Abstracts of research projects offered for October 2023
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.
Dr David Bulmer
Treating visceral pain in Irritable Bowel Syndrome
Irritable Bowel Syndrome (IBS) is a prevalent gastrointestinal disorder and a leading cause of chronic pain globally. The introduction of dietary regimes Low in FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) has been transformative in the treatment of IBS, although the underlying mechanisms contributing to this clinical efficacy remain elusive. Working closely with clinical colleagues in the Department of Gastroenterology, Addenbrookes Hospital, work in this studentship will explore the mechanisms by which pain-sensing nerves (called nociceptors) are activated in patients with IBS and how this activation is modulated by FODMAP diets and other interventional treatments. Work in this studentship will utilise electrophysiological and imaging techniques to study nociceptor signalling from the gastrointestinal tract.
Keywords: pain, nociceptors, electrophysiology, Ca2+ imaging, gastrointestinal
Dr Ioanna Mela
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. We explore 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. We recently showed the use 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. The aim of this project is 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.
Keywords: Antibiotic resistance, DNA aptamers, nanostructures, microscopy, drug development
Professor Laura Itzhaki
The major focus of our research is a class of proteins with very distinctive architecture, known as tandem-repeat proteins (e.g. ankyrin, tetratricopeptide and armadillo repeats), which are frequently deregulated in human diseases such as cancers and respiratory and cardiovascular diseases. These proteins function as scaffolds for molecular recognition and binding hubs for assembling large macromolecular machines. As suggested by their Slinky spring-like shapes, it is thought that they utilise various dynamic and elastic modes of action. For example: stretching and contracting to regulate the activity of a bound enzyme; reversible nanosprings to operate ion channels; proteins that wrap around their cargoes to transport them in and out of the nucleus. The simple modular architecture of repeat proteins makes them uniquely amenable to the dissection of their biophysical properties as well as their rational redesign. The following PhD projects are available:
- Exploiting the design-ability of repeat proteins to build artificial proteins with applications in synthetic biology (multivalent and multi-functional repeat proteins designed to rewire cellular pathways), repeat-protein therapeutics (designed repeat proteins as inhibitors or to harness the cell’s waste-disposal machinery to drive the destruction of disease-associated target proteins), and nanotechnology (self-assembling repeats proteins as genetically encoded phase-separating bioreactors).
- Peptide inhibitors to target disease-associated repeat proteins for therapeutic benefit.
- Protein engineering and design to determine how the distinctive structures of repeat proteins control their functions in the cell - e.g. building artificial repeat proteins to act as cellular force sensors.
Research in our group is at the interface between biology and chemistry; we also have close collaborations with computational groups and synthetic chemistry groups in Cambridge, and therefore students will be able to learn a broad range of techniques and approaches, including protein engineering, biochemistry and biophysical analysis, single-molecule techniques, cell biology and medicinal chemistry.
Selected references:
- Burbidge O et al. (2021) Nanobodies restore stability to cancer-associated mutants of tumor suppressor protein p16INK4a. BioRxiv doi: https://doi.org/10.1101/2021.07.01.450670
- Diamante A et al. (2021) Engineering mono- and multi-valent inhibitors on a modular scaffold. Chemical Science 12, 880
- Xu W et al. (2017) Macrocyclized extended peptides: Inhibiting the substrate-recognition domain of tankyrase. JACS 139, 2245
- Synakewicz M et al. (2022) Consensus tetratricopeptide repeat proteins are complex superhelical nanosprings. ACS Nano 16, 3895
Keywords: protein engineering, protein design, targeted protein degradation, cancer, biotherapeutics
Prof Mark Howarth
Innovating Protein Technologies for Therapeutic and Vaccine Design
Inspired by extraordinary molecular features from the natural world, our research develops new approaches for disease prevention and therapy. By engineering and evolving proteins, our projects range from fundamental analysis through to clinical application. We 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.
- Our 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 lab’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.
Key words: protein engineering, synthetic biology, cancer, infectious disease
Targeted protein degradation by the Ubiquitin-Proteasome System (UPS)
Targeted protein degradation occurs through ubiquitin-mediated pathways that bring about destruction of ubiquitin-tagged proteins at the 26S proteasome. Our 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. We are also exploring the ability of a new class of drugs, often referred to as PROTACs (Proteolysis Targeting Chimeras), to induce degradation of clinically relevant target proteins, opening up exciting new therapeutic avenues.
We study these questions using quantitative molecular and cell biology techniques, including timelapse fluorescence microscopy and cellular ubiquitination assays, and collaborate with chemists, biochemists and computational biologists. Please see our 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 Catherine Wilson
Harnessing Myc transcription to drive proliferation in non-regenerative organs
Myc is a transcription factor deregulated in the vast majority of cancers, its expression drives cells into cycle and, if unchecked, this deregulation leads to uncontrolled growth. We use acutely switchable models of Myc to assess the immediate molecular and pathological effects of switching Myc on and off. Using these systems, we have shown that Myc binds to a large set of genes common to all tissues that are involved in cell cycle entry; suggesting Myc is able to drive cell cycle progression in any type of cell. However, we found that despite acutely overexpressing Myc in all tissues, non-regenerative tissues like the heart remained almost entirely resistant to cell cycle entry, due to an inability of ectopic Myc to activate transcription of its target genes once bound.
We have established that Myc driven transcription, and consequently cell proliferation, is critically dependent on the level of P-TEFb activity within a specific tissue. Using the heart as a model system that has very limited capacity for proliferation, we have reactivated Myc transcription and proliferation by increasing the activity of P-TEFb. The aim of this project is to establish if restoring Myc driven transcription and proliferation in non-regenerative cells can be harnessed to stimulate endogenous tissue repair.
Please contact Dr Wilson to discuss the projects offered.
Keywords: Myc, transcription, cell cycle, cardiomyocyte, cardiovascular disease, cancer, regeneration, myocardial infarction.
Dr Janet Kumita
Linking protein self-assembly with biological function and disease (MPhil/PhD)
Our bodies contain some 100,000 proteins that enable or regulate essentially every biochemical process on which our lives depend. For these proteins to perform their normal roles, the vast majority must remain in their soluble functional states. To maintain this healthy balance, cells have evolved intricate quality control networks that identify aberrant and damaged components and destroy them. Normally, quality control mechanisms within the cell help to re-fold or eliminate misfolded proteins to maintain a balanced protein homeostasis, but growing evidence has shown that function of these processes can decline with age and that dysfunction of the quality control processes are associated with different pathologies, including “amyloid diseases” such as Parkinson’s disease, Alzheimer’s disease and motor neuron disease, which are associated with the formation and deposition of misfolded, proteinaceous aggregates. But protein self-association is not only linked with the decline of protein homeostasis, in fact Nature has an incredibly clever way of rapidly organising and dissipating biomolecules for cellular functions. It does this by forming membraneless droplets and these are found in diverse processes such as signalling, cellular stress and protein degradation. Interestingly, these biomolecular condensates exist in a fine balance of function versus pathology and are emerging as key targets in amyloid disease.
The work in my group is exploring the use of engineered biomolecular condensates to gain mechanistic insight into how Nature utilizes phase-separation to facilitate protein degradation via autophagy (the cell’s waste disposal machinery) and how we can use this information to create precision autophagy-targeting therapeutics to selectively bind neurodegenerative disease-causing proteins to facilitate their degradation. Given that amyloid and biomolecular condensates are not mutually exclusive, we are also exploring how and why the recruitment of proteins into biomolecular condensates leads to the irreversible ageing and formation of mature amyloid fibrils in an effort to develop therapeutic interventions.
We collaborate with several research groups in Cambridge, and therefore students will be introduced to a range of disciplines. We have a number of projects that would be suitable for postgraduate studies. These will allow the development a number of different experimental skills including:
- Molecular biology to create novel engineered proteins
- Recombinant protein expression and purification methodologies
- Biophysical techniques (e.g. fluorescence, circular dichroism and FTIR spectroscopies, microfluidics)
- Microscopy techniques (e.g. fluorescence-based, transmission electron microscopy)
- Biochemical assays (e.g. protein-protein interactions, aggregation, sedimentation assays)
- Cell biology techniques to relate in vitro findings to the more complex cellular environment
Key words: Biomolecular condensates, Amyloid, Protein design, Neurodegenerative diseases, Protein homeostasis
Dr Hendrik van Veen
Multidrug transporters in microorganisms and cancer cells
Multidrug transport proteins are located in the plasma membrane of cells, where they mediate the extrusion of cytotoxic drugs from the cellular interior to the exterior. These membrane transporters modulate the toxicity and pharmacokinetics of drugs in organisms ranging from bacteria to man. They are a cause of drug resistance in pathogenic microorganisms and cancers.
Using biochemical, biophysical, electrophysiological, microbiological and structural tools, we work on interesting and relevant questions:
- How are drugs recognised by multidrug transporters and how are they transported?
- What forms of metabolic energy are used by multidrug transporters, and how is this energy coupled to the drug transport reaction?
- Is drug transport the primary physiological role of multidrug transporters? Do these transporters also handle small ions, phospholipids, lipopolysaccharides and other physiological substrates, and if so, why and how?
- Selective inhibitors might improve the drug-based treatment of infectious diseases and cancers. Can we use the novel functional and mechanistic insights to generate inhibitors of multidrug transporters? What are the most efficient ways to inhibit these membrane proteins?
We study essential bacterial and human members of the ABC, MFS and MATE transporter families. Our work involves collaborations with chemists, structural biologists and biophysicists within the UK and abroad. Please, visit our lab website for further information, and feel free to contact Rik van Veen (hwv20@cam.ac.uk) to discuss possible PhD and MPhil projects.
Keywords: Antibiotic and anticancer drug resistance; multidrug transporters; transport mechanisms; physiological substrates; novel inhibitors.
Dr Delphine Larrieu
The nuclear envelope is a crucial cellular structure for maintaining cellular homeostasis, by preventing uncontrolled exchange of proteins between the nucleus and the cytoplasm, by acting as an anchoring platform for tethering chromatin, and by transmitting mechanical forces between the cytoplasm and the nucleus.
The importance of the nuclear envelope is highlighted by the catastrophic diseases caused when it is dysfunctional. These include cancers, muscular diseases, neurodegenerative syndromes and premature ageing syndromes (progeria) – the main focus of the lab. Importantly, nuclear envelope dysfunction also occurs in normal ageing but the mechanisms driving this remain unknown.
In the lab, we have implemented cutting-edge whole-genome CRISPR-Cas9 approaches to identify new players regulating nuclear envelope function. This led to the identification of new genes that can restore nuclear envelope defects in progeria cells. However, the function of these genes in the context of accelerated ageing remains unknown. Current projects in the lab are investigating the mechanisms behind this rescue by generating cellular models in which candidate genes are knocked out by CRISPR-Cas9 and studying the cellular phenotypes, the integrity of the nuclear envelope and the response of cells to mechanical stress. This work will contribute towards identifying new therapeutic strategies for premature ageing syndromes, that could also benefit diseases associated with physiological ageing.
Key words: Premature ageing, ageing, nuclear envelope, synthetic rescue
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
Ion channels play myriad functional roles in fundamental biology, for example by coordinating and powering muscle contraction, by generating axon potentials, and by mediating synaptic communication between neurones throughout the peripheral and central nervous system (CNS). As such, ion channels represent major therapeutic targets with small molecules against them being the third best-selling group of prescribed drugs. Despite this only a tiny fraction of channels are currently targeted from the estimated 400 predicted human ion channel genes. In recent decades antibody therapeutics (biologics) have rapidly risen to prominence in the drug market. One reason for the success of these agents is improved target specificity. However, no biologics against ion channels have yet made it into the clinic. Technically, ion channels represent challenging targets for the generation of useful biologic binders and modulators, in part due to difficulties in protein production of native forms, and in part due to a lack of penetrance of biologics into the CNS. The impact of breakthroughs in this area cannot be underestimated. Currently my research is aimed at using electrophysiological, biochemical, protein engineering and structural biology approaches to understand and develop novel antibody (nanobody) modulators with unique pharmacological properties against therapeutically relevant targets such as GABAARs, glycine receptors and sodium channels. Linked to this, we are also studying and engineering natural protein toxins into useful pharmacological tools. These ion channel types play important functional roles in the central and peripheral nervous system and are high value targets for new therapies against anxiety, chronic pain and many other neurological disorders. Naturally, following on from these studies aims are to test these proteins in relevant systems to uncover their impacts in neuronal function and to realise their therapeutic potential. A relevant example paper is: https://www.nature.com/articles/s41586-022-04402-z
These projects are currently unfunded, and so I particularly welcome applicants who would make strong candidates for prestigious scholarships, such as Gates Cambridge, Cambridge Trust, Vice Chancellor’s Awards, or similar (see www.graduate.study.cam.ac.uk/finance/funding for more details and deadlines).
Keywords: Cryo-EM, ion channels, electrophysiology, antibody modulators
Dr Marti 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, we apply a range of computational biology techniques to integrate structural, multi-omics, network biology, cell signalling, and pharmacogenomics data. We 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
Dr Walid T. Khaled
Identification and disruption of heterotypic cellular interactions during tumorigenesis
The early stages of tumour development are poorly understood and is an area which has the potential to improve the rates of early detection, prevention and treatment of cancer. Recent sequencing studies of normal tissue suggest that acquiring putative oncogenic drivers is not sufficient to initiate tumour development. This suggests a key role for the cell of origin, differentiation state and the microenvironment in mediating tumour initiation.
Research in our laboratory focuses on defining the early cellular and molecular events that drive tumour initiation and development. We particularly focus on how the cell of origin affect the differentiation trajectory of nascent tumour cells and dictate changes in the microenvironment thus, enabling tumour growth and immune evasion.
In this project the candidate will mine scRNAseq data we have generated in the lab from mouse models of breast cancer to identify putative and novel heterotypic ligand-receptor interactions between different cell types in the mammary gland. The candidate will then use primary mouse and human organoids to validate and understand the mechanism of these heterotypic interactions before attempting to disrupt them.
Keywords: single cell genomics, mouse models, organoids
Dr Taufiq Rahman
Rationally finding novel modulators of some calcium channels (MPhil/PhD)
A very common ways cells respond to extracellular stimuli is through transient elevation of cytosolic free calcium concentrations. For this, cells derive the 'extra' calcium from various intracellular stores that notably includes endo/sarcoplasmic reticulum and lysosome. From these organelles, calcium is mobilised through some calcium permeable ion channels that are gated by second messengers. In addition to these intracellular second messenger-gated ion channels, there are various calcium permeable channels in the plasma membrane that are gated by ligand, voltage or stretch and as such also support calcium entry from extracellular space. By now, we have the structures of most of these channel proteins elucidated through X-crystallography as well as cryo-EM. The project aims at exploiting these structures and then rationally identify novel small molecule scaffolds and peptides that could selectively modulate the function of these receptors. As techniques, you will use structure and ligand based in silico screening, Cell based calcium assays and potentially electrophysiological techniques.
If you are interested, please contact Dr Rahman to discuss further. It may be possible to tailor the project further to match your own interest.
Keywords: computer-aided drug design, ion channels, calcium assays
If you are a) currently doing an undergrad/MSc in a reputed institution and b) have proven expertise in using MD simulation packages (GROMACS, AMBER or NAMD), I will be interested to hear from you as a potential MPhil student to start in October 2023. Feel free to contact me with your CV and names of two referees, should you be keen.