleaves E-cadherin, filaggrin, and decorin leading to reduced epithelial barrier function and scarring. Based on these findings, I hypothesized that GzmB contributes to increased RD severity and delayed healing through the cleavage of epithelial barrier proteins and/or matrix proteins. GzmB expression and cell source, E-cadherin, filaggrin, and decorin levels were assessed using immunohistochemical analysis of biopsies from RD patients. The role of GzmB was investigated in an established RD murine model, comparing GzmB knockout (GzmB-/-) to wild type (WT) mice. The dorsal skin was exposed to a single 40 gray dose of radiation. RD severity was blindly scored. Tissues were harvested at days 4, 14, and 46 post-radiation exposure. Tissues were examined for GzmB, immune cell infiltrate, scarring, and decorin. Macrophages and mast cells expressed GzmB while E-cadherin, filaggrin, and decorin were reduced in human RD skin compared to healthy skin. GzmB-/- mice exhibited a decrease in RD severity compared to WT mice from day 4 to day 12. CD3+ T-cell levels were reduced and neutrophil infiltration was observed at day 14. GzmB was expressed by resident mast cells in WT mice. GzmB-/- mice exhibited less scar area and more decorin than WT mice at day 46. In summary, GzmB may …
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/85165
note: GRANZYME B: A NOVEL THERAPEUTIC TARGET FOR RADIATION DERMATITIS by Megan Pawluk B.Sc., The University of Victoria, 2020 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Pathology and Laboratory Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) June 2023 © Megan Pawluk, 2023 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the thesis entitled: Granzyme B: A Novel Therapeutic Target For Radiation Dermatitis submitted by Megan Pawluk in partial fulfilment of the requirements for the degree of Master of Science in Pathology and Laboratory Medicine Examining Committee: Dr. David Granville, Professor, Pathology and Laboratory Medicine, UBC Supervisor Dr. Tillie Hackett, Professor, Anesthesiology, Pharmacology and Therapeutics, UBC Supervisory Committee Member Dr. Christopher Carlsten, Professor, Medicine, UBC Additional Examiner Dr. Honglin Luo, Professor, Pathology and Laboratory Medicine, UBC Additional Examiner Additional Supervisory Committee Members: Dr. Kevin Bennewith, Professor, Pathology and Laboratory Medicine, UBC Supervisory Committee Member iii Abstract Radiation dermatitis (RD) is observed in up to 90% of patients receiving radiation therapy. Symptoms of RD include redness, scaling, and crusted wounds. Severe symptoms can prevent future radiation treatments. Current treatments are not effective and may cause severe side effects. Granzyme B (GzmB) was originally characterized as a serine protease secreted by cytotoxic lymphocytes to promote target cell apoptosis. It is now recognized that GzmB can be secreted by other immune cell and non-immune cell populations. GzmB is elevated in a number of inflammatory skin disorders, such as atopic dermatitis, autoimmune blistering, impaired wound healing and scarring. Previous studies suggest that extracellular GzmB cleaves…
has type: Thesis/Dissertation
date issued: 2023-11
is shown at: 10.14288/1.0433753
language: eng
degree discipline: Pathology and Laboratory Medicine
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: Granville, David James
type: Text
identifier URI: http://hdl.handle.net/2429/85165