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  EASTBIO: Modelling competition inside the cell: understanding how exogeneous and endogenous mRNAs compete for translational resources


   School of Natural and Computing Sciences

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  Prof M. C. Romano, Prof I Stansfield, Prof F Davidson  No more applications being accepted  Competition Funded PhD Project (UK Students Only)

About the Project

Supervisors:

Professor Maria Carmen Romano - Physics Department, School of Natural and Computing Sciences - [Email Address Removed]

Prof Ian Stansfield - Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen - [Email Address Removed]

Professor Fordyce Davidson - Mathematics, School of Science and Engineering, University of Dundee - [Email Address Removed]

Cells in any living system depend on the regulated production of proteins using the information encoded in genes at DNA level. How cells regulate the amount of proteins that they produce is crucially important in biotechnology, during production of therapeutic proteins, and in medicine, when infection of a cell by a virus can change the functioning of the host gene expression system.

The main objective of this project is to apply physics to develop a mathematical model that predicts how protein production is regulated within cells, and specifically, how protein production is affected when foreign mRNAs (e.g. viral) are introduced into a cell. This exciting application of physics will for the first time allow understanding of the highly complex processes that underpin cell functioning in health and disease, as well as every biotechnological process.

To make proteins in the cell, foreign mRNAs are translated into proteins using molecular machines called ribosomes. The ribosomes bind to the mRNA and advance through a series of 3-nucleotide (codon) steps, in doing so adding one amino acid at each step, until the mature protein has been assembled. This process can be mathematically described using a well-established model of transport in statistical physics called Totally Asymmetric Exclusion Process (TASEP). In this model, the mRNA is described by a one-dimensional lattice along which particles (ribosomes) can hop stochastically from site to site.

We have now extended the model to consider other translation resources, such as the small diffusing molecules called transfer RNAs that supply the amino acids to the ribosome. Cellular mRNAs compete for the same pool of translational resources with viral or other foreign RNAs such as those introduced in a biotechnology process, where cells are used as factories to produce proteins of interest for pharmaceutical or food industry purposes. In doing so, the balance of translational resource is distorted. Understanding how the balance between demand and supply for translational resources is distorted is critically important not only to understand gene expression regulation, but also for optimisation of heterologous gene expression.

Using physics, and sophisticated mathematical models of gene expression, the PhD student will work in a highly interdisciplinary team led by 3 supervisors (Physics, Mathematics and Molecular Biology), who have a long-established collaboration on this topic. Training in mathematical modelling and molecular biology will be provided, relevant for a wide range of research and other career destinations.

Application Procedure:

Please visit this page for full application information: BBSRC EASTBIO Doctoral Training Partnership Studentship | The School of Medicine, Medical Sciences and Nutrition | The University of Aberdeen (abdn.ac.uk)

Please send your completed EASTBIO application form, along with academic transcripts to Alison Innes at [Email Address Removed]

Two references should be provided by the deadline using the EASTBIO reference form.

Please advise your referees to return the reference form to [Email Address Removed]

Unfortunately, due to workload constraints, we cannot consider incomplete applications

Biological Sciences (4)

Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership.
This opportunity is open to home/UK candidates (including EU nationals that hold UK settled or pre-settled status) and provides funding to cover a stipend and tuition fees. Please refer to UKRI website and Annex B of the UKRI Training Grant Terms and Conditions for full eligibility criteria.
Candidates should have (or expect to achieve) a minimum of a 2:1 UK Honours degree, or the equivalent qualifications gained outside the UK, in a relevant subject.

References

[1] L Ciandrini , I Stansfield , M C Romano (2013) Ribosome Traffic on mRNAs Maps to Gene Ontology: Genome-wide Quantification of Translation Initiation Rates and Polysome Size Regulation. PLOS Computational Biology 9(1): e1002866.
[2] M R McFarland, C D Keller, B M Childers, S A Adeniyi, H Corrigall, A Raguin, M C Romano, I Stansfield (2020), The molecular aetiology of tRNA synthetase depletion: induction of a GCN4 amino acid starvation response despite homeostatic maintenance of charged tRNA levels, Nucleic Acids Research, 48 (6), 3071–3088.
[3] L Wang, M C Romano, and F A Davidson, Translational control of gene expression via interacting feedback loops (2019), Phys. Rev. E 100, 050402(R).

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