Projects and Supervisors
Choose from the projects listed below.
Applicants will be expected to have experience and evident knowledge of molecular cell biology, biochemistry.
Dr Hrvoje Augustin
Biology of ageing: investigating the effect of novel compounds on longevity and functionality
One of the goals of ageing research is to identify compounds that can extend lifespan and/or improve physical and cognitive performance in old age. The research of the last 20 years revealed a high level of conservation of genetic pathways and biochemical processes that regulate lifespan in organisms as diverse as yeast, worms, flies and humans. The fruit fly Drosophila, in particular, emerged as a pre-eminent model system for studying changes that occur during both normal and pathological ageing (~75 per cent of the genes that cause disease in humans are also found in the fruit fly!). The advantages of Drosophila include their relatively low cost, ease of use and a range of powerful tools available for their genetic manipulation.
Our Department recently identified several compounds with possible pro-longevity effects. The aim of this project is to assess the effect of these compounds during healthy ageing and in various Drosophila models of human diseases. The initial lifespan studies will be followed by an array of molecular, biochemical, imaging and functional analyses.
Modelling neurodegenerative disorders in Drosophila
We use the fruit-fly Drosophila to study different aspects of human neurodegenerative diseases such as Motor neurone disease, Parkinson’s disease, Frontotemporal dementia and others. Our main goals are to a) understand the molecular underpinning of these disorders, and b) identify novel molecular targets and therapeutic approaches for future treatments. The most promising genetic or pharmacological interventions identified in flies can then be tested in suitable mouse disease models.
Dr Philip Chen
Pharmacology of glycine-site agonists at NMDA receptors
This project will characterise a number of novel agonists at NMDA receptors using molecular biology and recording glutamate evoked inward currents from oocytes injected with mutant NMDARs under two-electrode voltage clamp configuration. The project will involve molecular techniques such as subcloning, site-directed mutagenesis, PCR and in vitro cRNA synthesis, injection of cRNA into Xenopus oocytes and two-electrode voltage clamp electrophysiology.
Examining the consequences of altered RNA editing on neuronal function
RNA editing is a process by which specific nucleotides are modified following gene transcription and disruptions in these processes have been linked to certain neurodegenerative conditions. We have developed a number of genetic tools to manipulate RNA editing and would like to explore their consequences on cell function. This project would involve mammalian tissue culture, RNA extraction, cell transfection and RT-PCR.
Professor Simon Cutting
Mucosal vaccines
Work consists of innovative bacterial delivery systems for mucosal vaccination (i.e. against malaria or TB). Due to the dynamics of our projects, they are ongoing and subject to change on a regular basis and cannot be specified in advance.
Research pages - Professor Cutting
Dr Alberto Malerba
Gene therapy of Oculopharyngeal muscular dystrophy (OPMD)
OPMD is a rare gain-of-function autosomal dominant, degenerative muscle disease that usually presents in the fifth decade of life. OPMD is due to mutations in the poly(A)-binding protein nuclear-1 (PABPN1) gene that codes for a protein that has a pivotal role in many biological pathways. We demonstrated that a gene therapy application based on silencing all endogenous PABPN1 and its replacement with normal protein can ameliorate the disease when delivered locally in the affected muscles. This approach is based on using a single viral vector that carries both the silencing and the replacement features. We are testing now different approaches where the protein inhibition is provided by destructive exon skipping where antisense therapeutics are designed to send out of frame the transcript and then produce a non-functional mRNA. This is expected to generate a safer, controllable approach that may allow the systemic treatment of the disease.
Modulation of expression of the Ribosome Proteins L3 and L3L to enhance muscle strength
We recently studied a very poorly characterized ribosome protein named Ribosomal protein L3-like (RPL3L), and we observed that its downregulation, obtained by delivering short harping RNA (shRNA) designed to target specifically RPL3L transcript, significantly increases muscle force in models of muscular dystrophy and muscle damage. We are now combining RPL3L downregulation with clinically relevant genetic strategies that we have developed in the laboratory, to counteract Duchenne muscular dystrophy (DMD) and Facioscapulohumeral muscular dystrophy (FSHD) in order to improve their functional efficacy.
Combination of gene therapy and pharmacological approaches for the treatment of Duchenne muscular dystrophy
Exon skipping and AAV-based gene therapy are among the most promising new approaches for the treatment of Duchenne muscular dystrophy (DMD). These strategies are based on the expression of truncated dystrophin proteins that retain some functionality and are expected to shift the pathology from the severe Duchenne to a milder Becker-like phenotype, or act to stabilise the DMD phenotype. However, evidences are growing that proteins with large truncated domains may fold in a non-native way with potential detrimental effects on protein stability and expression. Three processes have been described to directly modulate the shape of misfolded proteins: the protein folding activity of the ribosome (PFAR), the unfolded protein response (UPR) and the protein-chaperones interaction happening in the cytoplasm to maintain the correct folding of the proteins. We recently screened in vitro a number of UPR regulators in combination with dystrophin restoration by exon skipping and we found that guanabenz acetate, a commercially authorized drug modulating the UPR and the chaperone systems, is able to double exon skipping-rescued dystrophin protein expression in dystrophin deficient cells. This project seeks to expand the screening to identify other compounds that can enhance dystrophin restoration and establish the molecular mechanisms behind such effect.
In each of these projects, students will have the opportunity to learn several techniques that are widely used in laboratories engaged in biomedical research including: in vitro cell culture, molecular biology (e.g. Western blot, RT-PCR and quantitative PCR), histology (cryosectioning, stainings, immunofluorescence) and microscopy.
Dr James McEvoy
Antibiotic resistance in bacterial biofilms on orthopaedic pins
Bacterial biofilms are a common cause of infection in surgical implants, and pin tract infection is the major complication of external fixation of fractures. Furthermore, biofilm-focused infections are phenotypically resistant to antibiotic therapy. In this microbiological project, run in collaboration with Dr Shobana Dissanayeke (Royal Holloway) and Mr Arshad Khaleel (St Peter’s Hospital, Chertsey), you will use a bioreactor to grow bacterial biofilms on orthopaedic pins and study their response to antibiotic treatments. Guided by recent results from our laboratory1 you will investigate the social aspects of genotypic antibiotic resistance in multi-strain biofilms, extending this work by the addition of clinically relevant b-lactamase inhibitors. Our long-term objective is to inform surgical practice and reduce pin tract infection rates.
1. Amanatidou, E.; Raymond, B., Biofilms facilitate cheating and social exploitation of β-lactam resistance in Escherichia coli. npj Biofilms and Microbiomes 2019, 5, 36-36.
Research pages - Dr James McEvoy
Professor Pankaj Sharma
Epidemiology of global stroke in South Asians
You will be based in a group headed by a clinical academic.
Stroke is the third commonest cause of death in the UK. WHO estimates that by 2050 around 80% of all stroke will be in India and China. Our group has amassed the largest database of South Asian stroke in the world. We have data from UK, India and the Middle East.
It is expected that these projects will lead to publications in major international peer review journals.
This project will allow students to analyse this extensive database to search for interactions between stroke and established risk factors
Risk factors in South Asian stroke
You will be based in a group headed by a clinical academic.
Stroke is the third commonest cause of death in the UK. WHO estimates that by 2050 around 80% of all stroke will be in India and China. Our group has amassed the largest database of South Asian stroke in the world. We have data from UK, India and the Middle East.
It is expected that these projects will lead to publications in major international peer review journals.
This project will allow students to analyse this extensive database to search for novel risk factors in South Asians and compare and contrast such factors with stroke in Caucasians.
Designing a new strategy for ‘five-a-day’ intake
You will be based in a group headed by a clinical academic and be supervised by two clinicians.
The 5-a-day campaign was launched by the UK Government to ensure that the population eats at least five fruit and vegetables per day. Research suggests that those that do this have a lower risk of cardiovascular disease.
However, the evidence is that most people do not remember how many of their 5-a-day they have eaten. We propose to develop a new colour based flag strategy for each meal to replace the 5-a-day slogan.
This work potentially has large and important clinical and public health implications.
Research pages - Professor Sharma
Dr Stuart Snowdon
Exploring public perception of artificial intelligence in medicine and science.
Artificial intelligence is permeating all aspects of our lives and societies, and their potential to change the way in which we live is almost limitless. In this project we aim to explore the public's perceptions of artificial intelligence (AI) in science. As AI increasingly plays a significant role in various medical and scientific disciplines, understanding how the general population perceives its integration and impact is crucial.
The study will employ a range of methods focused around surveys distributed to a diverse sample population to provide statistical analysis and identify broader trends, to gather comprehensive insights into how people perceive the efficacy and ethical considerations of applying AI. Some of the key areas to be explored are:
Trust and Confidence: Investigating the level of trust the public has in AI-driven medical diagnosis and scientific outcomes.
Perceived Benefits: Assessing the perceived benefits of AI including enhanced efficiency, and accuracy of results.
Ethical Considerations: Examining ethical concerns related to AI implementation in scientific research and clinical medicine, including data privacy, bias, and accountability.
The research findings will provide valuable insights for scientists, policymakers, and educators to develop strategies for engaging with the public about AI in science and medicine effectively. By addressing concerns, promoting transparency, and highlighting the benefits, this research aims to bridge the gap between scientific advancements powered by AI and public understanding and acceptance, ultimately fostering a more inclusive and informed society.
Modelling the role of functional metabolism in neurodegeneration
Metabolomics has played a significant role in bridging the gap between genotype and phenotype. Whilst metabolic architecture (i.e. the order of reactions in a metabolic pathway) is well known and highly conserved even between disparate phenotypes, metabolism is highly dynamic and it is the flow of substrate through metabolic pathways that is responsible for determining metabolic function. Therefore, simply knowing the relative metabolite composition of two groups is insufficient to provide a detailed understanding of metabolism for example, higher abundance of a given metabolite could be the result of increased production or reduced breakdown with the two causes having very different biological implications.
Fluxomics approaches provide a dynamic readout of metabolic activity by introducing an isotopically labelled substrate into a system and mapping the ‘diffusion’ of isotopic label through the metabolic network. Traditionally, these approaches have used 13C-labelled glucose however this is expensive limiting its utility, in this project we will use this in conjunction with deuterium oxide to comprehensively map functional metabolism to identify novel targets for therapeutic intervention in C9orf72 drosophila melanogaster which is a common genetic cause of frontotemporal dementia (FTD) and Amyotrophic lateral sclerosis (ALS). This project will provide training in fly handling, microscopy, mass spectrometry and advanced data analysis.
Early life nutrition and lifelong health: elucidating the role of nutritional programming on metabolic resilience.
Malnutrition is often synonymous with severe under nutrition, however, the term encompasses any instance where poor diet negatively impacts health. Whilst usually considered to be a problem exclusive to the developing world, there is growing evidence that malnutrition is also a major public health problem in wealthy nations, with individuals consuming sufficient calories but insufficient vitamins to efficiently grow, function and fight disease.
Traditionally seen as an acute problem, there is growing acceptance that exposure to malnutrition in early life (pre 5 years of age) not only impacts the individual at the time of exposure but will negatively affect their health for the rest of their life. Poor nutrition has been shown to significantly affect metabolism with shifts in metabolic pathways involved in energy metabolism as well as both anabolism and catabolism being reported. However, to date there has been no work looking at the severity of early life malnutrition required to trigger metabolic reprogramming, and negatively affect whole life health.
The aim of this project is to explore the relationship between metabolism, early life malnutrition and whole life health. We will do this using drosophila models to determine how different forms of malnutrition, including undernutrition, overnutrition and specific vitamin insufficiencies effect life expectancy, mobility and cognition and subsequently identify the metabolic anomalies that drive these changes.
Dr Mikhail Soloviev
MSc projects are offered in the areas of protein engineering, molecular biomarkers of cancer, and nanoparticles and their applications. Examples of projects are listed below, applicants are invited to contact the supervisor, to discuss their research interests and project preferences.
Engineering of Protein-A derivatives for biotechnology applications
Staphylococcal Protein A (Protein A or "SPA") is a 42 kDa virulence factor produced by Staphylococcus aureus in its cell wall. SPA is well known for its ability to bind IgG molecules with very high affinity. It is widely used in biotechnology applications, such as antibody capture, immobilisation or purification to name just a few. SPA has been used widely in Life Sciences, but it has a few serious limitations. SPA recognises and binds IgGs of many different isotopes, but not all. For example native SPA does not recognise or binds human IgG3 and a few other IgGs. This severely limits its application range. This project aims to engineer SPA analogues capable of binding human IgG3. This research has huge commercial implications.
Molecular biomarkers of cancer
This project aims to address critical research gaps in the detection and treatment of cancer and will aid the development of molecular screening approaches. The overall project aims includes the identification of novel biomarkers suitable for the early detection and stratification of cancer and markers to assist prognosis and treatment. Key objectives of this research include (1) Prediction of up- and down-regulated genes associated with different stages of cancer; (2) Identification of subsets of genes and proteins where the pattern of their expression levels could be used as molecular signature for the early stages of cancer, as score classifiers to assist prognosis, to evaluate drug resistance and to predict recurrence; (3) Developing of analytical molecular assays for quantitative detection of the selected markers extracted from physiological materials (for example but not limited to tissues, blood, urine or saliva samples). Such assays may rely on immunoassays, quantitative liquid chromatography approaches, qPCR or their combinations. Training in bioinformatics methods and relevant laboratory techniques will be provided.
Biologically active lipopeptides for drug delivery
Members of the Bacillus genus, particularly the "Bacillus subtilis group", are known to produce amphipathic lipopeptides with biosurfactant activity. This includes the Surfactin, Fengycin and Iturin peptides that have been associated with antibacterial, antifungal, and anti-viral properties. These peptides can form micelles (small self-assembled complexes of just a few nanometres in diameter) that might affect bioavailability of these peptides. This project aims to investigate if such micelles could be used for encapsulating molecular therapeutics, and how such micelles are affected by primary bile acids synthesised in human liver, and by secondary bile acids that are formed in human intestine by intestinal bacteria. Training in relevant analytical laboratory techniques will be provided.
Protein engineering: stimuli-responsive proteins
Proteins are responsible for a vast range of biological functions. The ability to modify proteins in a rational manner yielded advanced therapeutics which top the list of the most commercially successful medicines (1). Yet we are only beginning to learn how to exploit the directed protein evolution (2) and how to engineer proteins or other biopolymers with the pre-determined structure or functions. One of the most interesting yet least developed areas of protein engineering research concerns the development of stimuli-sensitive molecules for therapeutic, biotechnology and materials applications. The key aim of this research PhD project is to create molecular systems capable of changing their physical or molecular properties in response to external stimuli such as ultrasound, thermal, mechanical, chemical or direct electric stimulation. In particular, we aim to develop and test thermo-responsive proteins capable of self-assembly in a sequence-specific manner and controllable disassembly in response to thermal stimuli. Another two systems under development are pH and voltage sensitive proteins. For example, we utilise self-assembling neuronal SNARE proteins as a template to devise novel stimuli-responsive proteins with tuneable sensitivity to environmental stimuli. Alternatively, the sensitivity is added to functional proteins by combining them with magnetic or elastic nanoparticles, by adding light-excitable or chemically-modifiable groups and their combinations to yield highly tuneable stimuli-responsive composite biomaterials suitable for a variety of life science and therapeutic applications.
Rocking proteins with AC/DC
In nature, electrically sensitive proteins are represented largely by voltage-gated ion channels that are abundant in excitable tissues. These are transmembrane proteins responsible for maintaining ion and electric gradients and for generating action potential across cellular membranes. However, without electrically insulating membranes no electric gradients are feasible inside or outside cells, and no voltage sensitivity is required of soluble proteins that do not span cellular membranes. One area where the effect of AC/DC electric fields has been studied extensively is cell permeabilization, electroporation, biomass sterilisation and drug delivery. The mechanism mediating the effect of AC electric field is believed to involve cell membrane rupture or increased permeability due to electroporation or depolarisation of cellular membranes mediated by aberrant gating of voltage-sensitive ion channels. But some observed effects remain unexplained. This project aims to investigate the effect of DC and AC electric stimulation on a range of model proteins. The ability of molecules to sense AC/DC electric field in solution rather than across biological membranes might provide new explanations to some unexplained biological phenomena and would allow a plethora of biotechnology applications, including the creation of biomolecular electronics and computer interfaces with biological matter. Training in relevant instrumental analysis techniques will be provided.
Recent publications by postgraduate students in the group are listed on the research pages - Dr Soloviev
Dr Jorge Tovar
Developing novel platforms for the molecular diagnosis of fungal infections
Human fungal infections represent one of the most pressing health problems in recent years. Endemic infections affect healthy immunocompetent individuals causing a range of diseases which generally resolve with chemotherapy but hospital-acquired nosocomial infections pose a serious threat to immunocompromised patients in hospital wards and intensive care units worldwide. Despite the availability of chemotherapy nosocomial infections frequently result in high mortality rates, often exceeding 50%. The development of timely and more efficient molecular diagnostic methods, along with the development of new drugs and anti-fungal vaccines, was recently identified as one of the most pressing needs in medical mycology research.
We are interested in developing and implementing simple nucleic acids diagnostic tests for a range of fungal infections, including both endemic and opportunistic. Using fungal genome data mining and isothermal DNA amplification this project will use Candida – the causative agent of endemic and nosocomial candidosis – to develop simple diagnostic tools that are both amenable to automation and applicable at the point of care.
Dr Chris Wilkinson
Melanoma and centrosomes
Melanoma, in common with all solid tumours, displays excessive numbers of centrosomes, which help form the mitotic spindle. Such supernumerary centrosomes are thought to drive carcinogenesis by contributing to aneuploidy and chromosomal instability. However, much remains to be understood about the origin and the contribution of excessive centrosomes in tumorigenesis. This Masters project will continue published work (by our laboratory, doi: 10.1016/j.jid.2020.01.024) on how centrosomes and cilia are affected in melanoma. The mechanisms underlying these changes will be investigated with the aim of developing better diagnostics and treatments. A combination of cell biology, immunocytochemistry, epifluorescence microscopy and protein analysis such as Western blotting will be used in this project.
Polycystic kidney disease and cilia
Cilia are hair-like structures on the surface of many animal cells. Cilium malfunction is linked to autosomal dominant polycystic kidney disease (ADPKD), which affects 1 in 1,000 of the population, as the cilium houses polycystin-1 whose gene is frequently mutated in ADPKD. This project will investigate the role of a novel protein that interacts with polycystin-1, in collaboration with Dr Richard Sandford at University of Cambridge. A variety of cell biology and embryological techniques will be used to investigate its function using cultured fish cells and zebrafish embryos.
Novel antibiotics from fish
Polyketide synthases are a class of enzymes that produce many of the antibiotics and other drugs used clinically today. Most polyketides are sourced from soil bacteria and fungi. They are also found in plants but have not been found in animals until now. We recently published a paper (https://doi.org/10.1016/j.mod.2019.04.001) showing for the first time that one such enzyme is present in fish. Although we studied the zebrafish enzyme, homologues are present in other fish as well as reptiles, birds and some mammals. What chemical is produced by this enzyme is unknown. This project will discover the product of this enzyme and test if it has antibacterial effects or other pharmaceutical activities. A combination of protein expression in cultured fish or mammalian cells or yeast or E. coli, followed by bioassays will be used in this project.
Parkinson’s disease and cilia
A hallmark of Parkinson’s disease is the presence of large aggregates of protein called Lewy Bodies in affected neurons. In collaboration with colleagues at the University of Cambridge, we have recently published a paper (doi: 10.1242/bio.054338) that shows that related, possibly precursor, structures called aggresomes prevent the centrosome and cilia from functioning. The centrosome is the microtubule organising centre of the cell and contributes to the internal organisation of the cell and intracellular transport. Loss of these functions could lead to neuronal disease. Notably, cilia are involved in olfaction, the sense of smell, which is lost in Parkinson’s disease, and the presence of aggresomes prevents cilia from forming. This project will investigate the mechanisms by which the aggresome affects these other two organelles. A combination of cell biology, immunocytochemistry, epifluorescence microscopy and zebrafish genetics will be used in this project.
Ear development
Early ear development in fish involves the formation of otoliths, protein-calcium calcium carbonate complexes whose generation and anchoring both involve the action of cilia. They are related to the structures in the human ear used in the sense of balance. We recently published, in collaboration with Ken Kramer and colleagues at Creighton University in the USA, a paper (doi: 10.1016/j.mod.2019.04.001) showing that a novel type of enzyme is involved in formation of these structures. This project will investigate the mechanism by which this enzyme contributes to otolith formation. A combination of zebrafish genetics, embryology and tissue expression techniques will be used in this project.
Cilia to control cancer
In many cancers the primary cilium that is present on healthy cells is lost. This may contribute to cancer development by disturbing the reception of the signals a cell receives that regulate cell division. Furthermore, cilia are incompatible with cell division, which is inappropriately and excessively occurring in cancer, as the component centrioles are required to form the poles of the mitotic spindle. In 2017 we published a paper (doi: 10.1242/jcs.196642) showing that a centrosome satellite protein called BCAP was a novel inhibitor of ciliogenesis. This project will test if inhibiting or removing BCAP from cells can prevent cell division and therefore be a potential anti-cancer drug target. A combination of cell biology, immunocytochemistry, epifluorescence microscopy and protein analysis such as Western blotting will be used in this project.
Professor Robin Williams
Molecular Cell Biology studies in Biomedical research using a tractable model system
Research into improving our understanding of disease treatments is often focused on the characterisation cell signalling regulation caused by current or new medicines or bioactive natural products. Rodents are traditionally used as models for these studies, in addition to human or mammalian cell lines. The models are often difficult to manipulate, and can be associated with ethical considerations. Our laboratory specialises in these studies using an innovative model system, the social amoeba Dictyostelium discoideum. This system allows the rapid manipulation of cells, including CRISPR knockout approaches and expression of fluorescently tagged proteins in isogenic cell line enabling biochemical assays, to discover the molecular and cellular effects and mechanisms of action of medicines or health/disease related natural products (e.g. Warren et al 2020 PNAS; Perry et al 2019 BJP; Sharma et al 2019 Autophagy). We used Dictyostelium to modelled the effects of compounds relating to a range of diseases include various cancer types, multiple epilepsies, Alzheimer’s disease, bipolar disorder, infection and polycystic kidney disease and others. We also often works with industry, focusing on wide-ranging compounds including various cannabinoids, medium chain fatty acid related to ketogenic diets, naturally occurring antibiotics, flavonoids, and traditional (herbal) remedies from around the world.
A Maters student joining our laboratory will learn a wide variety of key skills used widely in molecular cell biology and modelling, to equip them for ongoing academic studies or to move into an industry setting. We are fully equipped for research with bespoke facilities for tissue culture, microscopy and molecular biology studies.
We would be delighted to hear from high-achieving students with some background and interest in molecular cell biology, who are keen to developing their careers in a scientific setting.
Research Pages - Professor Williams
Professor Rafael Yanez
Gene therapy, viral vector, Spinal muscular atrophy
Our laboratory (http://AGCTlab.org) works on the development of new gene and stem cell therapies for rare and common diseases. Recently we have been working on novel therapeutic strategies for spinal cord injury, spinal muscular atrophy and ataxia telangiectasia (A-T). The latter is a rare disease characterised by progressive degeneration in cerebellum, high risk of cancer and immunodeficiency. It is caused by defects in the gene known as ataxia telangiectasia mutated (ATM). The most advanced gene therapy technology, “genome editing”, can be used to introduce specific changes in the DNA, including the repair of a faulty gene: this could be applied as a therapy for A-T. Genome editing has undergone a revolution over the last few years with the introduction of a system called CRISPR, which has greatly facilitated the process. For this research project we will use the CRISPR system to test several ways to repair the faulty gene in A-T. We will initially work with easy-to-grow human cells in the lab, and eventually the most effective A-T gene repair strategies will be tested in human blood stem cells. If our proposed studies are successful, follow-up projects would explore these novel gene repair methods in blood stem cells from people affected by A-T. We will also study possible side effects of these gene repair methods. If successful, this work could eventually pave the way for the treatment of blood disease in A-T.
