PhD Projects - Fully Funded
Dissecting the molecular pathways linking ribosome biogenesis, the nucleolar stress response and cell transformation
Supervisor: Dr Emma Thomson
Ribosome biogenesis is inextricably linked to cell growth and proliferation and uncontrolled cell growth is associated with increased levels of ribosome biogenesis. Further, it is emerging that the site of ribosome assembly, the nucleolus, acts as a key stress sensor, where many cellular stresses converge and act to trigger p53 stabilization resulting in growth arrest, apoptosis or cellular senescence. Multiple studies have suggested a link between ribosome biogenesis, cell transformation and the nucleolar stress response. However, the molecular mechanisms linking and regulating these processes remains largely uncharacterized. One factor that appears to connect these pathways is GLTSCR2 which has been shown to be directly involved in ribosome biogenesis and the nucleolar stress response. This project will investigate the overlapping roles that GLTSCR2 plays by dissecting the molecular interactions within each process to allow its disruption within one pathway, effectively uncoupling it from the other. This will be achieved using a combination of molecular biology techniques and subsequent in vivo analysis in embryonic stem cells.
The successful candidate will join a young and dynamic lab located within the highly collaborative environment of the Molecular biology and biotechnology department at the University of Sheffield. Candidates are expected to have, or about to obtain, an upper second class undergraduate degree in molecular biology, biochemistry or a related subject area. A Masters qualification in a similar area and relevant practical experience would be a distinct advantage
Developing de novo architectures of photosynthetic complexes for the control of photocurrent output from reaction centres
Photosynthesis, the ultimate source of most energy resources on Earth, starts with the absorption of solar energy by an extensive light-harvesting (LH) antenna consisting of hundreds of pigment molecules. The energy is then channelled towards specialised chlorophyll (Chl)-protein complexes called reaction centres (RCs), initiating a series of electron transfer reactions that capture some of the solar energy prior to its storage in a chemical form. Photosynthetic RCs operate with a quantum efficiency of 85-98%, far outstripping their artificial competitors. Thus, there is great interest in incorporating these RC’s into bio-hybrid devices that can absorb and transfer solar energy, and potentially generate electric current. In this project the candidate will biochemically purify native and artificial photosynthetic LH and RC proteins, develop ways to immobilize and pattern the proteins onto gold, glass and graphene surfaces using various surface chemistries and then investigate there function using fluorescence lifetime imaging and atomic force microscopy (including nonelectrical and nanomechanical imaging). The overall aim is to optimize these fabricated artificial photosynthetic networks in order to achieve efficient light absorption, excitation energy transfer and photocurrent generation. The candidate will receive extensive training in all relevant techniques as part of a large multidisciplinary research group.
|A new mathematical framework for Aβ peptide assembly in Alzheimer’s disease||
Amyloids are fibrous assemblies of misfolded protein which are responsible for a wide range of neurodegenerative diseases. While traditional models of nucleated polymerisation have been successfully applied to amyloid assembly under simplified experimental conditions, specific conditions in the human brain result in heterogeneous populations of immature assembly intermediates which add considerable complexity to the amyloid formation pathway. Although both atomistic and coarse-grained molecular dynamics simulations have provided crucial insights into the formation of these assemblies and their maturation into amyloid fibrils, computational limitations have prevented modelling of the entire amyloid assembly pathway. Moreover, although biochemical studies have provided evidence for positive feedback, by which mature fibrils facilitate the nucleation of additional amyloid fibrils and lead to spread of disease in the brain, the precise mechanistic details of this process have not been uncovered.
As part of an exciting new collaboration between the departments of Molecular Biology & Biotechnology and Physics & Astronomy at Sheffield, we are incorporating experimental biophysical and biochemical data into a realistic coarse-grained computational model of the amyloid-β (Aβ) peptide, the causative agent in Alzheimer’s disease. For this project, the successful candidate will take advantage of Sheffield’s high-performance computing facilities, including dedicated state-of-the-art Tesla P100 GPUs, to carry out large-scale Langevin Dynamics and Monte Carlo simulations using coarse-grained models. These simulations, which will be validated by additional atomistic dynamics simulations and comparison with structural and biophysical data, will then be used to predict the topology of amyloid assembly networks, and their associated transition rates and free energy changes. The physical data generated will then be incorporated into a generalised mathematical model of pathogenic Aβ assembly.
This project spans the fields of theoretical biophysics and computational structural biology. Techniques used will include molecular modelling, analysis of protein structures, statistical physics, and mathematical/computational modelling of the chemical kinetics of amyloid assembly. Together, the collaborators are part of a team of biochemists, physicists, and physical chemists studying the mechanistic basis of amyloid assembly. Due to the interdisciplinary nature of this project, applicants from physics, biology, applied mathematics, chemistry, or computer science will be considered. Because this project is primarily computational, prior experience of programming is essential. Experience in biochemistry/biophysics, molecular modelling, and/or statistical physics is desirable.
|Modelling complexity and redundancy in actin polymerization||
Cells contain very high concentrations of actin (100 mM). In vitro, it polymerises readily, but in vivo a pool is held in a monomeric state, but is capable of switching rapidly to different shapes of polymeric strands with appropriate stimuli. We now know many of the components of the system but we do not understand how they work. Why are there so many multiple weak interactions of similar affinity, and why are there tandem domains? Our hypothesis is that this complex system allows the cell to maintain high actin concentrations without catastrophic polymerization; and that it allows the system to switch to a different state (eg endocytosis) simply and rapidly, and switch off.
The project will use computational modelling as the main technique, using known affinities in the yeast Las17-actin-SLA1 system. Where key affinities are not known, the student will measure them using NMR, microscale thermophoresis or calorimetry. The project will provide training in both computational and experimental methods, and is expected to be a good example of systems biology at work. The student will be part of active labs focusing on actin polymerization (Ayscough), computation and NMR (Williamson, Craven). Computational experience is welcome but is not essentialEnquire
|Cryo-EM studies of Gene Loops and Transcription Control||
We will use the latest cryo-electron microscopy techniques to explore the structure of human genes engaged in transcription. The project will also give the student an opportunity to use the latest next generation DNA sequencing technologies to probe the functional activity of the protein complexes involved in transcription termination and maintaining gene architecture during transcription
|Structure and function of the Clostridium botulinum spore||
Future applications in the development of healthy and safe food will require a deep understanding of how bacteria can both spoil food and cause potentially lethal food poisoning. This multidisciplinary project will apply state of the art techniques of structural and molecular biology to investigate the food borne pathogen Clostridium botulinum and its close relatives. We are working towards interventions that could prevent C. botulinum spores from germinating and contaminating food. A crucial aspect of this work will involve mapping the proteins that make up spores in 3D molecular detail. To achieve this, we will exploit exciting new developments in microscopy - cryo-electron tomography - that allow us to visualise cells in unprecedented detail. We will create 3D images of the spore where we can even identify and locate individual molecules. We will then go on to visualise the structures of spores as they transform into active cells, as would happen when contaminated food is ingested. The project will exploit new developments in imaging methods that allow us to see the structures more clearly. It will involve combinations of molecular genetics, use and development of electron imaging approaches and computational image processing, tailored to suit the student’s interest.
|Understanding how magnetotactic bacteria respond to magnetic fields||
Some bacteria are magnetotactic, meaning that they have the unique capacity to sense and respond to a magnetic field. This means that we can manipulate the movement of these bacteria by simply exposing them to external magnetic fields. This capability is being exploited for biotechnological applications, such as turning bacteria into controllable drug delivery devices.
The molecular basis for motility in these bacteria is not well understood, and particularly how motility is affected by magnetic fields. We do know however that they move thanks to a flagellum, a corkscrew shaped appendage that generate thrust when it rotates. The aim of this project is to study the interplay between the magnetosome and the flagellum, using a range of approaches, covering biochemistry, structural biology, genetics, molecular biology, and microfluidics.
|Chickens, Chlorine and Campylobacter: New insights into the redox biology of the most prevalent food-borne bacterial pathogen||
Campylobacter jejuni is the most common cause of food-borne gastroenteritis in the western world. Human infections result from consumption of contaminated chicken and the incidence has increased in recent years, including the emergence of multi-drug resistant campylobacters. New interventions are needed to reduce the numbers of the bacteria in the food-chain. Proposals to introduce oxidative treatments in the UK such as chlorine washing of chicken carcasses are controversial and nothing is known about how C. jejuni responds to reactive chlorine species (RCS). This project will seek to understand RCS effects, especially oxidation of Met and Cys residues in proteins and how C. jejuni defends itself and reverses these effects, using cutting-edge proteomics analyses employing high-resolution mass spectrometry combined with mutant studies and biochemical analysis of protein function. Our approach will inform interventions to reduce the burden of Campylobacteriosis. This interdisciplinary project will provide training in molecular microbiological techniques including mutant construction and global protein expression analysis, as well as the application of proteomic techniques to an important biological problem.
|Single cell transcriptomics in plants: how variable is cell identity||
In multicellular organisms, individual cells must signal and respond to neighbouring cells and external signals in order to coordinate development. However, even with a single tissue, neighbouring cells of the same identity can be receiving different signals. This may impact on gene expression and their ability to respond to signals. Therefore, how similar are cells of the same identity in multicellular systems? We know very little about how much biological variability exists between individual cells within a single tissue and how this influences their ability to respond to external signals.
This project will answer these questions by performing single cell transcriptomic analyses coupled with computational biology methods. Working in the model plant Arabidopsis thaliana, you will isolate single cells by FACs sorting and sequence the transcriptomes. This will be followed by an in depth bioinformatics analysis, leading to further work in which imaging techniques will be used to analyse individual cells within leaves. The project will provide in depth training in molecular and computational biological techniques and is an exciting opportunity to advance our knowledge of cell identity and the significance of biological variability in systems.
|Combatting climate change by engineering crop water loss||
Supervisor: Prof. Julie Gray
Improving agricultural productivity under future climatic conditions will require the combination of efficient photosynthesis and stress tolerance. The production of drought tolerant cereal crops, with no yield penalty is a major goal for future agriculture, and of particular interest to our commercial partner, Biogemma.
Includes a tax-free stipend at the standard Research Council rate (~£14-£15K, to be confirmed for 2018)
|Uncovering underlying cellular mechanisms at work under high cell density E.coli protein production conditions in biotechnology||
Protein production for biopharmaceuticals is worth over $200 billion globally, with E. coli central to this sector. It is therefore key to more fully understand its’ behavior and physiology during industrially relevant growth conditions. This project will build on Proof-Of- Concept iTRAQ proteomics of E. coli under protein production conditions of a medically relevant model protein, with the aim to provide mechanistic insight into E. coli responses during recombinant protein production and apply this knowledge to guide media and strain engineering to enhance protein production and quality.
BBSRC DTP White Rose - Studentships commencing in October 2018
Deadline for applications: 5th January 2018.
Below are a list of PhD projects currently available in MBB funded by the BBSRC White Rose DTP.
The BBSRC White Rose DTP offers a 4-year programme of integrated research and skills training, with cross-disciplinary supervision and opportunities for professional internships with external partners.
Our vision is to train researchers of the future equipped to address and solve fundamental and strategic biological questions of national and global importance in the following areas:
• Food Security
• Industrial Biotechnology and Bioenergy
• World Class Bioscience
The programme builds on the excellent track records of the Universities of Leeds (The Faculties of Biological Sciences and Maths and Physical Science), Sheffield (Faculty of Science) and York (Departments of Biology and Chemistry) as leading centres of research and training in molecular and cellular biosciences.
These Projects are competitive studentships based at the University of Sheffield funded by BBSRC covering:
(i) a tax-free stipend at the standard Research Council rate (~£14-£15K, to be confirmed for 2018) for up to 4 years
(ii) research costs, and
(iii) tuition fees at the UK/EU rate for up to 4 years.
Studentships are available to UK and EU students who meet the UK residency requirements. Students from EU countries who do not meet the residency requirements may still be eligible for a fees-only award. Further information on eligibility Eligibility Criteria
Requirements: At least a 2:1 honours degree, or equivalent. There are language requirements for international students.
Application process: When you have found a project you want to apply for, you can apply using the University of Sheffield's online application form: Apply