- Library Home /
- Search Collections /
- Open Collections /
- Browse Collections /
- UBC Theses and Dissertations /
- Extracellular granzyme B and pathophysiological implications
Open Collections
UBC Theses and Dissertations
UBC Theses and Dissertations
Extracellular granzyme B and pathophysiological implications Boivin, Wendy Anne
Abstract
Granzyme B (GzmB) is a serine protease that contributes to immune-mediated elimination of cells by initiating a tightly-regulated form of death known as apoptosis. However, during inflammation, GzmB leaks out and accumulates in the extracellular space, retains its activity, and proficiently cleaves extracellular matrix (ECM) proteins. I therefore hypothesized that extracellular GzmB is capable of cleaving novel ECM substrates, contributing to dysregulated ECM integrity and function in disease. In the present dissertation I identified eleven novel extracellular GzmB substrates. Further investigations revealed that GzmB-mediated proteoglycan cleavage was implicated in the dysregulation of active transforming growth factorbeta (TGF-β) sequestration and bioavailability. GzmB cleavage sites were identified in biglycan and betaglycan and active TGF-β was shown to be released from decorin, biglycan and betaglycan. The pathophysiological role of my findings were further investigated and validated using animal models of disesase in which inflammation and elevated GzmB are observed. Evidence of fibrillin-1 and decorin cleavage were observed in atherosclerosis, abdominal aortic aneurysm and in skin aging pathogenesis. I also assessed the activity of GzmB in advanced atherosclerosis using perforin/apolipoprotein E- double knockout (Perf/apoE-DKO) and granzyme B/apolipoprotein E-double knockout (GzmB/apoE-DKO) mice. Interestingly, unlike our aneurysm findings whereby only GzmB/apoE-DKO mice were protected, both Perf/apoEDKO and GzmB/apoE-DKO mice were protected from atherosclerosis compared to apoE-KO controls, suggesting the intracellular Perf-dependent activities of granzymes are also important in the pathogenesis of atherosclerosis. In summary, GzmB is a protease that functions both intracellularly and extracellularly in disease. My findings suggest that the use of Perf knockout mice alone to study the role of GzmB in disease should be re-evaluated given the increasing evidence in both animal models and in human disease showing elevated GzmB in bodily fluids is associated with inflammation and age.
Item Metadata
Title |
Extracellular granzyme B and pathophysiological implications
|
Creator | |
Publisher |
University of British Columbia
|
Date Issued |
2012
|
Description |
Granzyme B (GzmB) is a serine protease that contributes to immune-mediated elimination of
cells by initiating a tightly-regulated form of death known as apoptosis. However, during
inflammation, GzmB leaks out and accumulates in the extracellular space, retains its activity,
and proficiently cleaves extracellular matrix (ECM) proteins. I therefore hypothesized that
extracellular GzmB is capable of cleaving novel ECM substrates, contributing to dysregulated
ECM integrity and function in disease. In the present dissertation I identified eleven novel
extracellular GzmB substrates. Further investigations revealed that GzmB-mediated
proteoglycan cleavage was implicated in the dysregulation of active transforming growth factorbeta
(TGF-β) sequestration and bioavailability. GzmB cleavage sites were identified in biglycan
and betaglycan and active TGF-β was shown to be released from decorin, biglycan and
betaglycan. The pathophysiological role of my findings were further investigated and validated
using animal models of disesase in which inflammation and elevated GzmB are observed.
Evidence of fibrillin-1 and decorin cleavage were observed in atherosclerosis, abdominal aortic
aneurysm and in skin aging pathogenesis. I also assessed the activity of GzmB in advanced
atherosclerosis using perforin/apolipoprotein E- double knockout (Perf/apoE-DKO) and
granzyme B/apolipoprotein E-double knockout (GzmB/apoE-DKO) mice. Interestingly, unlike
our aneurysm findings whereby only GzmB/apoE-DKO mice were protected, both Perf/apoEDKO
and GzmB/apoE-DKO mice were protected from atherosclerosis compared to apoE-KO
controls, suggesting the intracellular Perf-dependent activities of granzymes are also important
in the pathogenesis of atherosclerosis. In summary, GzmB is a protease that functions both
intracellularly and extracellularly in disease. My findings suggest that the use of Perf knockout
mice alone to study the role of GzmB in disease should be re-evaluated given the increasing evidence in both animal models and in human disease showing elevated GzmB in bodily fluids is associated with inflammation and age.
|
Genre | |
Type | |
Language |
eng
|
Date Available |
2013-07-31
|
Provider |
Vancouver : University of British Columbia Library
|
Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
|
DOI |
10.14288/1.0072932
|
URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
|
Graduation Date |
2012-11
|
Campus | |
Scholarly Level |
Graduate
|
Rights URI | |
Aggregated Source Repository |
DSpace
|
Item Media
Item Citations and Data
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International