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MRC DiMeN Doctoral Training Partnership: Understanding the molecular pathophysiology of stress on the developing and adult brain

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  • Full or part time
    Dr N Krone
    Dr V T Cunliffe
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Stress is associated with significant morbidity including depression and anxiety. Activation of the hypothalamic-pituitary-adrenal (HPA) axis leads to synthesis of cortisol, which is a key mediator of the pathology of chronic stress. Our work has established the presence of the entire pathway to cortisol biosynthesis not only in the adrenal, but also in the brain. This expression appears to be crucial to stress responses and the production of both adaptive and maladaptive changes in the zebrafish brain. Importantly, whilst the brain responds to steroid that are synthesised peripherally, it also synthesises neurosteroids de novo. We therefore, hypothesise that steroidogenic enzymes in the brain are key components of the pathophysiological mechanisms responding to stress in the central nervous system. Therefore, we have generated several glucocorticoid-deficient zebrafish lines (cyp11a2, cyp11c1, cyp21a2, cyp17a2, fdx1b) and a mutant with defective glucocorticoid receptor that cannot mediate glucocorticoid signalling and confers glucocorticoid resistance. This project will employ our in vivo models to dissect the molecular pathophysiology of dysregulated stress responses in zebrafish larvae and adults. In addition, the project will create novel brain-specific mutants in which neurosteroid biosynthesis is impaired. Our ultimate goal is the discovery of pathways that can be targeted to modulate stress-associated disorders such as anxiety and depression.

This project will:
1. define the downstream consequences of genetically disrupted stress responses.
2. define the impact of stress on neural progenitors and neural activity in the CNS.
3. perform a chemical screen to identify drugs ameliorating the adverse impacts of dysregulated stress responses in the brain.

Novelty: The expression patterns of steroidogenic enzymes in the brain have been characterized in teleosts and mammals, but their functional roles in maintaining brain health and their potential drug-targetability for treating pathophysiological states induced by stress, have not been studied.

Experimental approach: Firstly, this project will explore the dynamic regulation of steroidogenic enzyme expression patterns in the brain in response to both environmental stressors and genetic disruption, by employing RNA-seq, bioinformatic analysis and quantitative PCR. Secondly, the impact of stress on proliferation of neural progenitors in the CNS will be explored using in situ hybridisation techniques, cell proliferation assays, apoptosis assays, as well as bright-field and fluorescence microscopy. The impact of stress on neural activity in wild-type larvae and mutant larvae (exhibiting persistent HPA axis activation in the brain) will be monitored using a neuron-specific transgene encoding the neural activity reporter NBT:GCaMP3. Finally, we will use a standard library of 2000 compounds to screen for substances ameliorating acute and chronic stress-related changes in gene expression in wild-type and mutant larvae in the CNS. Thus, this project will address exciting research questions and provide a wide range of transferable skills to the applicant.

The work will be conducted in a vibrant, interdisciplinary research setting at the Bateson Centre, which was ranked in the UK top five for biological research. The work will be co-supervised by a clinician scientist (Dr Nils Krone) and a biologist (Dr Vincent Cunliffe), both of whom have extensive experience in basic science and translational research.

Overall, this project combines cutting-edge technology with cross-cutting research questions to discover important novel pathophysiological pathways in the central-nervous system that are relevant to treatments of stress-linked affective disorders.

Links to project supervisors:
https://www.sheffield.ac.uk/oncology-metabolism/staff/krone
https://www.sheffield.ac.uk/bms/research/cunliffe

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Includes:
Stipend at national UKRI standard rate
Tuition fees
Research training and support grant (RTSG)
Travel allowance
Studentships commence: 1st October 2019.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: https://goo.gl/8YfJf8
Good luck!

References

Glucocorticoid deficiency causes transcriptional and post-transcriptional reprogramming of glutamine metabolism. Weger M, Weger BD, Görling B, Poschet G, Yildiz M, Hell R, Luy B, Akcay T, Güran T, Dickmeis T, Müller F, Krone N. EBioMedicine. 2018 Oct;36:376-389

Imaging Neuronal Activity in the Optic Tectum of Late Stage Larval Zebrafish
Bergmann K, Santoscoy PM, Lygdas K, Nikolaev Y, MacDonald RB, Cunliffe VT, Nikolaev A. J Dev. Biol. 2018 Mar; 6(1): 6.

Expression and activity profiling of the steroidogenic enzymes of glucocorticoid biosynthesis and the fdx1 co-factors in zebrafish. Weger M, Diotel N, Weger BD, Beil T, Zaucker A, Eachus HL, Oakes JA, do Rego JL, Storbeck KH, Gut P, Strähle U, Rastegar S, Müller F, Krone N. J Neuroendocrinol. 2018 Apr;30(4):e12586

Genetic Disruption of 21-Hydroxylase in Zebrafish Causes Interrenal Hyperplasia. Eachus H, Zaucker A, Oakes JA, Griffin A, Weger M, Güran T, Taylor A, Harris A, Greenfield A, Quanson JL, Storbeck KH, Cunliffe VT, Müller F, Krone N. Endocrinology. 2017 Dec 1;158(12):4165-4173

How good is research at University of Sheffield in Clinical Medicine?

FTE Category A staff submitted: 63.95

Research output data provided by the Research Excellence Framework (REF)

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