Investigating changes in beta cell function by modulating CD47
Access status:
Open Access
Type
ThesisThesis type
Doctor of PhilosophyAuthor/s
Kale, Atharva Rajesh KumarAbstract
Diabetes is a global health burden characterised by β-cell death and loss of function. Islet transplantation is a recognised treatment for patients with Type 1 Diabetes Mellitus (T1DM) and hypoglycaemic unawareness, but broader application is constrained by limited islet survival ...
See moreDiabetes is a global health burden characterised by β-cell death and loss of function. Islet transplantation is a recognised treatment for patients with Type 1 Diabetes Mellitus (T1DM) and hypoglycaemic unawareness, but broader application is constrained by limited islet survival and function post transplantation. CD47 is a cell surface protein implicated in cellular stress responses, but its role in β-cell function remains relatively unexplored. The metabolic role for CD47 was characterised for the first time in β-cells. It was hypothesized that CD47 limits β-cell function and survival, and it was investigated whether CD47 signalling, or expression could be pharmacologically manipulated to enhance β-cell function and survival in the presence of various exogenous stressors, including hypoxia, hyperglycaemia, and endoplasmic reticulum (ER) stress, which are manifest in the peri-transplant period. CD47 inhibition via genetic deletion, silencing, or antibody blockade (in human islets and MIN6 β-cells) improved insulin protein expression. NOD mice treated with α-CD47 antibody had delayed development of hyperglycaemia. CD47-inhibited mouse islets compared to wildtype (WT, CD47+/+) mouse islets transplanted into diabetic mice significantly improved glucose control. Hypoxia increased CD47 expression while concurrently decreased insulin expression. CD47 inhibition under hypoxia increased insulin and pro-survival protein expression and limited senescence. CD47 inhibition protected MIN6 β-cells from ER stress by limiting the protein expression of ER stress markers (BiP, Ire1α and peif2a). Finally, CD47-silencing in MIN6 β-cells enhanced endothelial cell migration, via paracrine signalling. Overall, this thesis provides key insights into the essential role of CD47 as a novel regulator of islet dysfunction and inhibitor of cytoprotective responses to stress. Limiting CD47 activation may be a potential therapeutic tool in conditions where islet function is inadequate.
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See moreDiabetes is a global health burden characterised by β-cell death and loss of function. Islet transplantation is a recognised treatment for patients with Type 1 Diabetes Mellitus (T1DM) and hypoglycaemic unawareness, but broader application is constrained by limited islet survival and function post transplantation. CD47 is a cell surface protein implicated in cellular stress responses, but its role in β-cell function remains relatively unexplored. The metabolic role for CD47 was characterised for the first time in β-cells. It was hypothesized that CD47 limits β-cell function and survival, and it was investigated whether CD47 signalling, or expression could be pharmacologically manipulated to enhance β-cell function and survival in the presence of various exogenous stressors, including hypoxia, hyperglycaemia, and endoplasmic reticulum (ER) stress, which are manifest in the peri-transplant period. CD47 inhibition via genetic deletion, silencing, or antibody blockade (in human islets and MIN6 β-cells) improved insulin protein expression. NOD mice treated with α-CD47 antibody had delayed development of hyperglycaemia. CD47-inhibited mouse islets compared to wildtype (WT, CD47+/+) mouse islets transplanted into diabetic mice significantly improved glucose control. Hypoxia increased CD47 expression while concurrently decreased insulin expression. CD47 inhibition under hypoxia increased insulin and pro-survival protein expression and limited senescence. CD47 inhibition protected MIN6 β-cells from ER stress by limiting the protein expression of ER stress markers (BiP, Ire1α and peif2a). Finally, CD47-silencing in MIN6 β-cells enhanced endothelial cell migration, via paracrine signalling. Overall, this thesis provides key insights into the essential role of CD47 as a novel regulator of islet dysfunction and inhibitor of cytoprotective responses to stress. Limiting CD47 activation may be a potential therapeutic tool in conditions where islet function is inadequate.
See less
Date
2024Rights statement
The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.Faculty/School
Faculty of Medicine and HealthDepartment, Discipline or Centre
Sydney Medical SchoolAwarding institution
The University of SydneyShare