Projects available for October 2024

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Abstracts of research projects offered for October 2024

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:

1. Targeting the microbiota to treat visceral pain
2. Innovating Protein Technologies for Therapeutic and Vaccine Design
3. Targeted protein degradation by the Ubiquitin-Proteasome System (UPS)
4. Aptamers and DNA Nanostructures
5. Aptamers as a tool for targeting bacterial outer membrane proteins
6. BBSRC DTP PhD Project
7. Platelet procoagulant activity: regulation and inhibition
8. Study of Ion Channels and Biologic Partners
9. Context-specific receptor signalling in cell physiology and drug response
10. Mechanisms and inhibition of bacterial multidrug transporters (MPhil/PhD)
11. Assessing the regenerative effects of co-expression of Myc and Cyclin T1 in cardiomyocytes

Dr David Bulmer

Targeting the microbiota to treat visceral pain

Dysbiosis of the gut microbiome contributes to the development of chronic pain in nocicplastic pain syndromes such as fibromyalgia and irritable bowel syndrome (IBS). We have shown that treatment of IBS patients with a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) normalizes dysbiosis reducing in pain and IBS symptom scores to a greater extent than patients with healthy microbiomes. Metagenomic analysis has revealed the bacterial species contributing to this dysbiosis and pathways analysis has identified bacteria modulated by FODMAP intervention that produce metabolites such as short chain fatty acids (SCFAs), tryptophan and histidine. We hypothesise that these bacterial metabolites contribute to chronic pain in IBS and other nociplastic pain syndromes through the activation and sensitisation of visceral nociceptors, subsequent development of central sensitisation and anxiety related to dysregulation of gut-brain signalling. Targeting the production of bacterial metabolites may therefore offer a novel therapeutic approach to the treatment of chronic pain. This studentship will evaluate the impact of bacteria contributing to dysbiosis on gut function and nociceptor signalling identifying causative factors.

Professor Mark Howarth

Innovating Protein Technologies for Therapeutic and Vaccine Design

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, our projects range from fundamental analysis through to clinical application. They have PhD projects in various areas and are keen to design with you a project connecting to your interests.

• The gut is highly effective at degrading proteins, preventing the use of antibodies for targeting in the GI tract. We established a new antibody mimetic with exceptional protease resilience. We are developing this new targeting platform towards applications in autoimmune disease, infection and microbiome modulation.
• Their Plug-and-Protect vaccine platform has entered clinical trials for Covid-19, with other trials in preparation (CMV, malaria, pan-sarbecovirus). One project is to tailor antigens and protein nanoparticles, to harness better immune signalling and maximize protection for the most difficult 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 and make them effective against solid tumours.

Keywords: protein engineering, synthetic biology, cancer, infectious disease

Dr Catherine Lindon

Targeted protein degradation by the Ubiquitin-Proteasome System (UPS)

Targeted protein degradation occurs through ubiquitin-mediated pathways that bring about the destruction of ubiquitin-tagged proteins at the 26S proteasome. The Lindon Group’s research seeks to understand how these pathways control cell division and other cell fate decisions, with a focus on the major cell cycle regulator Aurora A kinase (AURKA). AURKA is a target of ubiquitin-mediated degradation by the APC/C-FZR1 ubiquitin ligase, and a key player in several types of cancer. They are also studying a new class of drugs, often referred to as PROTACs (Proteolysis Targeting Chimeras), that induce the degradation of clinically relevant target proteins such as AURKA. Although there is much excitement about the therapeutic potential of this new class of drug, there is still much to learn about the relevant ubiquitin-dependent pathways that operate within the cell to bring about target destruction. They aim to discover more of the cell biology of PROTAC action to assist in the design of successful PROTAC-based therapeutic strategies.

The Group studies these questions using quantitative molecular and cell biology techniques, including timelapse fluorescence microscopy and cellular ubiquitination assays, and we collaborate 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

Dr Ioanna Mela

Aptamers and DNA nanostructures

Antibiotic resistance is a growing worldwide human health issue. 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. One promising anchoring mechanism is the use of DNA aptamers. Aptamers are oligonucleotide or peptide molecules that bind to a specific target. They recently showed the use of DNA nanostructures for the specific targeting of bacterial cells, however, the selection of aptamers that bind specific proteins on the bacterial surface, still remains a challenge. This thus presents a unique opportunity for a novel therapeutic strategy and is timely in the face of the growing antibiotic resistance crisis. This project aims to select aptamers that are specific and show high binding affinity towards bacterial outer membrane proteins and characterise the interaction with the targets through a combination of atomic force microscopy, super-resolution microscopy and biochemical analysis.

BBSRC DTP PhD Project

In the Mela laboratory, they have combined DNA nanostructures and aptamer nanotechnology to create bacteria-specific delivery vehicles, with the potential to deliver a multitude of active compounds to bacterial targets. They will now build on this work, to develop novel, highly sophisticated DNA-based systems for targeted and controlled antimicrobial delivery and simultaneous blocking of bacterial receptors. The aim of this PhD project is the selection of aptamers (oligonucleotides that bind to specific target molecules with high affinity) that can bind specific surface proteins on particular bacterial strains, to maximise the specificity and efficiency of drug delivery. The focus will be on targeting aptamer-derivatised DNA nanostructures to two specific surface proteins that are crucial to the survival of MRSA and P. aeruginosa. On MRSA, the target proteins will be fibronectin-binding proteins A (FnBPA) and B (FnBPB). These proteins mediate the adhesion of MRSA to the extracellular matrix and are involved in MRSA invasion of host organisms and in the formation of biofilms. The target proteins on P. aeruginosa will be pseudomonas haem uptake (Phu) and haem assimilation (Has) receptors. The Phu and Has receptors are crucial for P. aeruginosa, as they facilitate the sourcing of iron — an essential micronutrient for the survival and virulence of Gram-negative pathogens — from haem. Once the best performing aptamers are selected, we will explore their potential as a tool against antibiotic resistance. They will assess the aptamers for their potential to drive the binding of nanostructures on the bacterial surface and as pharmacologically-relevant molecules, with the ability to disrupt crucial bacterial functions.

Keywords: Antibiotic resistance, DNA aptamers, nanostructures, microscopy, drug development

Dr Matthew Harper

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.

Please contact Dr Harper to discuss potential MPhil or PhD projects before applying.

Keywords: platelets, thrombosis

Dr Paul Miller

Study of Ion Channels and Biologic Partners

Keywords: Cryo-EM, ion channels, electrophysiology, antibody modulators

Dr Marti Maria Solano

Context-specific receptor signalling in cell physiology and drug response

G protein-coupled receptors (GPCRs) are an extensive family of proteins found across human cells and tissues. Individual family members detect different signals reaching the cell membrane (such as light, taste, neurotransmitters or hormones) and convey their messages to signalling partners that activate a variety of physiological responses inside our cells. Importantly, due to their capacity to regulate a wide variety of cell responses, GPCRs have become the most common drug target class. And still, some fundamental questions on GPCR function remain unresolved:

• How do different signals binding to the same receptor promote specific intracellular responses?
• Why does receptor activation by a particular signal or drug often produce contrasting responses when we compare different cells or tissues?
• How does our age, sex or genomic background determine the way we respond to GPCR-based therapies?

To address these questions, the Solano Group apply a range of computational biology techniques to integrate structural, multi-omics, network biology, cell signalling, and pharmacogenomics data. They also collaborate extensively with molecular pharmacologists, biophysicists, computational chemists, and clinicians within the UK and abroad.

By exploring receptor signalling from a systems pharmacology perspective, we not only intend to boost our understanding of receptor pathway physiology and its influence on cell function, but also to suggest new advanced models for the study of GPCRs in health and disease, guide the selection of pathway-specific GPCR drugs with improved efficacy and safety profiles, and ensure that we use the therapeutics that are currently in the clinic in a more personalised manner.

Keywords: computational biology, systems pharmacology, structural bioinformatics, receptor signalling, personalised medicine

Professor Hendrik van Veen

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, the van Veen Group aims 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:

The Group studies multidrug transporters in the ABC, MFS, and MATE families, and examines their roles in antibiotic resistance of bacterial cells using microbiological techniques. Furthermore, they 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, the Group applies 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 their 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.

Dr Catherine Wilson

Assessing the regenerative effects of co-expression of Myc and Cyclin T1 in cardiomyocytes

There are over 23 million heart failure patients worldwide, and regeneration of the heart is one of the best potential treatments. Our recent findings demonstrate that combined Myc and Cyclin T1 expression can elicit extensive cellular proliferation of adult mammalian cardiomyocytes. Indicating we can reprogram an organ with extremely limited endogenous regenerative potential towards cardiomyogenesis. Research in our laboratory focuses on developing a new class of regenerative therapeutics that allows transient delivery of Myc and Cyclin T1.

In this project, the candidate will analyse single nuclei RNA sequencing data that we have generated in the lab from mouse models of myocardial infarction to characterise dynamic shifts in cell populations following Myc-Cyclin T1 overexpression. The student will identify and validate novel ligand-receptor interactions between different cell types in the heart(immune cells, myofibroblasts, endothelial cells) with an aim to understand the regenerative processes provoked by Myc in the adult mammalian heart.

Please contact Dr Wilson to discuss the projects offered.

Key words: Myc, transcription, cell cycle, cardiomyocyte, cardiovascular disease, regeneration, myocardial infarction, single cell genomics.

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