Fixed-term

How do interaction mechanisms shape microbial ecosystems?

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Details Microbial ecosystems are some of the richest on the planet. For example, a single gram of soil can contain over a million different microbial species. This is an extraordinary amount of diversity for such a minute system, and how this diversity is maintained remains a mystery. Theoretical ecologists explain diversity using models built with ‘interactions’, the impact of one species on the growth of another. Microbes generally interact indirectly through changes to their chemical environment. Fierce competition for limited nutrients can cause one species to drive another to extinction, while secretion of beneficial metabolic by-products can help other community members. Many of these indirect mechanisms between species can occur simultaneously, leading to complex composite interactions in which the shifting balance between mechanisms in different chemical environments can create different interaction outcomes. For example, the presence of a toxin may cause one species to help another, while its absence may cause a harmful outcome instead. In this project, we will explore how the indirect basis of microbial interactions impacts their emergent ecology. Using a combination of ecological theory and controlled, lab-based experiments, we will address questions such as: – How do antibiotics change microbial interactions? – Is diversity maintained by mutual metabolic dependencies between microbes? – Can we engineer communities by chemically controlling interactions? The answers to these questions may have implications for human health (helping us to understand the role of microbes in the gut), planetary health (through microbes’ role in global carbon cycling) and agriculture (by helping us to suppress soil pathogens and boost nitrogen-fixing organisms). As part of the project, you will have the opportunity to learn cutting-edge techniques using the University of Sheffield’s world-class research facilities, including microscopy, high-throughput genomics and metabolomics. You will also learn how to integrate mathematical ecosystem modelling with experimental data. Our lab strongly supports cross-disciplinary approaches to research. We straddle the clusters of Molecular Microbiology and Ecology and Evolution, and you will have the opportunity to participate in the research culture of both through research seminars and social events. We are also integrated into a local network of researchers interested in applying ideas and techniques from physics to biological questions, which will provide the opportunity to develop partnerships with physicists and mathematicians outside the School of Biosciences. Please apply for this project using this link: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying Funding Notes Self-funded and externally funded students only References Key publication: https://doi.org/10.1111/ele.70027 Lab website: https://sites.google.com/sheffield.ac.uk/microbial-ecosystem-physics/home Apply Now

Peptide drug conjugates for cancer

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Details DNA damaging therapies have been successful in treating cancer patients for decades. The standard of care therapy for many cancers include small molecule inhibitors, however these therapies have widespread side-effects including; nephrotoxicity, hepatotoxicity and neurotoxicity. Greater than 25% of patients report serious side effects. There is a need to reduce toxicity in therapies. This PhD will use cell penetrating peptides, that have been shown to target cancer cells and chemically link them to small molecules that induce DNA damage. The purpose is to make novel peptide-drugs that can deliver safe therapies to patients that are highly effective. The PhD will work in both chemistry, cell biology and molecular laboratories designing and testing novel drugs. The candidate can be from either chemistry or molecular biosciences backgrounds. The PhD will use pharmacology techniques, synthesis of complex molecules, cell biology, molecular biology assays, immunological staining of cancer cells and imaging. Please apply for this project using this link: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying Funding Notes Self Funded or externally funded students only References Cirillo, S., et al., (2024) Antimicrobial peptide A9K as a gene delivery vector in cancer cells. European Journal of Pharmaceutics and Biopharmaceutics. Volume 198,114244, May, doi:10.1016/j.ejpb.2024.114244 Hadianamrei, R., et al.,. (2023) Surfactant like peptides for targeted gene delivery to cancer cells. Biochemical and Biophysical Research Communications. 652:35-45 Apr doi:10.1016/j.bbrc.2023.02.026 Cirillo, S., et al., (2021). Designed antitumor peptide for targeted siRNA delivery into cancer spheroids. ACS Applied Materials & Interfaces, 13(42), 49713-49728. doi:10.1021/acsami.1c14761 Apply Now

Bacteriophage engineering as a therapeutic strategy to target antibiotic resistant enterococci

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Details Due to the emergence of pathogens multi-resistant to antibiotics, there is a pressing need for novel antimicrobial strategies. Bacteriophages are highly suitable as therapeutic agents because they target specific pathogens within complex bacterial communities without causing a microbiome imbalance. Bacteriophages recognise specific structures at the bacterial cell surface and usually display a narrow host range, sometimes limited to a few strains. To circumvent this potential issue, phages isolated from the environment are combined to produce “phage cocktails” with an extended host range. An alternative approach is to carry out phage engineering to modify the receptor binding proteins, to generate tailored therapeutics. We propose to build on our preliminary work to develop phage therapeutics targeting Vancomycin-Resistant-Enterococci (VRE), which are opportunistic pathogens causing both community and hospital-acquired infections. The specific objectives of the project are the following: 1) Characterising the receptor binding proteins of phages targeting enterococci. We recently isolated virulent phages targeting Enterococcus faecalis and Enterococcus faecium. Three phages displayed high sequence identity but distinct host ranges. One phage was shown to recognise decorations of the Enterococcal Polysaccharide Antigen (EPA), variable between strains. Using the expertise of the primary supervisor in protein-bacterial cell wall interactions, we propose to investigate how phage receptor proteins recognise the EPA. We will use both bacterial mutants and phage resistant strains and in vitro interaction assays with recombinant receptor binding proteins and purified cell wall fragments to elucidate the molecular mechanism underpinning surface recognition by phages. 2) Engineering recombinant virulent phages with altered host range. Recombinant phages encoding distinct or combined receptor binding proteins will be assembled in vitro and “rebooted” using golden gate assembly to modify or expand their host range of. Using error-prone PCR, we will explore the possibility to generate phages with extended host range. 3) Exploring the therapeutic potential of recombinant phages. The antimicrobial activity of phages against planktonic cultures and biolfilms will be tested. We will also investigate how phages eradicate infections in the context of host-pathogen interaction using in vitro models and the zebrafish experimental model of infection. Please apply for this project using this link: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying References https://mesnagelab.weebly.com/ Apply Now

Characterisation of the role of extracellular proteases in controlling cancer cell behaviours.

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Details Breast and pancreatic tumours are characterised by excessive deposition of extracellular matrix (ECM) components, resulting in extensive fibrosis, which in turn promotes tumour progression and metastasis. Our lab has recently demonstrated that cancer cells, but not normal epithelial cells, are able to internalise ECM components, digest them in the lysosomes and use them as energy sources. Importantly, this process was required to promote cell growth and cell migration in both breast and pancreatic cancer cells. Therefore, identifying regulators of this process might lead to the development of novel anti-cancer therapies. Preliminary data indicate that the degradation of ECM by cathepsin proteases is required for ECM internalisation. The overall aim of this project is to elucidate the role of cathepsin in promoting cancer growth and migration, and define the molecular mechanisms behind it. In particular, this project is composed of 3 objectives: – Objective 1: we will characterise the expression of different members of the cathepsin family and elucidation of the role of specific cathepsins in controlling ECM uptake – Objective 2: as cathepsins are lysosomal protein that can be secreted, here we will define how cathepsin secretion works and whether this is stimulated during tumour progression – Objective 3: we will define the role of cathepsin in controlling cancer cell growth and invasion, using a variety of 2D and 3D cancer models. Together, this project will determine whether specific cathepsins might represent novel targets to prevent tumour growth and migration. Please apply for this project using this link: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying Funding Notes Self or externally funded students only. References Nazemi et al., PLOS Biology 2024 Martinez et al., PLOS Biology 2024 https://www.sheffield.ac.uk/biosciences/people/academic-staff/elena-rainero Apply Now

Investigating Roles for C9orf72 in Regulating FIS1-mediated Cell Death and Survival

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Details Mutation in the non-coding region of C9orf72 gene represents by far the most common genetic cause identified for amyotrophic lateral sclerosis (ALS), a rare, lethal, devastating but currently incurable, unstoppable and irreversible motor neuron disease. Moreover, reduced levels of C9orf72 transcript and C9orf72 (C9) expression have been associated with ALS patients, and C9orf72 is important for initiating autophagy (1), suggesting a mechanistic link between impaired autophagy and ALS pathogenesis. Intriguingly mitochondrial fission 1 protein (FIS1) is identified as a genetic interacting partner for C9 (2). FIS1 is a protein key to mitochondrial quality control and cell death induction (3, 4), and we have recently demonstrated that essential role for FIS1 for mitochondrial autophagy (mitophagy) induced by iron chelation drug deferiprone (DFP)(5, 6), which is under clinical trials (NCT02164253 and NCT03293069) for ALS treatment (7). This has led two questions: i) is C9 involved in initiating DFP-induced mitophagy? and ii) does C9 have a role in cell death mediated by FIS1? This project aims to answer the two questions. In addition to capitalising on the molecular biology, protein chemistry, imaging tools (e.g., mito-pHfluorin probe) and procedures, cell survival and death assays as well as model cell lines (WT and FIS1 knockout (KO) MEFs and WT and FIS1 KO HeLa cells) available in our lab, for manipulating cellular C9 levels, we will use validated C9 RNAi and constructs encoding C9 and C9 KO human cells as well as C9 and FIS1 binding defective mutants. With all these resources we are confident in determining the functional consequence due to the loss of C9orf72-Fis1 interaction in DFP-induced mitophagy and FIS1-induced cell death. To test the role of C9orf72 hexanucleotide in mitophagy induction by DFP and FIS1-mediated cell death, human C9 KO cells expressing C9orf72 WT and disease-causing C9orf72 mutant will be used through collaboration with Dr Hautbergue (8). Our mechanistic findings will be validated in motor-neuron-like NSC-34 cells and iPS-derived motor neurons. Outcomes from this project would reveal novel roles for C9 in mitophagy and cell death regulation and their relevance to ALS disease mechanisms. For more information about the project, or to discuss a potential application, please contact Dr Chun Guo (https://www.sheffield.ac.uk/biosciences/people/academic-staff/chun-guo; c.guo@sheffield.ac.uk) Science Graduate School As a PhD student in one of the science departments at the University of Sheffield, you’ll be part of the Science Graduate School. You’ll get access to training opportunities designed to support your career development by helping you gain professional skills that are essential in all areas of science. You’ll be able to learn how to recognise good research and research behaviour, improve your communication abilities and experience the breadth of technologies that are used in academia, industry and many related careers. Visit http://www.sheffield.ac.uk/sgs to learn more. Please apply for this project using this link: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying Funding Notes Available for self or externally funded students only. References 1. C. P. Webster et al., The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. Embo j 35, 1656-1676 (2016). DOI: 10.15252/embj.201694401 2. N. Chai et al., Genome-wide synthetic lethal CRISPR screen identifies FIS1 as a genetic interactor of ALS-linked C9ORF72. Brain research 1728, 146601 (2020). DOI: 10.1016/j.brainres.2019.146601 3. R. Iwasawa, A. L. Mahul-Mellier, C. Datler, E. Pazarentzos, S. Grimm, Fis1 and Bap31 bridge the mitochondria-ER interface to establish a platform for apoptosis induction. The EMBO journal 30, 556-568 (2011). DOI: 10.1038/emboj.2010.346 4. Q. Shen et al., Mutations in Fis1 disrupt orderly disposal of defective mitochondria. Molecular biology of the cell 25, 145-159 (2014). DOI: 10.1091/mbc.E13-09-0525 5. E. Waters et al., The SUMO protease SENP3 regulates mitochondrial autophagy mediated by Fis1. EMBO reports 23, e48754 (2022). DOI: 10.15252/embr.201948754 6. K. A. Wilkinson, C. Guo, Iron chelation promotes mitophagy through SENP3-mediated deSUMOylation of FIS1. Autophagy 18, 1743-1745 (2022). DOI: 10.1080/15548627.2022.2046898 7. C. Petillon et al., The Relevancy of Data Regarding the Metabolism of Iron to Our Understanding of Deregulated Mechanisms in ALS; Hypotheses and Pitfalls. Front Neurosci 12, 1031 (2018). DOI: 10.3389/fnins.2018.01031 8. L. M. Castelli et al., SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis. Mol Neurodegener 16, 53 (2021). DOI: 10.1186/s13024-021-00475-y Apply Now

The evolution and development of vertebrate skin appendage morphogenesis

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Details Project description: Morphogenesis—the process by which tissues acquire their shape—is central to the development and function of all multicellular life. It is increasingly clear that morphogenesis is often governed by a dynamic interplay between chemical (i.e. molecular) signalling and mechanical forces. However, this integrated control, known as mechanochemical signalling, remains poorly understood in vertebrates. Skin appendages are a diverse group of micro-organs, including scales, feathers, hair and teeth, that have been widely used as model systems to investigate embryonic development. This PhD project will investigate how mechanical cues influence chemical signalling to shape the development of skin appendages in two vertebrate models: the chicken embryo, a classical system in developmental biology, and the shark embryo, an emerging model from the cartilaginous fishes. Sharks display diverse scale morphologies across their body, providing an opportunity to investigate how mechanochemical systems underpin developmental diversity. This interdisciplinary project will use 3D fluorescence microscopy, biophysical analyses, transcriptomics (RNA-sequencing), and in vivo experimentation, to investigate and compare skin appendage development between the shark and chicken. This work will advance our understanding of how mechanical and chemical signalling interact to control morphogenesis, and how mechanochemical developmental processes have evolved across distinct vertebrate lineages. Candidate requirements: We welcome applicants with a strong background in biology, biophysics, biomedical sciences, or a related field. Experience in developmental biology, microscopy, or molecular biology is desirable but not essential. Applicants should demonstrate enthusiasm for evo-devo biology and interdisciplinary research. Please apply for this project using this link: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying Funding Notes This is a self-funded project. Applicants must secure their own funding or be eligible to apply for competitive doctoral scholarships. We are happy to support strong candidates in applying for institutional, national, or international funding opportunities. References For more information or to apply, please contact Dr Rory Cooper at r.l.cooper@sheffield.ac.uk Lab website: https://rorylcooper.wordpress.com/ Institution website: https://www.sheffield.ac.uk/biosciences/people/academic-staff/rory-cooper Selected relevant publications: Santos Durán, G., Cooper, R. L., Jahanbakhsh, E., Timin, G., & Milinkovitch, M. C., Self organised Patterning of Crocodile Head Scales by Compressive Folding. Nature 2025; 637, 375-383 Cooper, R. L., & Milinkovitch M. C., In-vivo sonic hedgehog pathway antagonism temporarily results in ancestral proto-feather-like structures in the chicken. PLOS Biology 2025; 23(3): e30003061 Cooper, R. L., Thiery, A. P., Fletcher, A. G., Delbarre, D., Rasch, L. J., & Fraser, G. J., An ancient Turing-like patterning mechanism regulates skin denticle development in sharks. Science Advances 2018; 4: eaau5484 Apply Now

Cell/extracellular matrix interaction during cell cycle progression: a novel role in controlling nucleotide metabolism?

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Details The deregulation of cell cycle progression is a common feature of cancer formation and progression. Cell/extracellular matrix (ECM) interaction is widely known to support the progression of the cells through the cell cycle. Recent data from our lab indicate that the internalisation of ECM components is promoted during the G1 phase of the cell cycle and this process is associated with an increased activation of mTOR signalling. Furthermore, we have shown that ECM uptake is, at least in part, mediated by b1 integrin, which internalisation seems to be induced when the cells are synchronised in G1 phase. These observations have been validated using the FUCCI system, a fluorescence-based reporter system which allow the visualisation of the different phases of the cell cycle without inducing any perturbation. Interestingly, cells in G1 strongly increase nucleotide synthesis, in preparation for DNA replication in S phase and our preliminary data suggest that ECM endocytosis might support nucleotide metabolism. This raises the intriguing hypothesis that ECM internalisation might support nucleotide synthesis in G1. In order to investigate this, this project will characterise: 1. The expression of known regulators of ECM internalisation and ECM receptors in the different phases of the cell cycle, to define the molecular mechanisms promoting ECM uptake in G1 2. The metabolic changes occurring in the different phases of the cell cycle, using a metabolomics approach, with a focus on nucleotide metabolism 3. The impact of ECM internalisation in controlling nucleotide synthesis Overall, this project will shed new light on how cell cycle progression is regulated, potentially identify novel therapeutic targets for the development of anti-cancer therapies. Please apply for this project using this link: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying Funding Notes Self or externally funded students only. References Nazemi et al., PLOS Biology 2024 Martinez et al., PLOS Biology 2024 https://www.sheffield.ac.uk/biosciences/people/academic-staff/elena-rainero Apply Now

Deciphering the evolution of male sexual ornaments and female preference in stalk-eyed flies

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Details The selected candidate will conduct cutting-edge research to investigate the evolution of male sexual ornaments and the role of female preference in shaping these traits. The project aims to unravel the underlying genomic, physiological, and behavioural mechanisms driving the elaborate displays, ornaments, and courtship behaviors observed in diverse species. Sexual selection is a powerful agent of evolution, responsible for some of the most striking traits in the animal kingdom. Many of these sexual traits are highly exaggerated, particularly in males, and are thought to have evolved as honest signals of male quality. Females then use these traits to decide who to mate and produce offspring with. Establishing how these traits arise is vital to understanding how and why the diversity of life is established and maintained. This project will study the evolution of male ornaments and female preferences using stalk-eyed flies. Stalk-eyed flies are a classic model of sexual selection as they exhibit highly-exaggerated eye-stalks, with males often having an eye span greater than their body length. Females prefer to mate with males with longer eye spans as it is an honest indicator of male quality. Specific questions and approaches taken can be tailored to the particular interests of the student, but objectives could include: (1) Applying cutting-edge genomic methods to study the development and evolution of honest male ornaments across numerous species (2) Develop innovative gene knockout techniques to identify the genes that produce honest traits (3) Design and execute laboratory experiments, such as experimental evolution and behavioural assays, to understand how sexual selection acts on honest traits and female preferences (4) Collaborate with neurobiologists to gain a deeper understanding of female preference and evolution of the brain and visual system The Team The PhD student will be joining a productive and collaborative research group in the School of Biosciences at the University of Sheffield. There will be many opportunities to collaborate with ongoing work in the lab. For more details see http://www.alisonewright.co.uk. Applicants are strongly encouraged to contact Dr Alison Wright, the lead supervisor, for more details on the group, project and facilities (a.e.wright@sheffield.ac.uk). Please apply for this project using this link: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying References www.alisonewright.co.uk Apply Now

How do plants reduce leaf growth at low humidity

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Details Short spells of hot dry air can cause fast desiccation of crop land, devastating crop yields. These ‘flash droughts’ are becoming more prevalent as the climate crisis worsens. This project will examine how the model plant, Arabidopsis, changes its canopy to cope with this kind of low humidity. At low humidity, plants produce smaller leaves with fewer stomata (pores) to prevent water loss, helping the plant survive. You will explore whether this reduction in leaf growth is due to hydraulic constraints on photosynthesis (closing stomata prevents CO2 uptake) or changes in growth regulating hormones such as abscisic acid, gibberellin, auxin and ethylene. You will work closely with Dr Jim Rowe, an expert in plant stress biology, molecular biology, imaging and image analysis and to learn modern research techniques, experimental design and data analysis methods. In this project, you will use the following techniques: Cutting edge microscopy (confocal and FRET) to image biosensors to detect hormone and sugar concentrations Raspberry pi cameras to track leaf growth over time in a variety of mutants Stomatal impressions and microscopy to count stomata Image analysis to measure stomatal number, leaf size and hormone concentrations Photosynthesis/water loss measurement Stress response assays Molecular biology and genetics 3D printing Microcontroller usage Lab Culture A culture of respect, dignity and safety and are at the heart of the Rowe research group. We believe that by helping each other, and fostering a collaborative, open team, we help each other achieve our goals. Diverse teams are not only fairer, but also more effective (e.g. https://www.nature.com/articles/s41467-018-07634-8) and we hope that anyone would feel welcome in the Rowe group. Before starting his group, Jim spent six years sitting on the SLCU Equality, Diversity and Inclusion committee, leading the Careers and Development committee. Candidate A good undergraduate honours degree in a relevant science subject is required. Any further research stays, publications or experience with imaging, plant growth / physiology, molecular biology, 3D printing, electronics or programming experience would be looked on favourably. The ideal candidate would have a thirst for knowledge, enthusiasm for plant science research and be eager to try or develop new techniques. Application For more information on the project/lab/university, candidates should email Dr Jim Rowe, but all applications should be through the web portal at https://www.sheffield.ac.uk/postgraduate/phd/apply/applying . Candidates should include a 2-page CV and a 1-page personal statement and explaining their experience and interest in the project. Funding Notes There is no funding allocated to this project and so the applicant would need to secure their own external funding in order to apply. References https://www.sheffield.ac.uk/biosciences/people/academic-staff/jim-rowe Apply Now

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