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Understanding apoptotic heterogeneity in cell populations


   Faculty of Biology, Medicine and Health

  ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Apoptosis is a form of programmed cell death that occurs in response to stress such as genomic damage. The decision to initiate apoptosis is taken at the outer mitochondrial membrane (OMM) by members of the Bcl-2 family of proteins. Bcl-2 proteins form pores in the OMM, releasing pro-apoptotic factors normally sequestered in mitochondria into the cytosol where they initiate caspase proteases that kill the cell. The relative proximity of a cell to apoptosis is termed mitochondrial priming and determines whether a cell will die in response to a subsequent insult. A complex interplay of interactions between the different Bcl-2 family proteins dictates the level of mitochondrial priming and whether the threshold for MOMP is passed. Differences in priming predict how patients respond to chemotherapy 1,2, and represents one of the hallmarks of cancer 3.

The Bcl-2 family comprises: pro-apoptotic Bax and Bak that permeabilise mitochondria; anti-apoptotic proteins, such as Bcl-XL, which inhibit Bax and Bak; and BH3-only proteins that regulate the activities of the others in response to stress and damage signals 4,5. A range different signalling pathways combine through the Bcl-2 protein family and establish a threshold for a cell to either remain alive or die following stress or damage. A significant issue in the context of cancer chemotherapy is that cell populations show considerable variation in their apoptotic response to these drugs, with some cells dying whilst others are resistant. The nature of this variation is unclear, but probably reflects cell-to-cell heterogeneity in Bcl-2 protein expression and function. By understanding this heterogeneity, we can design strategies to improve cancer response to chemotherapy.

This project will examine cell-to-cell variation in Bcl-2 protein expression in breast cancer cell lines that show different responses to chemotherapy. We will utilise CRIPSR/Cas9 gene editing to tag endogenous Bcl-2 family proteins and use these tags with cutting edge mass-spectrometry and imaging to quantify cell-to-cell variation in expression and localisation. Live cell imaging quantification of apoptosis will be used to model

Specific aims are:

1.          To quantify cell-to-cell heterogeneity in the BCl-2 protein landscape.

2.          Determine how this variation results in variation in the apoptotic response to chemotherapy

Training will include methods in cell culture, genome editing, mass-spectrometry and microscopy. 

1.     Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject.  

2.     For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the PhD title.

3.     For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit www.internationalphd.manchester.ac.uk

Entry Requirements

Applicants 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 an appropriate area of science, engineering or technology.

How to Apply

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the appropriate subject area.

For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences.

Equality, Diversity and Inclusion 

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/ 


Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website View Website

References

1 Ni Chonghaile, T. et al. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science 334, 1129-1133, doi:10.1126/science.1206727 (2011).
2 Sarosiek, K. A. et al. Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics. Cancer Cell 31, 142-156, doi:10.1016/j.ccell.2016.11.011 (2017).
3 Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646-674, doi:10.1016/j.cell.2011.02.013 (2011).
4 Happo, L., Strasser, A. & Cory, S. BH3-only proteins in apoptosis at a glance. J Cell Sci 125, 1081-1087, doi:10.1242/jcs.090514 (2012).
5 Youle, R. J. & Strasser, A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9, 47-59 (2008).

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