Characterization of the Rpd3 histone deacetylase as a stress signal transduction integration point

A competitively-funded PhD studentship to investigate the role of dinucleotides in the unfolded protein response is available from October 2015 in the groups of Dr. Martin Schröder and Dr. Paul Chazot in the School of Biological and Biomedical Sciences at Durham University. The studentship will include a three months industrial placement and a three months placement in the group of the project co-supervisor, Dr. Penny Lovat, at Newcastle University.
Endoplasmic reticulum (ER) stress has emerged as the underlying cause for several high-profile diseases afflicting Westernized societies, for example obesity-triggered type II diabetes and aging-associated neurodegenerative diseases including Parkinson’s and Alzheimer’s disease. The accumulation of mis- or unfolded proteins in the ER causes ER stress and activates the unfolded protein response. Three well-characterized ER membrane proteins, IRE1, PERK, and ATF6, sense the build-up of unfolded proteins in the ER and transduce the ER stress signal to the nucleus and cytoplasm to control gene expression programs and mRNA stability. Phosphorylation of the  subunit of the translation initiation factor eIF2 by the protein kinase PERK attenuates general cap-dependent translation initiation, but also stimulates translation initiation of mRNAs with specific structural features such as upstream open reading frames (uORFs) or internal ribosomal entry sites (IRES). The aim of this studentship is to characterise the role of translationally-regulated mRNAs in the mammalian unfolded protein response that have been identified in previous microarray-based screens in my group. Specifically, this project will ask how proteins encoded by some of these mRNAs are involved in transduction of the ER stress signal and how these proteins control viability of ER-stressed cells. These investigations will be performed in cell culture and ex vivo tissue culture models relevant to diseases caused by ER stress, such as type II diabetes and neurodegenerative diseases.
The studentship will provide methodological training in a large variety of state-of-the-art techniques ranging from protein biochemistry to molecular biology and sophisticated cell culture methodology. The successful candidate will employ a combination of gene knock-down technology using siRNAs or shRNAs, transfection, Western blotting, quantitative reverse transcriptase PCR, and characterization of gene silencing by miRNAs to successfully address the objectives of this project. In addition the student will be trained in the cultivation and differentiation of neuronal cells.
Applicants should possess at least a 2:1 Honours degree, or equivalent, in an appropriate subject (e.g. biochemistry, cell biology, molecular biology, neurobiology or biological sciences).