Funding provider: Lhasa ltd
Subject areas: Genotoxicity, DNA damage, carcinogenicity mechanisms
Project start date:
- 1 October 2023 (Enrolment open from mid-September)
Aligned programme of study: PhD in Medical and Health Care Studies
Mode of study: Full-time
Adverse outcome pathways are a sequential chain of causally linked events at different levels of biological organisation that lead to an adverse health effect. AOPs are being built to organise toxicological knowledge into a framework, that can subsequently be used to support chemical risk assessment based on mechanistic reasoning. A core component of chemical risk assessment is genotoxicity, whereby the ability of a compound to induce DNA damage is evaluated. DNA damage can take on several different forms and can arise via multiple mechanisms. Genotoxic compounds also have the capacity to potentially be carcinogenic and thus, genotoxicity evaluation is an important stage in identifying possible carcinogens. However, carcinogens may also be non-genotoxic. The molecular changes and mechanisms leading to carcinogenicity can therefore be described through multiple AOPs based on both genotoxic and non-genotoxic modes of action. AOPs are currently qualitative; developing a more quantitative understanding of AOPs (qAOPs) will therefore allow the field to move towards identifying the external exposure doses needed to cause a hazardous effect or adverse outcome in a dose–response assessment. This data is however currently missing and is a gap that will be addressed through this project.
The overarching aim of this project is therefore the development of qAOPs associated with genotoxicity, that can be extrapolated and/or linked to carcinogenicity, based upon the use of more physiologically relevant cell culture and exposure systems. The project will focus on the development and use of 3D human liver models to generate dose-response data that will determine if there are tipping points within an AOP pathway (i.e. identifying whether a particular dose-range needs to be achieved before one Key Event within an AOP pathway progresses into the next). The project will explore whether in vitro exposure times have an influence on improving the predictivity of the data sets underpinning qAOPs. Additionally, methodologies and approaches will be developed to experimentally evaluate Key Events that are not yet associated with assays in the in silico AOP networks, generating data to more fully inform qAOPs.
Candidates must normally hold an undergraduate degree at 2.1 (or Non-UK equivalent as defined by Swansea University).
English Language requirements: If applicable – IELTS 6.5 overall (with at least 5.5 in each individual component) or Swansea recognised equivalent.
Due to funding restrictions, this scholarship is open to applicants eligible to pay tuition fees at the UK rate only, as defined by UKCISA regulations.