Unravelling species differences in stress responses to inform the selection, and reduce the use, of animals in preclinical drug safety testing

Prior to a new medicine entering clinical trials, regulators require preclinical toxicity studies to be performed. These studies require hundreds of thousands of animals to test hundreds of drug candidates annually across the global pharmaceutical industry. The selection of relevant species for preclinical toxicity studies should be informed by a detailed understanding of the physiological similarities and differences between available preclinical models and humans. One important, yet relatively unexplored, aspect is the capacity of a given species to sense and adapt to chemical insult through activation of various stress response pathways that have evolved to protect against e.g. reactive oxygen species or protein misfolding. This project aims to test the hypothesis that there are important differences across species in the sensitivity and activity of stress response pathways that contribute to the human translatability of preclinical drug toxicity studies. Focussing on the liver as one of the most common targets of drug toxicity, we will assess differences in the resting and inducible expression levels of genes and proteins that reflect the activities of key stress response pathways, using archived liver tissue and primary hepatocytes from humans and relevant preclinical species. We will use computational biology approaches to integrate and compare these layers of data, and understand the genomic mechanisms that underlie any differences across species.

You will be based at the MRC Centre for Drug Safety Science at the University of Liverpool, and will also spend three months of the project working with one of the project supervisors at AstraZeneca, one of the world’s leading pharmaceutical companies. Together, the supervisory team will provide you with training in computational bioinformatics, the 2D/3D culture and pharmacological manipulation of primary hepatocytes and ‘omics analysis. The training will support the scientific progression of the project and provide you with a rounded, transferable skill set reflecting modern trends in biological science. As a result, you will be well positioned for a future career in either experimental or computational biology within academia or industry.

The fundamental biological understanding gained from this project will support the 3Rs in drug development by identifying the degree of conservation of key characteristics of animal and human physiology, and informing the selection of appropriate species to best reflect the stress response pathway capacity of humans. The ultimate impact will be a refinement of preclinical research, a reduction in animal usage by industry and an improvement in human health. 

Informal enquiries may be made to ian.copple@liverpool.ac.uk

HOW TO APPLY

Applications should be made by emailing bbsrcdtp@liverpool.ac.uk with a CV and a covering letter, including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project/s and at the selected University. Applications not meeting these criteria will be rejected. We will also require electronic copies of your degree certificates and transcripts.

In addition to the CV and covering letter, please email a completed copy of the Application Details Form (Word document) to bbsrcdtp@liverpool.ac.uk, noting the additional details that are required for your application which are listed in this form. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.