Animal models are widely used in assessing toxicity of drugs and other xenobiotics (e.g., plant secondary metabolites). However, the data from animal models can provide false negatives (i.e., no toxicity observed in the model but that in the humans) as well as false positives (i.e., toxicity observed in the model but not in the humans). Both errors pose a substantial challenge for safety assessment. While some of the discrepancy can be attributed to genetic differences, the role of microbiota is worthwhile considering as the gut microbiota can modulate compound availability and toxicity. The microbial composition of animal models and humans is vastly different both in terms of complexity and constituent strains. Further, animal microbiomes vary between species as well as within a species depending on the environmental context such as diet and social interactions.
This project will investigate a selected set of compounds for differences in biotransformation and bioaccumulation by human and animal model gut bacteria and their communities. We will select compounds for which known discrepancy exists between animal model and human toxicity data (e.g., Pyrrolizidine alkaloid N-Oxides). We will investigate the mechanistic basis of the differences between toxicity modulation by the human vs the animal microbes by using genetic libraries and metabolomics with the aim of uncovering the underlying genes and biochemical pathways. This mechanistic insight will be used to assess the potential for inter-host and inter-individual differences through mining of the readily available metagenomics datasets. The results will thus provide a mechanistic foundation for clinical studies towards personalised medicinal and food safety.
The Medical Research Council (MRC) Toxicology Unit is a leading International Research Institute within the School of Biological Sciences, University of Cambridge. The Unit delivers mechanistic toxicology research, pursuing hypothesis-driven toxicological questions with a particular focus on the study of the causal links between exposure to endogenous and exogenous toxicants, molecular initiating events and adverse outcome pathways. The Unit's overall aims are to carry out pioneering research which leads to improved health and to train and mentor the next generation of toxicologists.
The Unit provides a supportive learning environment designed to meet the scientific and transferable skills required for an internationally competitive career. Our PhD Programme aims to train the scientific leaders of the future, giving them rewarding research projects with access to world-class facilities and expertise. Students receive toxicology-specific training in the Unit and through the Integrated Toxicology Training Partnership (ITTP).
Students are registered for their PhD with the Graduate School of Life Sciences at the University of Cambridge and have membership of a University of Cambridge College.
The ideal candidate will have excellent academic abilities (a good 2.1 honours degree or equivalent undergraduate degree) combined with strong communication and team working skills in order to make the most of interdisciplinary training opportunities.
To apply please visit the Toxicology Unit website and follow the instructions provided: Applications | MRC Toxicology Unit (cam.ac.uk)