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Title: The unfolded protein response as a marker of drug-induced cardiotoxicity
Authors: Holkham, Harry Oliver
Supervisors: Herbert, Terence
Award date: 1-Apr-2015
Presented at: University of Leicester
Abstract: Drug induced cardiotoxicity is, simply, an undesirable effect on the structure and function of the heart caused by treatment with a drug or a combination of drugs. Deleterious effects on the heart can have a dramatic effect on patient health and survival. Compounds that cause these effects are unlikely to be approved to become drugs and if they do then they are unlikely to be first line treatments. Cardiotoxicity is an umbrella term that covers a series of different pathologies. It is currently hard to predict one group of pathologies, the structural cardiotoxicities. These are structural changes in the heart that are often associated with chronic treatments. The cardiotoxicity associated with some clinically used oncology drugs has been attributed to or associated with activation of the unfolded protein response. The unfolded protein response is a cellular stress pathway that occurs upon perturbation of the endoplasmic reticulum luminal environment. It is mediated through three membrane bound transducers, PERK, IRE1 and ATF6. Screening assays were developed to assess activation of the unfolded protein response. A battery of compounds were screened for BiP induction (a downstream marker of activation of the unfolded protein response), XBP1 splicing (a marker of IRE1 activity) and activity at the endoplasmic reticulum stress response element (a marker of ATF6 activation). Findings were largely inconclusive due to a number of potential concerns about the assays being highlighted. The immunofluorescence based BiP assay is likely to have produced artifactual results when cells no longer had a healthy cellular morphology. It was showed that some compounds were autofluorescent which confounded the XBP1 screen. Although the ATF6 assay gave some promising results the assay window was small and severe limitations were noted with the analysis carried out that would need to be addressed before firm conclusions are made.
Type: Thesis
Level: Masters
Qualification: MPhil
Rights: Copyright © the author. All rights reserved.
Appears in Collections:Theses, Dept. of Cell Physiology and Pharmacology
Leicester Theses

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