Website Durham University
About the Project
A self-funded PhD studentship to develop chemical genetic tools to study signal transduction in the unfolded protein response in human cells is available in the group of Dr. Martin Schröder in the Department of Biosciences at Durham University, Durham, United Kingdom.
Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and activates a signalling network called the unfolded protein response (UPR) [1, 2]. ER stress and the UPR contribute to the onset and progression of many diseases including neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease or metabolic diseases, for example diabetes.
Three proximal ER stress sensors, ATF6, IRE1, and PERK initiate signalling events in the UPR [1, 2]. The bifunctional protein kinase-RNase IRE1 is a key signalling molecule in the UPR. The RNase domain of activated IRE1α initiates non-spliceosomal splicing of the mRNA for the transcription factor XBP1 [3]. The protein kinase domain of IRE1 controls the activity of its RNase domain.
The successful candidate will develop a chemical genetic system that will allow activation of IRE1 without activation of either ATF6 or PERK or the accumulation of unfolded proteins in the ER. This chemical genetic system will allow investigation of signalling events downstream of IRE1 in isolation as well as investigation of how, and if at all, downstream signalling events initiated by IRE1 are modulated by activation of other ER stress sensors or unfolded proteins in the ER.
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 IRE1, immunoprecipitation/Western blotting techniques to characterise the phosphorylation status of IRE1, and fluorescence microscopy to characterise the subcellular distribution of IRE1 in unstressed cells and cells experiencing endoplasmic reticulum stress.
The student will be trained in cloning, state-of-the-art molecular genetic and molecular biology techniques, as well as biochemical and cell biological techniques, including electrophoresis of proteins, Western blotting and immunoprecipitation techniques to characterise the phosphorylation status of IRE1α or cell-based assays to monitor cell viability and activation of cell death programs.
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).
Funding Notes
If you are interested in applying, send your CV and covering letter detailing your reasons for applying for this studentship to the prospective project supervisor, Dr. Martin Schröder, at martin.schroeder@durham.ac.uk.
References
1. Hetz, C., K. Zhang, and R.J. Kaufman, Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol, 2020. 21(8): p. 421-438.
2. Read, A. and M. Schröder, The Unfolded Protein Response: An Overview. Biology (Basel), 2021. 10(5): p. 384.
3. Yoshida, H., et al., XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell, 2001. 107(7): p. 881-91
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