Fixed-term

Details We are looking for a driven applicant, enthusiastic about joining our interdisciplinary team, to help unravel key sperm functions and how they underpin natural and assisted conception. At least 1 in 6 couples worldwide struggle to get pregnant without assistance. The Centre for Human Reproductive Science team work across the University of Birmingham and Birmingham Women’s Fertility Centre, in globally leading research that addresses fertility and miscarriage. We will develop project ideas in detail with the successful candidate, these will always be human sperm-based with a translational medicine focus, we will not be looking for projects that involve stem cells, in-vitro maturation and, or spermatogenesis. The concepts and ideas motivating our work are clear on our website and any project would be similar in nature – we suggest you clarify and discuss this with us informally before applying. We firmly believe improving sperm diagnostics and selection underpin future improvements across medically assisted reproduction and contraceptive interventions. The successful PhD project applicant will work with a lab-base in the team of Professor Jackson Kirkman-Brown MBE and Dr Meurig T Gallagher. More about their work can be found online at: www.birmingham.ac.uk/ChRS. Past students have gone on to successful careers in Embryology, Academia and Industry. Applications should in the first instance be to the contact not via other systems. Funding Notes This project is now only open for self-funded candidates. Apply Now

Details Background Head and neck squamous cell carcinoma (HNSCC) is the 7th most common cancer worldwide with an annual incidence of ~890,000 cases/year and deaths of ~450,000 cases/year. There has been a particularly rapid rise in the incidence of human papillomavirus type 16 (HPV)-associated tumours of the oropharynx. However interestingly, HPV-positive patients respond better to radiotherapy and chemotherapy in comparison to patients with HPV-negative disease whose outcome is very poor. Despite this, acute and long-term side adverse effects of radiotherapy treatment in HNSCC patients are common. Therefore, more targeted and effective treatments for HNSCC, particularly radioresistant HPV-negative disease, are actively being sought. Proton beam therapy (PBT) is capable of delivering radiation of a higher biological effectiveness direct to the tumour. Furthermore, the delivery of PBT at ultra-high dose rates (>40 Gy/s; FLASH) has been shown to promote significant normal tissue sparing whilst still maintaining tumour control. Helium ion therapy (HIT) is significantly more effective than X-rays and PBT in tumour cell killing. Additionally, boron neutron capture therapy (BNCT) is an alternative targeted treatment in which specific uptake of boronated compounds by the tumour cells and irradiation with thermal neutron beams generates highly reactive particle ions causing cell death. However, there is significant biological and clinical uncertainty in the utilisation of these novel radiotherapy techniques, although they have huge translational potential for patient benefit. Objectives This exciting PhD studentship will develop novel research investigating the comparative effect of PBT (at both conventional and FLASH dose rates), HIT and BNCT, versus conventional X-ray radiation, at the molecular and cellular level, using normal and tumour cell models of HNSCC. This will be achieved through the use of established 2D cell lines, 3D spheroids, patient-derived organoids and the in vivo chick embryo model. The project will involve an examination of end-points such as cell survival, DNA damage and repair, cell death mechanisms and tumour growth. The long-term goal of the project is to enhance our biological understanding of PBT (including at FLASH dose rates), as well as HIT and BNCT, particularly using tumour models of HNSCC and to contribute to determining the optimal radiotherapy treatment for HNSCC patients. Impact and training This molecular and cellular biology-focussed research project will utilise the unique resources present at the University of Birmingham, including the MC40 cyclotron for proton and helium ion irradiations at both conventional and FLASH dose rates, and the high flux accelerator-driven neutron facility for BNCT. This novel work is at the interface of clinical and translational medicine, and which has high translational potential in the establishment of more effective and safer treatments for HNSCC using radiotherapy, particularly PBT, HIT and BNCT. How to apply Applications should be directed to Professor Jason Parsons at j.parsons.3@bham.ac.uk. To apply, please send: ·   A Detailed CV, including your nationality and country of birth; ·  Names and addresses of two referees; ·  A covering letter highlighting your research experience/capabilities; ·  Copies of your degree transcripts; ·  Evidence of your proficiency in the English language, if applicable. Funding Notes Applications are invited from self-funded students. Candidates are expected to hold (or about to obtain) a minimum second-class honours degree (or equivalent) in a related area/subject. References 1. Melia, E., Fisch, A.S., Tinhofer, I., and Parsons, J.L. (2025) Targeting Chk1 and Wee1 kinases enhances radiosensitivity of 2D and 3D head and neck cancer models to X-rays and low/high-LET protons. Cell Death Dis., 16 (1):128. doi: 10.1038/s41419-025-07435-0. 2. Punshon, L.D., Fabbrizi, M.R., Phoenix, B., Green, S., Parsons, J.L. (2024) Current insights into the radiobiology of boron neutron capture therapy and the potential for further improving biological effectiveness. Cells. 13 (24):2065. doi.org/10.3390/cells13242065. 3. Fabbrizi, M.R., Doggett, T.J., Hughes, J.R., Melia, E., Dufficy, E.R., Hill, R.M., Goula, A., Phoenix, B., and Parsons, J.L. (2024) Inhibition of key DNA double strand break repair protein kinases enhances radiosensitivity of head and neck cancer cells to X-ray and proton irradiation. Cell Death Discov., 10 (1):282. doi: 10.1038/s41420-024-02059-3. 4. Fabbrizi, M.R., Nickson, C.M., Hughes, J.R., Robinson, E.A., Vaidya, K., Rubbi, C.P., Kacperek, A., Bryant, H.E., Helleday, T., and Parsons, J.L. (2024) Targeting OGG1 and PARG radiosensitises head and neck cancer cells to high-LET protons through complex DNA damage persistence. Cell Death Dis., 15 (2):150. doi: 10.1038/s41419-024-06541-9. 5. Zhou, C., Fabbrizi, M.R., Hughes, J.R., Grundy, G.J., and Parsons, J.L. (2022) Effectiveness of PARP inhibition in enhancing the radiosensitivity of 3D spheroids of head and neck squamous cell carcinoma. Front. Oncol., 12:940377. doi: 10.3389/fonc.2022.940377. 6. Hughes, J.R., and Parsons, J.L. (2020) FLASH radiotherapy: Current knowledge and future insights using proton beam therapy. Int. J. Mol. Sci., 18:6492, doi: 10.3389/ijms21186492. 7. Zhou, C., and Parsons, J.L. (2020) The radiobiology of HPV-positive and HPV-negative head and neck squamous cell carcinoma. Expert Rev. Mol. Med., 22:e3, doi: 10.1017/erm.2020.4. 8. Vitti, E-T., Kacperek, A., and Parsons, J.L. (2020) Targeting DNA double-strand break repair enhances radiosensitivity of HPV-positive and HPV-negative head and neck squamous cell carcinoma to photons and protons. Cancers., 12 (6):1490, doi: 10.3390/cancers12061490. 9. Carter, R.J., Nickson, C.M., Thompson, J.M., Kacperek, A., Hill, M.A., and Parsons, J.L. (2019) Characterisation of deubiquitylating enzymes involved in the cellular response to high-LET ionising radiation and complex DNA damage. Int. J. Radiat. Oncol. Biol. Phys., 104 (3), 656-665, doi: 10.1016/j.ijrobp.2019.02.053. 10. Carter, R.J., Nickson, C.M., Thompson, J.M., Kacperek, A., Hill, M.A., and Parsons, J.L. (2018) Complex DNA damage induced by high linear energy transfer alpha-particles and protons triggers a specific cellular DNA damage response. Int. J. Radiat. Oncol. Biol. Phys., 100 (3), 776-784, doi: 10.1016/j.ijrobp.2017.11.012. Apply Now

Details Alzheimer’s disease (AD) is the most common cause of dementia, affecting millions worldwide and placing an increasing burden on patients, families and healthcare systems. While emerging therapeutics targeting amyloid pathology show promise, treatment options remain limited and do not address all aspects of disease progression. At the same time, strong epidemiological evidence suggests that lifestyle factors, particularly regular physical activity, can substantially reduce dementia risk and enhance cognitive function. However, the biological mechanisms by which exercise exerts these beneficial effects are not fully understood. One hypothesis is that skeletal muscle communicates with the brain through a cocktail of secreted proteins, peptides and extracellular vesicles (collectively termed “exerkines”) that can modulate neurotrophic pathways, inflammation and metabolic function. Yet much of this signalling remains poorly characterised, and almost nothing is known about how these pathways may differ in individuals carrying AD-causing genetic mutations. Human-relevant models capable of capturing muscle biology, contraction and secretion are essential to address these gaps. This PhD studentship focuses on developing and applying novel human iPSC-derived skeletal muscle model to explore how muscle-secreted factors influence AD-relevant brain cell function. Aims and Approach The overarching aim is to establish a physiologically relevant human muscle platform and use it to test how muscle-derived signals affect amyloid precursor protein (APP) processing, inflammatory pathways and metabolic resilience in human iPSC-derived neurons and astrocytes. Key objectives include: 1. Generation and characterisation of iPSC-derived myotubes. Using self-assembling functionalised hydrogel scaffolds you will differentiate iPSCs into mature, contractile myotubes. You will characterise myofibre development, contractility, calcium handling and expression of key structural and metabolic markers in both healthy and familial AD mutation lines. 2. Profiling the muscle secretome and metabolic function. You will quantify secreted proteins, peptides and extracellular vesicles under resting and stimulated (e.g. electrically induced contraction) conditions. This will include analysis of cargo relevant to neurotrophic signalling, metabolism and APP-related pathways. 3. Integrating muscle and brain models. Using complementary systems including conditioned medium transfer, transwell co-culture incorporating a human microvascular endothelial “blood–brain barrier” layer, and microfluidic devices, you will deliver muscle-derived signals to iPSC-derived neurons and astrocytes. Downstream effects on APP processing, neuroinflammation, mitochondrial function and vesicle uptake will be measured using imaging, biochemical assays and live-cell analyses. Training and Environment You will join an interdisciplinary team at the University of Birmingham working at the interface of exercise biology, neurodegeneration, stem cell modelling and bioengineering. Full training will be provided in iPSC culture and differentiation, extracellular vesicle isolation, quantitative microscopy, molecular assays and fluidic-device-based co-culture systems. Close collaboration with an industry partner will offer additional experience in biomaterials and translational technology development. Expected Outcomes and Impact This project will deliver a novel human iPSC-derived muscle platform specifically designed to interrogate muscle–brain signalling in Alzheimer’s disease. By identifying the key muscle-derived factors and mechanisms that influence AD-related cellular vulnerability, the research will advance our understanding of how physical activity promotes brain health. Ultimately, these insights could inform optimised exercise prescriptions, new biomarkers of brain–muscle communication and potential “exercise-mimetic” therapeutic strategies for individuals unable to engage in strenuous activity. Funding Notes This is for students considering self-funding their PhD studies. Bench fees (for lab work only) are funded by the Supervisors existing funding. Apply Now

Project Description: The goal of this project is to develop and validate a new phenomenological model of muscle contraction—the Active Spring Muscle Model (ASMM)—through in vivo experiments on single muscles in small animals (mouse/rat). Although the sliding filament model of actin and myosin has long provided the foundation for understanding muscle contraction, it has limited capacity to explain the complex mechanical behaviour of muscles under dynamic conditions, particularly during eccentric contractions when muscles act as efficient brakes with minimal energy use. The ASMM aims to overcome these limitations by incorporating titin—a giant elastic protein that links the actin and myosin filaments—as an additional active, spring-like element. This novel approach could explain several long-standing gaps in our understanding of real muscle behaviour. In this project, we will conduct in vivo single-muscle experiments using a controlled mouse or rat muscle preparation to record force–length–velocity characteristics during dynamic contractions, including eccentric and locomotion-like stimulation patterns. The resulting data will be used to construct and validate the mechanical model of muscle contraction. Techniques and Skills: The project will involve: In vivo small-animal muscle preparation and mechanical testing Data acquisition and signal processing Development and validation of a mechanical muscle model using MATLAB or Python Candidates with prior wet-lab experience, particularly in animal physiology, biomechanics, or related fields, are highly encouraged to apply. The project requires a combination of experimental and computational skills and will provide training in both. Eligibility Requirements: An Undergraduate Honours degree with a minimum classification of 2.1 (or equivalent) in a science, life science, clinical, or engineering discipline. English Language qualification is required for international students. To find out more about studying for a PhD at the University of Birmingham, including full details of research in the School, available funding opportunities, and guidance on making your application, please visit: www.birmingham.ac.uk/drp References Yeo, S. H., & Herzog, W. (2023). Can a Simple Phenomenological Model Explain the Mechanics of Eccentric Contractions?. bioRxiv, 2023-03. Yeo, S. H., Verheul, J., Herzog, W., & Sueda, S. (2023). Numerical instability of Hill-type muscle models. Journal of the Royal Society Interface, 20(199), 20220430. Yeo, S. H., Monroy, J. A., Lappin, A. K., Nishikawa, K. C., & Pai, D. K. (2013). Phenomenological models of the dynamics of muscle during isotonic shortening. Journal of biomechanics, 46(14), 2419-2425. Apply Now

Details Lewy Body Dementia (LBD) consists of two syndromes, Dementia with Lewy Bodies (DLB) and Parkinson’s Disease with Dementia (PDD). Cognitive and motor symptom order differs, but phenotypes eventually converge. Dopaminergic (DA) neurons within a midbrain structure, the Substantia Nigra pars compacta, degenerate extensively during both LBD syndromes. Pathological molecular interactions between misfolded protein aggregates (e.g. α-synuclein (αSYN) and tau) forming within DA-SNpc neurons, the ‘metalome’ (free metal ion distribution), and mitochondria—encoding oxidative phosphorylation components to biochemically generate cellular energy—may cause progressive neurodegeneration. Furthermore, the dopamine precursor Levodopa, used as a ‘gold-standard’ treatment in LBD and also Parkinson’s disease, may further disrupt this triad of interactors, to driving the disease further. To untangle this pathological interplay, this project will use methods optimised in our labs applied to patient-derived cell models and human post-mortem brain samples. For insight into toxic metal-related pathways activated by accumulation of the dementia-associated protein species, we will apply label-free synchrotron X-ray fluorescence (XRF) metal imaging to map metal element distribution in individual DA-SNpc neurons of post-mortem human brain samples, comparing control, DLB and PDD cases’ relative levels. Neurons will be mapped at >2 μm resolution, permitting accurate discrimination of individual metal elements: redox-active transition metals (e.g. iron (Fe) and copper (Cu)) and biometals (e.g. zinc (Zn) and calcium (Ca)), all essential for brain function. PyMCA software will fit multi-element XRF spectra per pixel to produce distribution intensity maps per metal element from individual neurons. Polarized light microscopy will screen for pathological protein structures. To dissect metalome-mitochondrial cause-effect relationships, the DLB vs PDD-related metal dyshomeostasis patterns will be modelled in 3D dopaminergic human neuronal in vitro models treated with human αSYN protein aggregates, using an established protocol from our lab, and the identified dysregulated metal specie(s)followed by mitochondrial functional profiling, e.g. mass spectrometry-based mitochondrial metabolomics and Seahorse-based respiratory analysis. Using this model system we will further profile how the use of Levodopa, at clinically-relevant dosages, might further amplify the mitochondrial respiratory pathology. The project will allow a student to acquire state-of-the-art molecular biology, biochemistry and biophysical techniques, and attain expertise in using a variety of software packages, all whilst being highly clinically translational. The project will take place at the University of Birmingham, a top UK University that forms part of the prestigious Russell group of research-intense universities. To apply, please contact Dr Ilse Pienaar at i.pienaar@bham.ac.uk.

Details Multiple System Atrophy (MSA) is a rare, progressive neurological disorder that is without cure, that causes nerve cell loss in the brain, leading to issues with movement, balance, blood pressure, bladder control, and digestion, as the autonomic system is also affected. During MSA, select cell types within specific brain regions progressively degenerate. In MSA-susceptible neurons and in glial oligodendrocytes there is buildup of α-synuclein (αSyn) protein aggregates, spreading cell-to-cell. This self-funded PhD project will make use of human adult-derived iPSC (Induced Pluripotent Stem Cells) cells, that will be chemically reprogrammed to turn their neurochemical identities into specific cell types associates with particular neurotransmitters. These will be co-cultured with stem-cell like oligodendrocytes, and applying αSyn protein aggregates engineered from recombinant protein. Furthermore, to better reflect the brain environment, scaffolding systems will be tested and optimised, to bet support culturing of the cell system in a 3-dimensional format. The experimental platform will then be used to assess for neuronal excitability, cytotoxicity/-stress markers & cholinergic metabolome/cytokine profiles in cell culture lysates/supernatants. The data will instigate future work to directly benefit MSA patients via improved differential diagnostics & treatments, whilst serving as training for a PhD student in various state-of-the-art clinically translational methods. To apply, please contact Dr Ilse Pienaar at i.pienaar@bham.ac.uk.