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MRC DiMeN Doctoral Training Partnership: Activation of Aurora Kinase A by DNA damage – understanding the signalling pathway to improve radiotherapy response

  • Full or part time


    Prof P Eyers
  • Application Deadline
    Monday, January 06, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Radiation is a mainstay of cancer therapy, however radioresistance is a significant challenge in the treatment of locally advanced, recurrent and metastatic cancers. Novel ways to improve radiation response in hard to treat cancers are urgently needed.

We find that clinical inhibitors of the serine/threonine kinase Aurora A (AURKA) are cancer cell radiosensitizers, and that AURKA overexpression correlates with radioresistance in cancer, including lung cancer. Interestingly, AURKA is activated with delayed kinetics following DNA damage induced by ionizing radiation. This exciting studentship focuses on phosphoproteomic approaches for identification and characterization of functionally relevant AURKA-dependent signaling pathways activated by DNA damage (including ionizing radiation). The project will provide new, mechanistic insights into the role of AURKA following DNA damage, and will ultimately complement and guide future pre-clinical studies.

Specific objectives: (1) Quantitative proteomic analysis of the DNA damage response and (phospho)proteome following Radiation-induced DNA damage. (2) Pathway and target analysis of AURKA activation and inactivation and downstream target activation after DNA damage and (3) In vivo analysis of AURKA signaling networks relevant to tumour radiotherapy.

Experimental Approach: The studentship offers a unique training opportunity in a broad range of skills involved in pre-clinical drug development, including SILAC and TMT-based Mass spectroscopy biochemical and cell biology assays (such as DNA damage, cell cycle and in vitro kinase assays) and in vivo analysis of AURKA and its downstream targets in patient material (Non Small Cell Lung Cancer (NSCLC) specimens).

Environment: In Sheffield the student will be part of the Bryant lab, a supportive, dynamic multidisciplinary team spanning chemists to clinical fellows, who are all working together to develop better treatments for cancer. In particular the student will work in parallel to a clinical fellow who is currently evaluating the clinical implications of AURKA inhibition and developing clinical trails of radiosenstizing agents. You will also benefit from being part of the wider research within Sheffield as part of the Sheffield Institute for Nucleic Acids and Sheffield ECMC centers. The student will also spend time training in the Eyers lab in the Centre for Proteome Research, a state of the art mass-spectrometry facility at University of Liverpool. Here the student will join a vibrant group of biochemists involved in developing novel techniques for analyzing signaling pathways.

https://www.liverpool.ac.uk/integrative-biology/facilities-and-services/centreforproteomeresearch/

You will join an active, friendly and lively PhD student cohort at the University of Sheffield, which hosts regular social events alongside networking and career development opportunities. We are committed to supporting the career development of our students and encourage attendance at International and UK meetings, conferences and training courses to develop your research skills and interests.

This multidisciplinary project is suited to students from a diverse range of backgrounds, e.g. biochemistry, cell biology, biomedical sciences, medical chemistry or related disciplines, ideally with a strong background in the molecular basis of cell signalling. Interested applicants should contact Dr Bryant to discuss the project further ()

Primary Supervisor: Dr Helen Bryant (University of Sheffield)
https://www.sheffield.ac.uk/oncology-metabolism/staff/bryant
Second supervisor: Prof. Claire Eyers
https://www.liverpool.ac.uk/integrative-biology/staff/claire-eyers/
Third Supervisor: Prof. Patrick Eyers
https://www.liverpool.ac.uk/integrative-biology/staff/patrick-eyers/


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 2020.

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: View Website

Good luck!

References

Tsuchiya Y et al. (2019) Covalent Aurora A regulation by the metabolic integrator coenzyme A. Redox Biology, 28:101318

Gravells P, et al. (2018) Radiosensitization with an inhibitor of poly(ADP-ribose) glycohydrolase; a comparison with the PARP1/2/3 inhibitor olaparib. DNA Repair, 61, 25-36.

Ferries SJ et al. (2017) Evaluation of Parameters for Confident Phosphorylation Site Localization Using an Orbitrap Fusion Tribrid Mass Spectrometer. J Proteome Research 16, 3448

How good is research at University of Sheffield in Allied Health Professions, Dentistry, Nursing and Pharmacy?
Biomedical science

FTE Category A staff submitted: 64.66

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

Click here to see the results for all UK universities

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