Super-resolution fluorescence microscopy has revolutionized the understanding of cellular organization by allowing quantitative analysis of protein assemblies architecture, in situ, at the nanoscale (Sydor et al. Trends in Cell Biology, 2015). Despite its success, applications have been limited to specific research questions requiring low throughput data acquisition (Sigal et al Science 2018). This is mainly attributable to several technological limitations: lack of multicolour imaging capability in the low nanometer regime; reagents availability; automated acquisition and data analysis (Baddeley et al. Annual Review of Biochemistry, 2018).
The very recent emergence of super-resolution fluorescence technologies based on lattice Structured Illumination Microscopy (SIM) and dual iterative reconstruction algorithms, which are capable of multicolour 60 nm in plane resolution (Loschberger et al. BioXRiv 2021), together with systematic efforts to develop validated antibodies against the human proteome (Thul et al. Protein Science 2018), enable systematic mapping of the structural organization of organelle and larger assembly at the nanoscale (Liu et al Science Translational Medicine, 2020).
This proposal is aimed at developing a nanometer scale protein atlas of two main cellular structures: mitochondria whose structural organization and integrity is disrupted by toxic insults such as pesticides (Zolkipli-Cunningham et al. Toxicology, 2020) and drugs used in clinical treatment such as antidepressants (Beauchemin et al Pharmacological Research, 2020) and cell-cell junctions, which are linked to undesired irritant effect of inhaled drugs used in clinical setting (Balogh Sivars et al. Toxicological Sciences, 2018).
The nanometer scale atlas will comprise imaging data and relative quantitative measurements that will be used as a reference to assess the effect of benchmark toxicity compounds. Data will be subsequently used to train CNN artificial intelligence algorithms to recognize structural changes associated with toxicity endpoint.
Altogether, this project will deliver fundamental knowledge in cellular biology and tools that will be used to predict toxic effects of novel compounds and detect early timepoints of toxicity.
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)