Advancing understanding of Glucocorticoid effects in fish - Biosciences – PhD

The University of Exeter’s College of Life and Environmental Sciences, in partnership with AstraZeneca, is inviting applications for a fully-funded BBSRC CTP PhD studentship to commence in January 2018 or as soon as possible thereafter. For eligible students the studentship will cover UK/EU tuition fees plus an annual tax-free stipend of at least £14,553 for 4 years full-time, or pro rata for part-time study. The student would be based in Biosciences in the College of Life and Environmental Sciences at the Streatham Campus in Exeter.

Synthetic glucocorticoid drugs are used by millions of people worldwide on a daily basis to treat a wide variety of conditions that involve inflammation. However, how glucocorticoids work in non mammalian vertebrates is poorly understood and this is a major knowledge gap as these drugs enter into aquatic environments. In mammals, there are several proposed modes of action that could explain how glucocorticoids reduce inflammation and regulate cortisol in fish, but despite extensive study there is yet no agreed mechanistic process that can explain both the nuclear and nongenomic pathways of cortisol action. Recently members of this team have published information that explains effects observed in extensive and multiple in vivo studies and goes some way to addressing the lack of fundamental understanding as to how this class of compounds acts in fish. However, some unexpected exposure effects have been reported showing poor survival in the offspring for parental exposures in zebrafish. These findings cannot be explained from our current understanding of fish physiology.

The aim of this PhD studentship is to understand the fundamental mechanism(s) of glucocorticoid action using the zebrafish as the experimental model. We believe that the adverse (lethal) effects reported in the offspring derived from parental zebrafish exposed to corticosteroid may be explained by a hypersensitisation in the offspring to glucocorticoid drug action. The most likely effect pathways for this are via alterations to insulin/insulin like growth factor signaling, blood glucose control, immune function, and/or disruption to the development of the cardio vascular system. The studentship will focus on these pathways but flexibility will be maintained to allow the project results to dictate the direction of study. The work will include generating juvenile zebrafish from adults exposed to glucocorticoids at concentrations already known to cause detectable effects and assessing for effects in the offspring subsequently exposed to glucocorticoid drugs to establish when (in which life stages) the adverse effects occur to refine the study life stage window. Assessments of the heart development and function (blood flow, valve function) will then be undertaken in the offspring via a combination of morphometry and imaging. Effects on IGF signaling will be assessed via comparisons of the liver transciptomes (RNA Seq) in exposed and non exposed fish. Comparison between drug treated and non treated fish will also be made on blood glucose, cortisol levels (which can be measured non-invasively via the water), appetite and growth. To investigate for possible effects on immune function we will generate the required glucocorticoid drug exposed offspring for transgenic fish in which we are able to quantify responses of fluorescently labelled macrophages and neutrophils via imaging where they have been subject to an immunological challenge. Once identified which systems are impacted, and as time allows, models can be generated using the principles of inducing response either by direct inflammation or knock-in approaches (using CRISPR-Cas) to provide zebrafish with a phenotype that can be rescued with the glucocorticoid.

The student will work principally at the University of Exeter under the supervision of Prof Tyler and Dr Winter, but with supporting expertise of Dr Margiotta-Casaluci from Institute of Environment, Health and Societies at Brunel University London and the pharmaceutical company AstraZeneca. The student will have access to exceptionally facilities for both in-life fish exposures and molecular biology and imaging and 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.

For more information see: http://www.exeter.ac.uk/studying/funding/award/?id=2688.