Advancing transgenic zebrafish bioassays for drug analysis using imaging, Biosciences - PhD

Existing collaborations with the University of Exeter, funded by BBSRC and AstraZeneca, are developing in-life models using various transgenic fish lines. These are used to identify pharmaceutically active chemicals that may cause adverse effects to humans and/or the environment; such as endocrine disruption or oxidative stress; earlier in the product discovery and development process. Here, it is critical to be able to identify products with these properties at the earliest stage before significant investments are made in their further development. In recent years there have been significant advances with alternative, (to mammalian), models to determine the clinical efficacy and safety of medicinal products. The combination of transparent transgenic zebrafish with advanced imaging methods allow for the non-invasive visualising of responses to chemicals, including drugs, in live fish in real time, which offers exciting opportunities for truly advancing our understanding of how chemicals work in the body. However, these assays require the use of advanced imaging and image processing to maximise the benefits from this research.

The aim of this PhD studentship is to optimise the use of imaging approaches to better exploit the advantages of our transgenic zebrafish models, and to advance our ability to better understand the effects that chemicals may have on fish (and by extrapolation to mammalian) health. At Exeter we hold an exciting array of transgenic fish for this work including models for oestrogens, oxidative stress, immune function, and neural function amongst others and the model choices will depend on the drugs/chemical investigated. In this project the student will seek to develop imaging approaches that will allow accurate location of a specific tissue or region (e.g. brain, heart, liver, hair cell, gut etc.) within the zebrafish, delineate this chosen target from a complex background and quantify the signal and/or morphology in transgenically modified animal. Considerable background work for this studentship has been conducted at Exeter, using a variety of imaging platforms which will support and enable this exciting project. The studentship will involve conducting in-life exposures of the various transgenic fish lines to specific drugs and chemicals for the imaging work, followed by imaging on a number of platforms from high-throughput plate readers to more specific confocal and possibly light sheet and Mass spec. imaging. The studentship may also provide the opportunity to link this imaging work with in situ metabolomics to better understand how the chemical fate with the biological effects observed. Considerable expertise in all the proposed techniques for this studentship is held within the team at Exeter for supporting this work.

The student will work under the supervision of Prof Tyler and Dr Hetheridge, with supporting expertise from an extensive team of researchers at Exeter working in imaging, image analysis, transgenic fish, and ecotoxicology. The student will also have direct support from a pharmaceutical company, AstraZeneca, with regular short research placements with them. The student will have access to exceptionally facilities for all aspects of this project including: in-life fish exposures, molecular biology, imaging (including Confocal and possibly light-sheet microscopy, mass spec imaging) and advanced image analysis, and will receive multidisciplinary training in techniques spanning molecular biology, bioinformatics, immunology, toxicology and tissue imaging. (S)he will thus develop a valuable set of technical and theoretical expertise that will boost a successful career as an independent scientist.

The studentship will cover a stipend at the minimum Research Council rate, currently £14,553 per annum, research costs and tuition fees at the UK/EU rate for students who meet the residency requirements outlined by the BBSRC. Students from EU countries who do not meet the residency requirements may still be eligible for a fees-only award but no stipend. Applicants who are classed as International for tuition fee purposes are not eligible for funding. Further information about eligibility can be found here.

The studentship will be awarded on the basis of merit for 3.5 years of full-time study to commence in January 2018 and is subject to confirmation of funding.

For further information please see http://www.exeter.ac.uk/studying/funding/award/?id=2659