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http://theses.ncl.ac.uk/jspui/handle/10443/6560
Title: | Investigating the role of cardiomyocyte senescence in delayed-onset doxorubicin cardiotoxicity |
Authors: | Booth, Laura K. |
Issue Date: | 2025 |
Publisher: | Newcastle University |
Abstract: | Although cancer survival rates are continually improving, the delayed onset of cardiotoxicity as a result of chemotherapeutic treatment, particularly the anthracycline class of drug, places an increasing burden on healthcare systems: yesterday’s cancer survivors are fast becoming today’s heart failure patients. Cellular senescence (a cell fate defined by irreversible cell cycle exit, phenotypic alterations including mitochondrial dysfunction, and the expression of the pro-inflammatory senescence associated secretory phenotype) has gained significant attention as a contributor to this pathology. Studies have shown that pharmacological elimination of senescence prevents maladaptive remodelling and myocardial dysfunction in preclinical models of anthracycline-induced (specifically doxorubicin-induced) cardiotoxicity, but the interplay of senescence and cardiotoxicity remains poorly characterised at a cellular and molecular level. In this thesis, using clinically representative in vitro models of cardiac cells, it was demonstrated that classical senescence is initiated in these cells following exposure to doxorubicin, and these phenotypic hallmarks persist following removal of the drug. Furthermore, these cells exhibit far-reaching changes in their transcriptome. The cardiomyocytes also produce a classical senescence-associated secretome, which in isolation modulates the cardiac fibroblast phenotype and cellular response. Overall, these studies establish an in vitro model of doxorubicin-induced cardiomyocyte senescence, the secretome of which can influence other cardiac cell lineages – this may contribute to more global maladaptive myocardial remodelling (e.g. fibrosis) and long-term cardiotoxicity. Building on this work, targeting aspects of the senescent cardiomyocyte phenotype may prove a therapeutic strategy to prevent or treat anthracycline-induced cardiac dysfunction in the future. |
Description: | PhD Thesis |
URI: | http://hdl.handle.net/10443/6560 |
Appears in Collections: | Translational and Clinical Research Institute |
Files in This Item:
File | Description | Size | Format | |
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BoothLK2025.pdf | Thesis | 5.57 MB | Adobe PDF | View/Open |
dspacelicence.pdf | Licence | 43.82 kB | Adobe PDF | View/Open |
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