Glucocorticoid drugs and their effects in fish - Biosciences – PhD (Funded) Ref: 2688

About the award

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.

Academic Supervisors:

Professor Charles Tyler, University of Exeter

Dr Matthew Winter, University of Exeter

Dr Luigi Margiotta-Casaluci, Brunel University

Dr Stewart Owen, AstraZeneca

 

Project Description:

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.          

  

Project aim and approach

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 results will shape the current understanding of how drugs designed for human use can act in fish with known similar targets but unknown pharmacological mechanism. Characterising this response will require multiple glucocorticoid drugs that will provide a range of different efficacies and so allow further questions as to the effects of simple mixtures and poly-pharmacology to be addressed in non-mammal models.

Project training

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.

The studentship will be awarded on the basis of merit for 4 years of full-time study to commence in January 2018.    

Entry requirements:

Applicants for this studentship must have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in biology, biochemistry or molecular biology.

If English is not your first language you will need to have achieved at least 6.5 in IELTS and no less than 6.0 in any section by the start of the project.  Alternative tests may be acceptable (see http://www.exeter.ac.uk/postgraduate/apply/english/).

How to apply

Click here to apply

In the application process you will be asked to upload several documents.  Please note our preferred format is PDF, each file named with your surname and the name of the document, eg. “Smith – CV.pdf”, “Smith – Cover Letter.pdf”, “Smith – Transcript.pdf”. 

  • CV
  • Letter of application (outlining your academic interests, prior research experience and reasons for wishing to undertake the project).
  • Research proposal
  • Transcript(s) giving full details of subjects studied and grades/marks obtained (this should be an interim transcript if you are still studying)
  • 2 references from referees familiar with your academic work (if your referees prefer, they can email the reference direct to cles-studentships@exeter.ac.uk. If we don't receive your references, we will not request them unless you have been shortlisted)
  • If you are not a national of a majority English-speaking country you will need to submit evidence of your proficiency in English.

The closing date for applications is midnight on 15 October 2017. Interviews will be held on the University of Exeter Streatham Campus.

 

Summary

Application deadline:15th October 2017
Number of awards:1
Value:£14,553 for 4 years
Duration of award:per year
Contact: +44 (0)1392 725150 pgr-cles-admissions@exeter.ac.uk