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Characterisation of cell death pathways upon activation of the endoplasmic reticulum stress sensor IRE1alpha


   Department of Biosciences

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  Dr M Schroeder  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

A PhD studentship to investigate cell death pathways activated by endoplasmic reticulum (ER) stress is available in the group of Dr. Martin Schröder in the Department of Biosciences at Durham University, Durham, United Kingdom.

Mammalian cells that experience ER stress mount a protective response to this stress, called the unfolded protein response (UPR), but commit to apoptotic cell death if the stress situation cannot be resolved (1,2). How cells make this decision between life and death remains poorly understood. To gain further insight into this fundamental question, this project will investigate how one ER stress sensor, IRE1α, commits cells to apoptotic cell death.

IRE1α is a transmembrane protein of the ER with cytosolic protein kinase and endoribonuclease (RNase) domains (1). Its ER luminal domain senses ER stress and activates its protein kinase and RNase domains to generate the ER stress signal. The RNase domain is thought to produce a largely cytoprotective signal by processing the mRNA for the transcription factor XBP1, while its protein kinase domain controls the activity of the RNase domain and activates apoptotic signalling. This project will make use of technology established at Durham University that allows the generation of isogenic mammalian cell lines that solely express wild type or mutant IRE1α.

The successful candidate will characterise the effect of specific point mutations in IRE1α on signal transduction and processing of XBP1 mRNA by IRE1α. To this end, the student will use molecular genetic approaches to generate new stably transfected mammalian cell lines, reverse transcriptase PCR and quantitative PCR to study processing of XBP1 mRNA and other mRNA substrates by IRE1α, immunoprecipitation/Western blotting techniques to characterise the phosphorylation status of IRE1α, and fluorescence microscopy to characterise the subcellular distribution of IRE1α. In addition, the student will use cell biological and biochemical techniques to characterise apoptotic signalling in cells expressing wild type and mutant IRE1α.

Applicants should possess at least a 2:1 Honours degree, or equivalent, in an appropriate subject (e.g. biochemistry, cell biology, molecular biology, or genetics).

To apply, send a CV including the names of two references and a one page personal statement describing clearly your background, interest and experience in scientific research to [Email Address Removed]. Further information on this studentship can be obtained by contacting Dr. Martin Schroeder.


Funding Notes

This project is in competition with others for funding. Success will depend on the quality of applications received, relative to those for competing projects. If you are interested in applying, in the first instance contact the supervisor, with a CV and covering letter, detailing your reasons for applying for the project.

References

1. Schröder, M. (2008) Endoplasmic reticulum stress responses. Cell Mol Life Sci 65, 862-894
2. Brown, M., Strudwick, N., Suwara, M., Sutcliffe, L. K., Mihai, A. D., Ali, A. A., Watson, J. N., and Schröder, M. (2016) An initial phase of JNK activation inhibits cell death early in the endoplasmic reticulum stress response. J Cell Sci 129, 2317-2328
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