Fixed-term

Details High-grade serous ovarian cancer (HGSOC) is the most lethal gynaecological malignancy, with survival rates that have changed little in decades. Two persistent challenges contribute to this: most cases are diagnosed only at an advanced stage, and even when initial chemotherapy is effective, relapse with drug-resistant disease is common. Tackling both late detection and therapy resistance remains a major unmet need. Within our programme there are several complementary strands of work addressing these challenges. One area seeks to understand the earliest stages of HGSOC development in the fallopian tube, where pre-cancerous serous tubal intraepithelial carcinoma (STIC) lesions provide a potential window for earlier detection. Another focuses on how altered DNA-damage response pathways and novel protein-modifying systems contribute to chemoresistance in established tumours. Together, these strands offer opportunities to generate new insights into disease biology and to identify targets for improved diagnosis and treatment. Potential projects in this space could include developing and characterising patient-derived or organoid models of early lesions to study their secreted factors as candidate biomarkers, or interrogating post-translational modifications and repair pathways that enable tumour cells to withstand chemotherapy. Findings from such work would be integrated with clinical material from Manchester’s partner hospitals to ensure translational relevance. You will receive training in state-of-the-art molecular biology, cell biology, proteomics, and translational cancer research methods, and have scope to tailor the project within these themes. By investigating either early lesion biology or mechanisms of therapy resistance, the research has potential to contribute to earlier detection, better patient stratification and the development of more effective, less invasive treatments for women with the hardest-to-treat ovarian cancers. Further information on our research and institute can be found here: Genome Stability Lab (GSL) Entry requirements Applicants are expected to hold (or about to obtain) a minimum upper second-class undergraduate honours degree (or equivalent) in Biochemistry, Cancer Sciences, Biotechnology, or Cell Biology or another related subject area. Research experience in Molecular Biology, Biochemistry, Cell Biology and Ovarian Cancer is desirable. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How To Apply For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select PhD Cancer Sciences. For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit https://www.bmh.manchester.ac.uk/study/research/programmes/integrated-teaching/ Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk. 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/ Funding Notes Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/funding-fees/fees/ References 1. Wang Z , Foster BM , da Costa IC , Wu Y , Behera D , Conte F , Trotter EW , Cabello-Lobato MJ , Choudhary S , Wiener R ,Beli P, Smith DL , Banks WH, Bagley S , McKee S , Minnis M, Meyer S , Chaplin AK, Dörner W, Mootz D , Hagan IM , Galanty Y, Larrosa I, Cliff MJ, Schmidt CK. UFMylation orchestrates chromatin engagement of core NHEJ components to promote DNA double-strand break repair. bioRXiv (2025). https://www.biorxiv.org/cgi/content/short/2025.06.16.659844v1 2. Schmidt CK*, Medina-Sánchez M*, Edmondson RJ, Schmidt OG*. Engineering microrobots for targeted cancer therapies from a medical perspective. Nature Communications (2020). DOI: 10.1038/s41467-020-19322-7. 3. Xu H, Medina-Sánchez M*, Zhang W, Seaton M, Brison DR, Edmondson RJ, Taylor SS, Nelson L, Zeng K, Bagley S, Ribeiro C, Restrepo LP, Lucena E, Schmidt CK*, Schmidt OG*. Human spermbots for patient-representative 3D ovarian cancer cell treatment. Nanoscale (2020). DOI: 10.1039/D0NR04488A. 4. Cabello-Lobato MJ, Jenner M, Cisneros-Aguirre M, Brüninghoff K, Sandy Z, da Costa IC, Jowitt TA, Loch CM, Jackson SP, Wu Q, Mootz HD, Stark JM, Cliff MJ, Schmidt CK. Microarray screening reveals two non-conventional SUMO-binding modules linked to DNA repair by non-homologous end-joining. Nucl. Acids Res. (2022). 50(8), 4732. 5. Osborne HC, Foster BM, Al-Hazmi H, Meyer S, Larrosa I, Schmidt CK. Small-molecule inhibition of CBX4/7 hypersensitises homologous recombination-impaired cancer to radiation by compromising CtIP-mediated DNA end resection. Cancers (2024). 16 (11), 2155.

Details Background: Psoriatic arthritis (PsA) is an inflammatory arthritis which causes joint inflammation, pain and resultant disability. PsA affects up to 30% of those with psoriasis (PSc). It is a genetically complex disease, characterised by environmental and genetic risk factors. Biologic drugs, such as TNF inhibitor (TNFi) drugs are prescribed to treat the disease. Not everyone responds to TNFi medication, however, up to 30-40% of patients will experience non-response. Targeting TNFi medication to those who are most likely to respond would be a major shift in treatment leading to a stratified/precision medicine approach. Genomic, transcriptomic and proteomic studies have discovered putative signals of association with response. It is unlikely that a single omics platform will be predictive for translation into the clinic, however. This project incorporates advanced methodologies such as machine learning to uncover molecular mechanisms underlying TNFi response, setting the foundation for stratified, precision medicine approaches in PsA and PSc. Aim: This project will measure and integrate multi-omics to develop a model of response to advanced therapeutics in psoriatic arthritis and psoriasis. Methods: Patient data and blood samples from the Outcomes of Treatment in PsA Study Syndicate (OUTPASS) will be available. Corresponding data from psoriasis will be from The Biomarkers and Stratification To Optimise outcomes in Psoriasis study (B-STOP) established in 2011 led from King’s College London. The successful candidate will: 1.  conduct a literature review to establish previously identified multi-omics predictors of response to TNFi. 2.  Proteomic Techniques: Proteome-Wide Hypothesis-Free Screening will identify novel biomarkers. 3.  Mendelian Randomization will evaluate causal relationships between specific proteins and TNFi response 4.  Genetic and transcriptomic data has been generated for a sub-set of these patients. Machine learning models will predict TNFi response, integrating multi-omics data. Eligibility  Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Bioinformatics Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk 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: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/

Details Melanoma, a deadly skin cancer, exhibits remarkable adaptability, enabling metastasis, therapy resistance, and immune evasion. Central to this adaptability is the ability of melanoma cells to transition between distinct functional states, a process rooted in mechanisms of cell fate choice. These transitions are driven by dynamic interactions between transcription factors, such as Sox10, Zeb1 and Mitf, which define tumour cell phenotypes and influence therapy response. Understanding how these factors coordinate cell fate decisions is essential for identifying novel therapeutic vulnerabilities. This PhD project will unravel how intrinsic gene regulatory networks and extrinsic signalling cues drive cell fate choice in melanoma plasticity. This PhD project will focus on exploring the transcriptional dynamics of Sox10, Zeb1 and Mitf during melanoma cell-state transitions. Using cutting-edge CRISPR-mediated fluorescent reporter models, advanced imaging, and transcriptomic analyses, the candidate will: 1. Investigate Sox10, Zeb1 and Mitf expression dynamics and regulation under diverse environmental and genetic conditions. 2. Uncover molecular mechanisms and regulatory networks driving melanoma cell-state transitions. The successful candidate will be part of an interdisciplinary team, collaborating with mathematicians and employing state-of-the-art techniques such as high-resolution imaging, siRNA screening, and ‘Omics analyses to understand and perturb mechanisms of multipotency and plastic adaptation in melanoma. This work will generate critical insights into cancer biology, with the goal of identifying novel therapeutic strategies. We seek a highly motivated candidate with a strong academic background in cancer biology, molecular biology, life sciences or related fields. We will accept self-funded applicants to this post. Applicants with Master’s-level research experience or equivalent lab-based experience are particularly encouraged to apply. Candidates are expected to hold (or be about to obtain) a minimum 2:1 Bachelors Degree with Honours (or equivalent) in a related area/subject. We would be particularly happy to receive applications from individuals with a strong academic track record and Masters-level and/or other laboratory research experience in cancer biology or life sciences. Additional computational or maths training would be viewed favourable (although not essential). Eligibility  Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Cancer Sciences Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk 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: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band Standard fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/ References Gopalan, V., Day, C.P., Perez-Guijarro, E., Lee, M.P., Yang, H.H., Alves-Constantino, M., Sassano, A., Smith, C., Chin, S., Ebersole, J., Gruen, C., Wu, E., Hannenhalli, S., Merlino, G., and Marie, K.L. Comprehensive single-cell transcriptomic analysis of embryonic melanoblasts uncovers lineage-specific mechanisms of melanoma metastasis and therapy resistance. (2022) bioRxiv 2022.10.14.512297; doi: https://doi.org/10.1101/2022.10.14.512297 Marie KL, Sassano A, Yang HH, Michalowski AM, Michael HT, Guo T, Tsai YC, Weissman AM, Lee MP, Jenkins LM, Zaidi MR, Pérez-Guijarro E, Day CP, Ylaya K, Hewitt SM, Patel NL, Arnheiter H, Davis S, Meltzer PS, Merlino G, Mishra PJ. Melanoblast transcriptome analysis reveals pathways promoting melanoma metastasis. Nature Communications. 2020 Jan 16;11(1):333. Johansson JA*, Marie KL*, Lu Y, Brombin A, Santoriello C, Zeng Z, Zich J, Gautier P, von Kriegsheim A, Brunsdon H, Wheeler AP, Dreger M, Houston DR, Dooley CM, Sims AH, Busch-Nentwich EM, Zon LI, Illingworth RS, Patton EE. PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation. Developmental Cell. 2020 Aug 10;54(3):317-332.e9. Pérez-Guijarro E, Yang HH, Araya RE, El Meskini R, Michael HT, Vodnala SK, Marie KL, Smith C, Chin S, Lam KC, Thorkelsson A, Iacovelli AJ, Kulaga A, Fon A, Michalowski AM, Hugo W, Lo RS, Restifo NP, Sharan SK, Van Dyke T, Goldszmid RS, Weaver Ohler Z, Lee MP, Day CP, Merlino G. Multimodel preclinical platform predicts clinical response of melanoma to immunotherapy. Nature Medicine. 2020 May;26(5):781-791. Davis JR, Ainslie AP, Williamson JJ, Ferreira A, Torres-Sánchez A, Hoppe A, Mangione F, Smith MB, Martin-Blanco E, Salbreux G, Tapon N. ECM degradation in the Drosophila abdominal epidermis initiates tissue growth that ceases with rapid cell-cycle exit. Curr Biol. 2022 Mar 28;32(6):1285-1300.e4. doi: 10.1016/j.cub.2022.01.045. Epub 2022 Feb 14. PMID: 35167804; PMCID: PMC8967408.

Details Overview This project will explore recently discovered mechano-sensitive cancer cell signalling pathways and seeks to understand the mechanisms by which force is transmitted from the tumour microenvironment into the nucleus to control tumour growth. Background and hypothesis Early diagnosis is one of the most powerful tools for improving cancer outcomes and reducing both the economic and personal burden of disease. Lung cancer remains the leading cause of cancer-related death worldwide, and its early detection is particularly challenging. To address this, we must better understand the biological mechanisms that drive tumour progression at its earliest stages. This PhD project investigates how mechanical forces within the lung tumour microenvironment influence cancer cell behaviour and immune cell interactions. Gene dysregulation is a hallmark of cancer, and recent evidence suggests that physical changes in the extracellular matrix (ECM), such as tissue stiffening, can directly alter gene expression by transmitting force to the cell nucleus. However, the molecular mechanisms that link mechanical cues to gene regulation and immune modulation remain poorly understood. We have discovered that a subset of cell adhesion proteins, typically found at the cell surface, can localise to the nucleus and regulate gene expression. Several of these proteins regulate the cytoskeleton, which transmits force from the cell surface to the nuclear envelope. This project will explore how selected cytoskeleton regulators contribute to mechanosensitive gene regulation and how this affects immune cell phenotypes in lung cancer. Key approaches You will use cutting-edge techniques, including genome editing, tuneable biomaterials, proximity-dependent proteomics and quantitative mass spectrometry, chromatin mapping, RNA sequencing, immune profiling and advanced microscopy. Team This interdisciplinary project is supported by a collaborative team with expertise in cancer cell adhesion, mechanobiology, lung immunology and bioinformatics. You will receive training in advanced cell biology, genomics, proteomics and computational network modelling. You’ll be part of a friendly, supportive team committed to scientific excellence and innovation. Candidates are expected to hold (or be about to obtain) a minimum 2:1 Bachelors Degree with Honours (or equivalent) in cell biology, molecular biology, biochemistry or cancer biology. Research experience in a wet-lab environment is highly desirable. Eligibility  Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline. Before you Apply  Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply  To be considered for this project you MUST submit a formal online application form – on the application form select PhD Cell Biology Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk 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: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/ References Li Mow Chee, F., Beernaert, B., Griffith, B. G. C., Loftus, A. E. P., Kumar, Y., Wills, J. C., Lee, M., Valli, J., Wheeler, A. P., Armstrong, J. D., Parsons, M., Leigh, I. M., Proby, C. M., von Kriegsheim, A., Bickmore, W. A., Frame, M. C., Byron, A.* Mena regulates nesprin-2 to control actin-nuclear lamina associations, trans-nuclear membrane signalling and gene expression. Nat. Commun. 14, 1602 (2023). doi: 10.1038/s41467-023-37021-x Ginn, L., Maltas, J., Baker, M. J., Chaturvedi, A., Wilson, L., Guilbert, R., Amaral, F. M. R., Priest, L., Mole, H., Blackhall, F., Diamantopoulou, Z., Somervaille, T. C. P., Hurlstone, A., Malliri, A.* A TIAM1-TRIM28 complex mediates epigenetic silencing of protocadherins to promote migration of lung cancer cells. Proc. Natl. Acad. Sci. USA 120, e2300489120 (2023). doi: 10.1073/pnas.2300489120 Byron, A.*, Griffith, B. G. C., Herrero, A., Loftus, A. E. P., Koeleman, E. S., Kogerman, L., Dawson, J. C., McGivern, N., Culley, J., Grimes, G. R., Serrels, B., von Kriegsheim, A., Brunton, V. G. and Frame, M. C. Characterisation of a nucleo-adhesome. Nat. Commun. 13, 3053 (2022). doi: 10.1038/s41467-022-30556-5 Payapilly, A., Guilbert, R., Descamps, T., White, G., Magee, P., Zhou, C., Kerr, A., Simpson, K. L., Blackhall, F., Dive, C., Malliri, A.* TIAM1-RAC1 promote small-cell lung cancer cell survival through antagonizing Nur77-induced BCL2 conformational change. Cell Rep. 37, 109979 (2021). doi: 10.1016/j.celrep.2021.109979 Mann, E. R., Menon, M., Knight, S. B., Konkel, J. E., Jagger, C., Shaw, T. N., Krishnan, S., Rattray, M., Ustianowski, A., Bakerly, N. D., Dark, P., Lord, G., Simpson, A., Felton, T., Ho, L. P.; NIHR Respiratory TRC; Feldmann, M.; CIRCO; Grainger, J. R.*, Hussell, T.* Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19. Sci. Immunol. 5, eabd6197 (2020). doi: 10.1126/sciimmunol.abd6197

Details Idiopathic pulmonary fibrosis (IPF) is a severe progressive chronic respiratory condition, affecting 3 million individuals globally 1. Life expectancy post diagnosis is roughly 3-4 years, with diagnosis often occurring late 2,3. Exacerbations in IPF are characterised by diffuse alveolar damage in the airways, which also drastically impact life expectancy with studies citing only a 50% survival rate for patients 3 months post exacerbation 4. Only recently have researchers began to unveil the role of infection in these acute exacerbation (AE) events. Showing that like in other chronic respiratory conditions, respiratory viruses and bacteria may contribute to IPF disease pathology. Studies indicate that 34.8% of acute exacerbations are due to infection 5, with AEs largely occurring in winter months again providing evidence for an infectious seasonal viral cause of exacerbations 5-7. In another study exploring AEs in hospitalized patitents, researchers observed respiratory infection with viruses in 17.9% of patients and bacteria in 10.4% of patients8. Rhinovirus was the most prevalent virus (7.1%) and Haemophilus influenzae most prevalent bacteria (4.8%). This study further explored the prevalence and impact of co-infection on IPF patients. Co-infection was observed in 59.4% of patients and this was associated with lower FVC and higher mortality rates 8. Broad-spectrum antibiotics are widely prescribed (56% patients) during acute exacerbations 9. A randomised control trial to assess the impact of antibiotic use in IPF patients (Co-trimoxazole), found increased quality of life and reduce mortality rates in the test group 10. The lung microbiome is increasingly recognised as a critical factor in respiratory health and disease. In IPF, the microbial community structure appears altered, with shifts in abundance of key lung commensals and a reduction in overall microbial diversity compared to healthy individuals 11,12. Studies in IPF have shown at the time of diagnosis IPF patients have a higher abundance of bacteria in the airways, but lower bacterial diversity. Veillonella, Neisseria, Streptococcus and Haemophilus species were predominant in IPF airways, and reduced levels of proteobacteria were observed compared to healthy controls 11,13. Skewed microbiome was associated with more rapid disease progression and mortality. In another study the presence of Streptococcus spp and Staphylococcus spp in the lower airways was associated with disease progression and mortality 14. These changes may contribute to a pro-inflammatory airway environment and heightened susceptibility to infections. Using primary airway epithelial cells (AECs) as a physiologically relevant model, we aim to explore how the presence or absence of key commensal bacteria influences the outcome of viral and bacterial infection in the IPF airway. Understanding these interactions could reveal whether restoring or supporting beneficial microbial communities reduces the severity of infection-driven exacerbations. Such insights may open opportunities for novel therapeutic strategies, including microbiome-targeted interventions, to complement existing antifibrotic and antimicrobial approaches in IPF management. To do this we will model bacterial and viral infections in the respiratory tract in IPF using primary differentiated airway epithelial cells. Then expand these models to co-culture these organisms with respiratory flora. Using these models, we will evaluate how biofilm formation, inflammation and airway damage as well as other factors differs in health and disease. Focus will be on key respiratory pathogens, Streptococcus pneumoniae, H. influenzae, Staphylococcus aureus, Pseudomonas aeruginosa and Rhinovirus, known to cause exacerbations in individuals with chronic respiratory disease. We will then explore how these readouts differ in the presence of beneficial airway microbes. The main questions we wish to answer are: 1.    Can we develop models to study the impact of infection in IPF? 2.    Does biofilm formation, inflammation, and other disease markers differ in health and disease in response to infection in IPF? 3.    Can respiratory flora and non-intestinal GRAS (generally regarded as safe) bacteria reduce the impact of infection in the IPF airway? 4.    Can primary airway epithelial infection models be used to evaluate novel biotherapeutics and  antimicrobial susceptibility. Candidates are expected to hold (or be about to obtain) a minimum 2:1 Bachelors Degree with Honours (or equivalent) in a related area/subject. An MSc/ MRes degree (merit or above) is desirable. Candidates with experience in bacteriology and/or virology are encouraged to apply. Also experience in working with tissue culture cells/ primary cells is desirable. Eligibility  Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline. Before you Apply  Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply  To be considered for this project you MUST submit a formal online application form – on the application form select PhD Infectious Diseases Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk 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: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/ References Abbas, N., Willmott, T., Campbell, P. M., Singh, G., Basu, M., Reid, F., & McBain, A. J. (2025). Distinct microbiome profiles on vaginally inserted polypropylene mid-urethral mesh slings compared to vaginal, urinary, and skin microbiomes. Applied and Environmental Microbiology, 91(7), e02463-24. https://doi.org/10.1128/aem.02463-24. Mercer, S.D., Doherty, C., Singh, G., Willmott, T., Cheesapcharoen, T., Teanpaisan, R., O’Neill, C., Ledder, R.G. and McBain, A.J. (2025) ‘Lactobacillus lysates protect oral epithelial cells from pathogen-associated damage, increase secretion of pro-inflammatory cytokines and enhance barrier integrity’, Scientific Reports, 15(1), 5894. doi:10.1038/s41598-025-86914-y. Dilhari, A., Campbell, P. M., Munasinghe, A., Brown, H., Kaluarachchi, T. D. J., Gunasekara, C., Pathirage, S., Fernando, N., Weerasekara, D., Humphreys, G. J., McBain, A. J., & Weerasekera, M. (2024). Biofilms and microbiome profiles in chronic wounds: Links to antibiotic use and wound severity in a Sri Lankan cohort. Journal of Applied Microbiology, 135(11), lxae262. https://doi.org/10.1093/jambio/lxae262 Aljohani, A. M., El-Chami, C., Alhubail, M., Ledder, R. G., O’Neill, C. A., & McBain, A. J. (2023). Escherichia coli Nissle 1917 inhibits biofilm

Details Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmia syndrome characterized by the onset of life-threatening arrhythmias during exertion or emotional stress. CPVT is caused by mutations of the cardiac ryanodine receptor gene (RYR2). Mutations of RYR2 predispose to the onset calcium waves delayed afterdepolarization that lead to arrhythmias especially following adrenergic stimulation. Most of these mutations are missense mutations (substitution of one amino acid). Deletion of the third exon of RYR2 (exon-3 deletion) causes a more complex syndrome characterized by a combination of typical CPVT, dilated cardiomyopathy and sinus node dysfunction. The mechanisms responsible for this complex syndrome are not understood. The main objective of this project will be to elucidate these mechanisms and identify potential treatment strategies. An inducible pluripotent stem cell (iPSC) line with exon-3 deletion will be generated from the control line using well-established genome editing techniques. The iPSC will be differentiated into cardiac ventricular myocytes and sinus node myocytes using standardized differentiation protocols. A detailed transcriptomic study will be performed to understand whether exon -3 deletion causes any alterations in the cardiac transcriptome that can explain the onset of cardiomyopathy. Fluorescent indicators (both biological and non-biological) will be utilized to characterize Calcium transient and action potential characteristics both at baseline and following adrenergic stimulation. Ca waves, delayed afterdepolarizations and arrhythmias will be induced using adrenergic stimulation and/or cardiac glycosides. Finally we will test the efficacy of various anti-arrhythmic agents in preventing calcium waves, delayed afterdepolarizations and arrhythmias. Candidates are expected to hold (or be about to obtain) a minimum 2:1 Bachelors Degree with Honours (or equivalent) in a related area/subject. Eligibility  Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Cardiovascular Sciences Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk 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: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/ References Bhuiyan ZA, van den Berg MP, van Tintelen JP et al. Expanding spectrum of human RYR2-related disease: new electrocardiographic, structural, and genetic features Circulation. 2007 Oct 2;116(14):1569-76 Steinberg C, Roston TM, van der Werf C et al. RYR2-ryanodinopathies: from calcium overload to calcium deficiency Europace. 2023 Jun 2;25(6):euad156 Toth N, Zhang XH, Zamaro A, Morad M. Calcium Signaling Consequences of RyR2-S4938F Mutation Expressed in Human iPSC-Derived Cardiomyocytes Int J Mol Sci. 2023 Oct 18;24(20):15307

Details Respiratory viral infections such as those caused by influenza viruses, respiratory syncytial viruses or coronaviruses are a major cause of morbidity and mortality globally. Patterns of human immune responses to viruses and how this impacts risk of infections or onset/exacerbation of chronic respiratory diseases is increasingly being recognised. However, how human immune responses to viruses affect antimicrobial responses to a second unrelated infectious diseases agent is not fully understood and this is critical to prevent the development of polymicrobial respiratory infections which frequently require the use of combinatorial antimicrobial therapy. The aim of this project is to understand how viral infections shape antifungal immunity and whether these responses are aberrant in patients with underlying respiratory conditions. We will focus on the effect of viral exposure (influenza and respiratory syncytial viral infections) on antimicrobial responses against the mould pathogen Aspergillus fumigatus because is a frequent cause of disease in immunocompromised patients and in those with a prior respiratory condition such as asthma. We will use a range of immunological and microbiological approaches to identify the main pathways that contribute to shape antifungal responses upon viral infection. We will explore whether stimuli, cytokines and underlying condition as variables allow us to provide a framework for a greater understanding of host susceptibility and responses to secondary infections. We will also explore whether the fungal community in the respiratory tract (mycobiome) can influence host responses to viral infections. Candidates are expected to hold (or be about to obtain) a minimum 2:1 Bachelors Degree with Honours (or equivalent) in Biology or a related area / subject. Candidates with experience in molecular biology approaches or with an interest in fungal biology, virology and host-pathogen interactions are encouraged to apply. Eligibility  Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Microbiology Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk 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: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/ References Weaver D, Gago S, Bassetti M, Giacobbe DR, Prattes J, Hoenigl M, Reizine F, Guegan H, Gangneux J-P, Bromley MJ, Bowyer P. Mycobiome analyses of critically ill COVID-19 patients. Microbiol Spectr. 2025 Feb 4;13(2):e0411023. doi: 10.1128/spectrum.04110-23. Epub 2024 Dec 19. Lin L, Curtin JA, Regis E, Hirsman A, Howard R, Tutino M, Edwards MR, Prosperi M, Simpson A, Rattray M, Custovic A, Johnston SL. A systems immunology approach to investigate cytokine responses to viruses and bacteria and their association with disease. Sci Rep. 2022 Aug 5;12(1):13463. doi: 10.1038/s41598-022-16509-4. Wilson JC, Kealy D, James SR, Plowman T, Newling K, Jagger C, Filbey K, Mann ER, Konkel JE, Menon M, Knight SB, Simpson A; CIRCO Collaborative Group; Prihartadi A, Forshaw G, Todd N, Yates DRA, Grainger JR, Hussell T, Kaye PM, Signoret N, Lagos D. Integrated miRNA/cytokine/chemokine profiling reveals severity-associated step changes and principal correlates of fatality in COVID-19. iScience. 2022 Jan 21;25(1):103672. doi: 10.1016/j.isci.2021.103672. Epub 2021 Dec 20. Mann ER, Menon M, Knight SB, Konkel JE, Jagger C, Shaw TN, Krishnan S, Rattray M, Ustianowski A, Bakerly ND, Dark P, Lord G, Simpson A, Felton T, Ho LP, TRC NR, Feldmann M, Circo, Grainger JR, Hussell T. Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19. Sci Immunol. 2020;5(51).

Details Motor nerves connect the spinal cord and brain with muscles in our face, arms, legs and internal organs. The motor nerves send signals which tell these muscles to contract. When motor nerves go wrong, people experience unpleasant and crippling symptoms, often lasting many years. Curative treatments for such diseases are urgently needed but are currently almost nonexistent. We know that diseases of motor nerves have varied causes, including diseases such as diabetes or genetic causes. At the University of Manchester, we discovered that mutation in the LRIG2 gene causes urofacial syndrome (UFS), a congenital disease causing grimacing of the face and defects in bladder voiding. Lrig2 mutations prevent normal peripheral nerve patterning and cause functional nerve defects. It is a transmembrane protein thought to regulate growth factor signalling, but very little is known about its biological role(s) in vivo. The goal of this project is to characterise the role of Lrig2 in motor nerve development to help us understand the pathobiology and aetiology of UFS. We study the role of Lrig2 during the development of nerves in the frog Xenopus tropicalis. Xenopus has unique advantages: it is easy to obtain large number of eggs, which develop externally and are accessible at all stages of development. The genome of Xenopus tropicalis has been sequenced and shows striking similarities with the human genome, meaning that findings from Xenopus provide insight into many human conditions and diseases. We have developed a frog knockout for lrig2 gene. Initial analyses of the phenotype show that Lrig2 is essential for spinal cord and somite formation. Using this model, we will answer fundamental questions regarding Lrig2 biology: What is its signalling activity? What is the role of Lrig2 during nerve and muscle development? What is its role during mammalian neurogenesis? In turn, these results will inform the logical design of novel therapies to help damaged nerves to grow normally in patients affected by diseases such as UFS. Eligibility  Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject with at least one year lab experience. Candidates with experience with in vivo work or with an interest in neuro-biology are encouraged to apply. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Neuroscience Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk 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: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 2 (medium) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/ References Pelzer D., Phipps L.S., Thuret R., Gallardo-Dodd C.J., Baker M.S. and Dorey K. (2021) ‘Foxm1 regulates neural progenitor fate during spinal cord regeneration’, EMBO reports. doi: 10.15252/embr.202050932. Phipps, L.S., Dorey K., and Amaya E. (2020) ‘Model systems for regeneration: Xenopus’, Development, 147(6), p. dev180844. doi: 10.1242/dev.180844. Roberts NA, Hilton EN, Lopes FM, Singh S, Randles MJ, Gardiner NJ, Chopra K, Coletta R, Bajwa Z, Hall RJ, Yue WW, Schaefer F, Weber S, Henriksson R, Stuart HM, Hedman H, Newman WG, Woolf AS. (2019) Lrig2 and Hpse2, mutated in urofacial syndrome, pattern nerves in the urinary bladder Kidney Int. 95(5):1138-1152 Manak I, Gurney AM, McCloskey KD, Woolf AS, Roberts NA. (2020) Dysfunctional bladder neurophysiology in urofacial syndrome Hpse2 mutant mice Neurourol Urodyn. 39(7):1930-1938 Woolf AS, Lopes FM, Ranjzad P, Roberts NA. (2019) Congenital disorders of the human urinary tract: recent insights from genetic and molecular studies. Front Pediatr 7:136