The correct regulation of gene expression is critical to multicellular life. A key regulated step is mRNA translation; one regulatory mechanism is that ribosomes can stall on particular mRNA sequences until they are able to resume elongation or are released from the mRNA. Understanding ribosome stalling is critically important, as it is associated with proteotoxic stress in cells and neurodegenerative diseases. The aim of this project is to determine how ribosome stalling contributes to the regulation of translation during embryonic development. To address this question, a combination of molecular biology, biochemical, developmental biology, live imaging, genome editing and computational approaches will be used. We will exploit the Drosophila embryo as a model as it has several unique advantages that make it perfectly suited to this research. These include its rapid life cycle, tractability, ease of manipulation, amenability to genetic and genome engineering approaches, as well as recent advances that allow transcription and translation to be imaged live and at single molecule resolution. Firstly, existing data sets will be mined to identify mRNAs associated with ribosome pausing in the early embryo. Then, for a subset of these mRNAs, the presence of stalled ribosomes will be verified biochemically using extracts prepared from the early embryo. Following the validation of mRNAs with stalled ribosomes, we will exploit our ability to image translation at single mRNA resolution in the embryo in order to determine the translation kinetics on mRNAs with ribosome pause sites in vivo. Finally, ribosome pause sites will be mutated to determine the effect of reduced ribosome pausing on early embryonic development. Overall, findings from this research will provide new information about ribosome stalling, which is critical for cellular homeostasis and is misregulated in disease.
www.ashelab.com https://www.research.manchester.ac.uk/portal/mark.p.ashe.html
https://sgjlab.org
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.
Applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible.
How To Apply
To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website www.manchester.ac.uk/bbsrcdtpstudentships
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/
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