Abstracts of research projects offered for October 2025
This page lists all the projects on offer to MPhil and PhD candidates in the Department.
Candidates are advised to read about the research interests of members of the Department in conjunction with the following information.
Please find information about funding opportunities here.
We also have a range of PhD funding options available here. These listings are regularly updated, so be sure to check it often.
Projects on offer:
- Mechanisms and inhibition of bacterial multidrug transporters
- Gut Feelings
- Targeted protein degradation by the Ubiquitin-Proteasome System (UPS)
- The tipping point: what drives the progression of breast precancer cells?
- Linking protein self-assembly with biological function and disease (MPhil/PhD)
- Platelet procoagulant activity: regulation and inhibition
- Mechanisms of nociception
- Innovating Protein Technologies for Therapeutic and Vaccine Design
- DNA Nanostructures
Mechanisms and inhibition of bacterial multidrug transporters (MPhil/PhD)
Multidrug transporters are membrane proteins found in the plasma membrane of cells. These transporters play a crucial role in mediating the extrusion of therapeutic agents across the plasma membrane. This extrusion process occurs from the cellular interior to the exterior, effectively overcoming the toxic effects of antibiotics and allowing cells to continue growing. Multidrug transporters are not only responsible for antibiotic resistance in pathogenic bacteria and other microorganisms but also contribute to the development of anticancer drug resistance in tumours. Furthermore, they affect the toxicity and pharmacokinetics of drugs in all organisms, from bacteria to humans. Therefore, understanding the structure-function relationships of bacterial multidrug transporters has a more general relevance and is the focus of our project. By delving into the intricate details of these relationships, we aim to gain valuable insights that can potentially inform the development of novel strategies to combat antibiotic resistance and enhance the efficacy of existing antibiotics.
Relevant techniques:
We study multidrug transporters in the ABC, MFS, and MATE families, and examine their roles in antibiotic resistance of bacterial cells using microbiological techniques. Furthermore, we use biochemical and genetic techniques to purify and functionally reconstitute wildtype and mutant proteins in artificial lipid bilayers (proteoliposomes) and other lipid systems, including lipidic nanodiscs and peptidiscs. Finally, we apply biochemical, biophysical, and structural techniques to study the mechanisms of antibiotic binding and transport. Our research also involves collaborations with key research groups within the UK and abroad. Together, these approaches are rewarding and informative in our search for answers to the scientific questions that we set.
Please, visit our lab website for further information, and feel free to contact Hendrik van Veen (hwv20@cam.ac.uk) to discuss possible MPhil and PhD projects.
Some references:
Raturi, S., Nair, A. V., Shinoda, K., Singh, H., Bai, B., Murakami, S., Fujitani, H., van Veen, H. W. (2021) Engineered MATE multidrug transporters reveal two functionally distinct ion-coupling pathways in NorM from Vibrio cholerae. Commun. Biol. 4: 558. PMID: 33976372
Guffick, C., Hsieh, P.,-Y., Ali, A., Shi, W., Howard, J., Chinthapalli, D.K., Kong, A.C., Salaa, I., Crouch, L.I., Ansbro, M.R., Isaacson, S.C., Singh, H., Barrera, N.P., Nair, A.V., Robinson, C.V., Deery, M.J., van Veen, H.W. (2022) Drug-dependent inhibition of nucleotide hydrolysis in the heterodimeric ABC multidrug transporter PatAB from Streptococcus pneumoniae. FEBS J. 289: 3770-3788. doi: 10.1111/febs.16366. PMID: 35066976
Guo, D., Singh, H., Shimoyama, A., Guffick, C., Tang, Y., Rowe, S.M., Noel, T., Spring, D.R., Fukase, K., van Veen, H.W. (2022) Energetics of lipid transport by the ABC transporter MsbA is lipid dependent. Commun Biol. 4(1):1379. doi: 10.1038/s42003-021-02902-8. PMID: 348875433
Bali, K., Guffick, C., McCoy, R., Lu, Z., Kaminski, C.F., Mela, I., Owens, R.M., van Veen, H.W. (2023) Biosensor for multimodal characterization of an essential ABC transporter for next-generation antibiotic research. ACS Applied Materials & Interfaces. Epub ahead of print. doi: 10.1021/acsami.2c21556. PMID: 36866935
Keywords: Antibiotic resistance; multidrug transporters; mechanisms; inhibitors.
Abdominal pain is amongst the most common reasons why people seek medical help. Despite this treatment options are limited as many commonly used pain killers do not work well against abdominal pain and cause gut related side-effects. To tackle this problem, we have profiled gene expression in colonic biopsies taken from people with gastrointestinal diseases which cause abdominal pain such as irritable bowel syndrome (IBS) and colitis to identify potential mediators of pain. We have compared the receptor expression for these mediators in pain sensing nerves (nociceptors) innervating the gut using our single cell RNAseq database of transcript expression in colonic nociceptors to identify novel pain signalling pathways which can be targeted to treat abdominal pain.
Based on these findings we are pleased to offer 2 potential projects.
Project 1: will explore the contribution of matrix metalloproteinase (MMP) signalling to the activation of colonic nociceptors in colitis. This project will build on our current pilot data which indicates that MMPs produced during colitis interact to regulate nociceptor activity via cleavage of the protease activated receptor, PAR1.
Project 2: will explore the contribution of mechanosensitive GPCRs such as the angiotensin receptor AT1 and the histamine H1 receptor to the development of visceral hypersensitivity and colonic nociception in conditions such as colitis and IBS where tissue angiotensin II and histamine levels are elevated.
Key words
Pain, neuroscience, electrophysiology, Ca2+ imaging, GPCRs
Targeted protein degradation by the Ubiquitin-Proteasome System (UPS) - PhD Only
Targeted protein degradation occurs through ubiquitin-mediated pathways that bring about the destruction of ubiquitin-tagged proteins at the 26S proteasome. Research in the Lindon group seeks to understand how these pathways interact with the cell cycle, and how they can be harnessed for novel therapeutic strategies. One major focus of the lab is the cell cycle regulator Aurora A kinase (AURKA). AURKA is a target of ubiquitin-mediated degradation by the APC/C-FZR1 ubiquitin ligase, a key player in several types of cancer, and a potential target for new oncology drugs.
One novel class of drugs, often referred to as PROTACs (Proteolysis Targeting Chimeras), harness the UPS to induce the degradation of clinically relevant target proteins, and the group are studying a number of PROTAC compounds effective against AURKA. Although there is much excitement about the therapeutic potential of this approach, there is still much to learn about the relevant ubiquitin-dependent pathways that operate within the cell to bring about target destruction. Research in the Lindon group therefore aims to discover more of the cell biology of PROTAC action to assist in the design of successful PROTAC-based therapeutic strategies.
These questions are studied using quantitative molecular and cell biology techniques, including timelapse fluorescence microscopy and cellular ubiquitination assays, and involves collaboration with chemists, biochemists and computational biologists. Please see the lab pages and recent publications for more information. Interested candidates should contact Dr Lindon to discuss potential PhD projects.
Key words: ubiquitin, mitosis, APC/C, Aurora kinase, degron, proteolysis, targeted protein degradation, PROTAC
The tipping point: what drives the progression of breast precancer cells?
Understanding the molecular and cellular mechanisms of how epithelial tissues maintain a homeostatic state throughout the lifespan of mammals is a major challenge for developmental and stem cell biology. From a developmental perspective, the epithelium of the mammary gland is unique as it undergoes most of its development during adulthood. Despite recent efforts of characterising the tissue homeostasis at a cellular level little is known about how this is affected by various developmental processes such as pregnancy or aging and how this might ultimately disrupt epithelial homeostasis resulting in malignant outgrowth. In this study we wish to further our understanding of the changing nature of the differentiation dynamics of the mammary gland. To fully understand how tissue homeostasis is affected by parity and other events it is mandatory to characterise the differentiation dynamics in an age-dependent manner. This becomes evident when looking at epidemiological data. Age is the greatest risk factor for breast carcinomas, and it has been suggested that this is not only due to accumulation of mutations but also due to decreased clonality and selection of clones with proliferative advantage. More importantly, the age-dependent risk of tumorigenesis is modulated by for example parity, which attenuates the risk or predisposing germline mutations which increase the age-associated risk. However, the exact mechanisms and effects of the interaction of these risk factors on tissue homeostasis of the mammary gland remain to be elucidated. To tackle these questions, the Khaled lab has been using single cell genomics, mouse models and human samples to study the effects of parity, ageing and germline mutation (BRCA1/2) on the homeostasis of the mammary gland in mouse and human (1-7).
They are offering two types of projects:
Wet lab:
For this project the student will be using a new lentiviral system, (LECHE), they developed in the lab that is designed to induce and facilitate comprehensive characterisation of dynamic changes in the mammary epithelium of Cre-inducible mouse models, such as confetti and tumour suppressor flox mouse models. In addition, the student will have the opportunity to validate some of the findings using orthogonal spatial technologies with the aim of translating these findings to therapeutic cancer prevention approaches.
Dry lab:
For this project the student will be analysing a large dataset of mouse and human scRNAseq which has been collected over several years to identify mechanisms that promote the transition of precancerous cells to cancer. This project will suit someone with some experience in using R and/or Python.
References:
1. Reed, A. D., Pensa, S., et al. A single-cell atlas enables mapping of homeostatic cellular shifts in the adult human breast. Nat Genet 56, (2024).
Linking protein self-assembly with biological function and disease (MPhil/PhD)
The group uses a multidisciplinary approach, including biophysics, cell biology and protein engineering, to study the molecular processes underlying protein self-assembly. Amyloid fibril formation is associated with a wide range of human disorders including Alzheimer’s and Parkinson’s diseases and motor neurone disease. Due to the prevalence of these disorders, they are studying the structural attributes of species formed during amyloid formation to increase our understanding of the mechanisms by which disease-associated proteins behave aberrantly. This will enable the group to find ways to inhibit or neutralise the formation of toxic species that lead to cellular dysfunction.
But protein self-association is not only linked with disease, in fact Nature has an incredibly clever way of rapidly assembling and dissipating biomolecules for cellular functions. It does this by forming membraneless droplets involved in cellular processes such as signalling, cellular stress and protein degradation. We are exploring the use of engineered biomolecular condensates to gain mechanistic insight into how Nature utilizes phase-separation to facilitate protein degradation via autophagy (1). We are using this information to create precision autophagy-targeting therapeutics to bind neurodegenerative disease-causing proteins and facilitate their degradation.
Interestingly, some biomolecular condensates exist in a fine balance of function versus pathology and are emerging as key targets in amyloid disease. Given that amyloid and biomolecular condensates are not mutually exclusive, we are also exploring how and why protein recruitment into biomolecular condensates leads to formation of mature amyloid fibrils to develop therapeutic interventions.
- Ng TLC, Hoare MP, Maristany MJ et al. J.R. Kumita (2024) bioRxiv https://doi.org/10.1101/2024.04.16.589709
Platelet procoagulant activity: regulation and inhibition
Platelets are necessary for normal haemostasis but platelet activation at the wrong time or place drives arterial thrombosis, leading to heart attacks and ischaemic stroke. One of the prothrombotic roles of platelets is to enhance coagulation by exposing phosphatidylserine (PS) on their outer surface and by releasing procoagulant extracellular vesicles (EVs).
In the Harper lab, we aim to understand how platelet PS exposure and EV release are regulated, and whether we can pharmacologically inhibit these dangerous processes to reduce thrombosis. Our recent work has identified that ‘supramaximal’ Ca2+ underlies platelet PS exposure, identified the platelet ‘flippase’ as a novel approach to reducing coagulation, and explored a diverse range of potential antithrombotic molecules.
Future research projects will involve continuing to further our understanding of platelet PS exposure and EV release. Please contact Dr Harper to discuss potential MPhil or PhD projects before applying to discuss potential research directions.
Keywords: platelets, thrombosis, novel therapeutics
The ability to detect potentially damaging stimuli provides a vital protective function, but in chronic pain syndromes (e.g. osteoarthritis and inflammatory bowel disease) the gain in pain goes wrong and the pain experienced has a major impact on an individual’s well-being. In our lab, we employ a range of molecular biology, electrophysiology and behavioural techniques to understand how sensory neurons function and this changes in chronic pain states, the overall aim being to identify new targets for the treatment of pain. Recent work has used single-cell RNA-sequencing to describe 7 distinct sensory neuron subsets innervating the distal colon (a prime source of visceral pain), employed chemogenetic approaches to relieve joint pain and demonstrated the ability of mesenchymal stem cell-extracellular vesicles (MSC-EVs) to alleviate neuronal excitability and pain-related behaviours in an osteoarthritis mouse model. A further area of interest is use of the naked mole-rat as a model organism, a rodent that lives for 35+ years, exhibiting extreme cancer resistance, although naked mole-rat cells are susceptible to oncogenic transformation, an absence of neurodegeneration and a range of unusual pain phenotypes.
Future research projects will involve continuing to further our understanding of chronic pain using similar approaches in the fields of visceral pain and joint pain.
Key words
Pain, neuroscience, electrophysiology, behaviour
Innovating Protein Technologies for Therapeutic and Vaccine Design - PhD Only
Inspired by extraordinary molecular features from the natural world, the Howarth Group’s research develops new approaches for disease prevention and therapy. By engineering and evolving proteins, projects range from fundamental analysis through to clinical application. There are PhD projects in various areas and the group is keen to design with you a project connecting to your interests.
- The group's Plug-and-Protect vaccine platform has entered clinical trials for malaria, coronavirus and CMV. One project is to tailor antigens and protein nanoparticles, to induce the most potent cell signalling and maximize protection for the most important global health challenges.
- The group’s SpyTag/SpyCatcher technology for covalent ligation is being widely applied for basic research and biotechnology. A new project uses SpyTag to enhance how antibodies can be combined for combinatorial control of CAR-T and cancer cell signalling. A key goal is to modify the cell surface to improve CAR-T cell selectivity in killing of solid tumours.
- The gut is highly effective at degrading proteins, preventing the use of antibodies for targeting in the gastrointestinal tract. The group has established a new antibody mimetic with exceptional protease resilience. One project will use library selection and computational design with machine learning to advance the targeting platform, towards tackling important challenges in autoimmune disease, infection or microbiome modulation.
Keywords: protein engineering, synthetic biology, cancer, infectious disease
Antibiotic resistance is a growing worldwide human health issue with major socio-economic implications. A review from the Antimicrobial Resistance and Healthcare Associated Infections Reference Unit estimates that by 2050 the global cost of antimicrobial resistance will be up to $100 trillion and will account for 10 million extra deaths a year, reinforcing the urgency of finding novel and efficient ways to treat this problem. The Mela Group explores the potential of DNA nanostructures, both as a sensor that binds to bacteria in a specific and efficient manner and as a platform to deliver active antimicrobials to bacterial cells.
DNA nanostructures are made by exploiting the base-pairing property of DNA to construct two- or three-dimensional nanostructures that can be easily customised to deliver a variety of payloads and also to carry “anchors” that will enable attachment to specific targets
Project 1
This proposed project aims to investigate the interactions of 3D DNA nanostructures of different sizes with bacterial targets, and the potential of these nanostructures to enter the bacterial cell. The nanostructures will be tested for targeting potential both “naked” and encapsulated in liposomes. We will then functionalise the nanostructures with active antimicrobials and explore the relationship between size and cargo in the efficiency of these nanostructures as antimicrobial drug delivery vehicles.
Project 2
In this project, we aim to use DNA nanostructures that have the ability to change conformation depending on environmental conditions. We will functionalise the nanostructures so that they can tightly bind on the bacterial membrane and then induce conformational changes (linear to spiral structures). We will assess and quantify the effects of these conformational changes to the membrane integrity of bacteria and therefore their viability, and develop these nanostructures as potential antimicrobial nano-robots.
Keywords: Antibiotic resistance, DNA nanostechnology, microscopy, drug delivery