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Understanding the immunomodulatory activity of pharmaceuticals in zebrafish using high content imaging and phenotypic profiling


   London Interdisciplinary Biosciences Consortium (LIDo)

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  Dr Luigi Margiotta-Casaluci, Prof C Hogstrand  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

Applications are invited from PhD candidates to join the Integrative & Translational Toxicology group led by Dr Margiotta-Casaluci (King’s College London) on a project in collaboration with the pharmaceutical company AstraZeneca. This academia-industry collaboration will provide the exciting opportunity to work with an interdisciplinary scientific team on the application of novel technologies to unravel key outstanding biological questions with practical implications for the industry sector. 

Many human pharmaceuticals enter the aquatic environment via wastewaters, and the pharmaceutical industry is required to assess their risk to wildlife. Due to the evolutionary and functional similarities with humans, fish are one of the taxonomic groups at higher risk of being adversely affected by these compounds. Thus, it is of vital importance that adverse effects in fish can be predicted to avoid unintended ecological impacts.

Using computational and in vivo approaches, our previous research demonstrated that different classes of pharmaceuticals induce immune-mediated adverse effects in fish as they do in humans (e.g. Margiotta-Casaluci et al., 2016). However, we also found that this high functional similarity is in contrast with the low degree of evolutionary conservation of key immune drug targets and signalling molecules (Gunnarson et al., 2019). This mismatch between functional and evolutionary conservation implies that drug-mediated immune effects in fish cannot simply be predicted using known mammalian drug-target interaction profiles, but their characterisation requires the use of traditional in vivo fish testing. Thus, there is an urgent need to advance our understanding of the fundamental mechanisms that mediate fish-specific immune responses to pharmaceuticals. In turn, this knowledge can be used to develop novel predictive non-animal methods (NAMs) able to inform drug safety assessment without in vivo testing.

To address this challenge, the student will apply cutting-edge high-content imaging technologies to visualise and quantify the effects of drugs on isolated cell types involved in innate immunity and inflammation. To assess the concordance between in vitro an in vivo data, a selected set of pharmaceuticals will also be tested using non-protected transgenic zebrafish larvae that express immune cells tagged with fluorescent proteins. In vivo immune cells dynamics will be quantified using in vivo imaging approaches based on confocal microscopy. Due to the rapidly increasing popularity of the zebrafish as model species for both environmental and biomedical research, the outcome of this project will have far reaching implications in any field where zebrafish are used to investigate immune responses.

The student will be based at King’s College London (Department of Analytical, Environmental, and Forensic Sciences; School of Cancer and Pharmaceutical Sciences) and will work in close contact with the industry partner AstraZeneca. Throughout the project, the student will be able to develop transferable skills (i.e., High-Content-imaging, image analysis, phenotypic profiling, non-animal approaches, big data analysis, science communication) that are in high demand beyond academia.  

Application

This Industrial collaborative (iCASE) PhD Project is offered via the London Interdisciplinary Biosciences Consortium (LIDo), the largest BBSRC funded Doctoral Training Partnerships in the UK. The consortium provides students with a unique opportunity to pursue innovative interdisciplinary research projects in the heart of one of the world's most vibrant cities.

For details on how to apply and the link to our online application form please go to the LIDo application page.

The application window will close on Tuesday 10th January 2023 at 5pm.


Funding Notes

Fully funded place including home (UK) tuition fees and a tax-free stipend in the region of £19,668. Additional funding to cover full overseas fees is available for a maximum of 11 studentships.

References

Gunnarsson, L.; Snape, J.; Verbruggen, B.; Owen, S.; Kristiansson, E.; Margiotta-Casaluci, L.; Österlund, T.; Hutchinson, K.; Leverett, D.; Marks; B.; Tyler C.R. (2019) Pharmacology beyond the patient – the environmental risk of human drugs. Environment International 129, 320-332
Margiotta-Casaluci, L., Owen, S.F., Huerta, B., Rodríguez-Mozaz, S., Kugathas, S., Barceló, D., Rand-Weaver, M., Sumpter, J.P. (2016) Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish. Nature Scientific Reports, 6
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