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Development and application of a multi-component 3-D in vitro model for predictive pharmacokinetics of environmental pharmaceuticals in fish

  • Full or part time
  • Application Deadline
    Friday, January 24, 2020
  • Funded PhD Project (UK Students Only)
    Funded PhD Project (UK Students Only)

Project Description

Many medicinal drugs end up in the aquatic environment through patient use and the pharmaceutical industry is required to assess their risk to non-target organisms. Fish is the group of organisms of highest risk of harm from environmental pharmaceuticals. To replace fish in laboratory experiments we have developed an in vitro Fish Gill Cell System (FIGCS), to study uptake, excretion and toxicity of pollutants1,2,3. FIGCS are grown on semi-permeable culture inserts and resemble the gill so closely that they tolerate water apically while the basolateral compartment is kept in culture medium, representing the blood. This provides a model of the gill that can let us test hypotheses that would be difficult if not impossible in intact fish. In previous BBSRC projects we found that pharmaceuticals are taken up by a combination of processes and used Machine Learning (ML) to derive molecular descriptors determining uptake4,5.

The combination of ML and FIGCS allow us to mechanistically understand and computationally model pharmacokinetics (PK) of compounds in fish rapidly across a two-compartment model. However, PK models benefit from data on multiple compartments, including target organs. We established that FIGCS can be co-cultured with 3-dimensional, multicellular organoids derived from fish livers that represent functional alternatives to an intact fish that are able to metabolise a range of xenobiotics. In this PhD project, we will validate these co-cultures and use them to determine PK of model drugs and their dependency on structure and water chemistry. In this highly interdisciplinary project, the student will deploy FIGCS-liver organoid co-culture and analytical chemistry to measure uptake, distribution, metabolism and excretion for 60+ pharmaceuticals, using non-targeted LC-MS and ML assisted full-scan high resolution mass spectrometry (HRMS) methods6,7.

The PhD student will be based at King’s College London, which is ranked 9th in Europe (QS World University Rankings 2019) with 26,000 students from 185 countries and 7,000 employees, providing cutting-edge research and world-class teaching. The student will benefit from a highly experienced and successful supervisory team, consisting of Prof Christer Hogstrand and Dr Leon Barron (King’s College London), Prof Nic Bury (University of Suffolk) and Dr Stewart Owen (AstraZeneca). This arrangement will enable expert training in all aspects of this interdisciplinary project including experimental design, in vitro cell culture, analytical chemistry, Artificial Intelligence and ecotoxicology. There will be opportunities to work with the industrial collaborator and we expect the student to communicate their findings through scientific manuscripts and international conferences. Most importantly, the student will lead their project to better understand how pharmaceuticals are taken from the water by fish, metabolised and excreted. This information is essential to better understand and predict adverse effects of these micro pollutants in the environment.

The BBSRC LIDo programme offers unrivalled training opportunities for PhD students. Additionally, the Health Schools Doctoral Training Centre (DTC) offers a range of PhD student courses in ML, data carpentering, statistics, and coding in R and Python. Sessions in transferrable skills provided by DTC are also planned for the student as provided by the DTC including scientific writing, research methods, statistics and presentation skills. The student will receive King’s Researcher Development Programme support developing, employability and transferable skills, a learning needs analysis, and a personal development log. Students also benefit from seminar programmes featuring invited speakers, student-led symposia, and journal clubs.

Applications

Applications must be complete, including both references, by 24th January 2020

Funding Notes

Fully funded place including home (UK) tuition fees and a tax-free stipend in the region of £17,009 and an additional generous contribution from the Industrial partner AstraZeneca. Students from the EU are welcome to submit an application for funding, any offers will be subject to BBSRC approval and criteria.

References

1 Toxicol Appl Pharmacol 2008, 230:67;
2 Aquat Toxicol 2015, 159:127;
3 Nat Protoc. 2016, 11:490;
4 Environ Sci Technol 2019, 53:1576;
5 Sci Total Environ 2019, 648:80;
6 Talanta 2016, 147:261;
7 J Chromatogr A 2015, 1542:82; Aquatic Toxicol 2009, 93:217

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