Probing the secondary effects of Tp53 and BRCA gene mutations upon cellular physiology using advanced analytical techniques.

Prof R Edmondson, Prof P Gardner, Dr N Lockyer, Dr J Denbigh

Deadline: 17 November 2017

Cancer is a disease of DNA in which genomic events allow the cell to develop the autonomy, increased proliferation and other fundamental hallmarks of the disease. This process is often initiated by mutation of one or two key driver genes. Understanding the effects of these driver mutations is crucial in order to not only improve our understanding of the disease process but also to develop new screening and detection methods for cancer. In this exciting PhD the student will develop a novel cell model using primary human tissue to replicate the earliest phases in the development of high grade serous cancer, the commonest and most deadly pelvic cancer. The model will be created using fallopian tube epithelial cells which will be cultured ex vivo. Tp53 and BRCA1 genes will then be silenced using Crispr technology.

The student will then apply novel bioanalytical tools to these models to probe the effects of each of the mutations, alone and in combination. Specifically the student will use a combination of mass spectrometry and vibrational spectroscopy approaches that are being pioneered in Manchester for biomolecular characterization. Signatures generated using these techniques will then be validated using RNAseq.

Taken together these studies represent a novel approach and make use of an existing collaboration to integrate advanced cell culture modelling with a unique analytical strategy. Results from these studies will provide important insights into the effect of these driver mutations upon cellular physiology which will pave the way for development of novel screening and detection methodologies.

The student will develop a wide range of transferable lab and analytical skills to enhance their career development.

Links

https://www.research.manchester.ac.uk/portal/en/researchers/richard-edmondson
http://www.manchester.ac.uk/research/peter.gardner/
http://www.sarc.manchester.ac.uk/index.php/group-members/nick-lockyer/
http://www.chemistry.manchester.ac.uk/people/staff/profile/?ea=nick.lockyer
http://www.salford.ac.uk/environment-life-sciences/els-academics/joanna-denbigh

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form – full details on how to apply can be found on the BBSRC DTP website: http://www.manchester.ac.uk/bbsrcdtpstudentships

Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject. https://www.bmh.manchester.ac.uk/study/research/bbsrc-dtp/apply/

FindAPhD

https://www.findaphd.com/search/ProjectDetails.aspx?PJID=89927&LID=1020

References

1. Bowtell, D.D., Edmondson RJ et al.,
   Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer.
   Nat Rev Cancer, 2015. 15(11): p. 668-79.
2. Denbigh, J. L., Perez-Guaita, D., Vernooij, R., Tobin, M., Bambery, K., Xu, Y., Southam, A., Khanim, F., Drayson, M., Lockyer, N., Goodacre, R., and Wood, B.
   Probing the action of a novel anti-leukaemic drug therapy at the single cell level using modern vibrational spectroscopy techniques,
   Scientific Reports, 2017. 7(1): 2649
3. McCormick, A., Edmondson RJ et al.,
   Ovarian Cancers Harbour Defects in Non-Homologous End Joining Resulting in Resistance to Rucaparib.
   Clin Cancer Res, 2016
4. A. L. M. Batista de Carvalho, M. Pilling, P. Gardner, J. Doherty, G. Cinque, K. Wehbe, C. Kelley, L. A. E. Batista de Carvalho and M. P. M. Marquesa,
   Chemotherapeutic Response to Cisplatin-like Drugs in Human Breast Cancer Cells Probed by Vibrational Microspectroscopy.
   Faraday Discussion, 2016, 187, 273-298
5. M. Pilling and P. Gardner,
   Fundamental developments in infrared spectroscopic imaging for biomedical applications.
   Chemical Society Reviews, 2016, 45, 1935 – 1957