PhD Studentship (Basic)

Interplay between Nod-like receptor apoptosis inhibitory proteins and prostaglandins in colonic infection, inflammation and cancer Maintenance of gut health is dependent on the complex interactions between different cell types in the intestines and the immune system. Communication between these cells ensures that the barrier between the body and the gut contents is not disrupted and enables threats, such as harmful bacteria, to be detected by one cell subset and eliminated by another. The interactions between these cell types are disrupted during inflammation and disease, such as colitis, cancer, and infection. Understanding these signals and how they are perturbed during disease is vital. Certain bacteria are detected using receptors called NAIPs; we aim to understand how activation of NAIPs subsequently affects the rest of the immune system and how this impacts disease development. We will delete NAIPs from epithelial cells in the gut and identify resultant changes in immune cells. We will test this in models of colitis, colorectal cancer and Salmonella infection. I will look at changes in gene expression following NAIP deletion and identify the soluble mediators which influence the immune response. This project will aid our understanding of NAIPs during inflammatory disease development and thus generate potential targets for treating these diseases in the future.

Grants awarded from 1 October 2005 to 30 June 2021


PhD Studentship (Basic)

Investigating the role of IFNg in controlling checkpoint receptor expression in response to immunotherapy Cancers are composed of mutant self-cells that exploit their environment to grow. The immune system can identify these altered cells as harmful and kill them. However, in some patients this immune response can become dampened over time. This is due to expression of "immune checkpoints" on a population of white blood cells called T cells. These checkpoints act as brakes on the immune response. In recent years, scientists have developed drugs to block these checkpoints, with the aim of releasing the brake on the immune system to attack the tumour (called immune checkpoint blockade ICB). However, ICB is effective in less than half of patients. One of the effects of ICB is to encourage T cells to make the inflammatory cytokine IFNgamma, which aids in eliminating the cancerous cells. Our initial studies suggest that some important immune checkpoints, such as Lag3, are increased by the cytokine IFNgamma, which may limit the success of ICB therapy. We aim to understand how IFNgamma controls these immune checkpoints on T cells in animal models of cancer. By using mice where their T cells cannot sense IFNgamma we will test whether making T cells insensitive to IFNgamma can improve ICB therapy.

Creative Commons Attribution 4.0 International (CC BY 4.0)


PhD Studentship (Basic)

Investigating the mechanisms of thromboinflammation induced by infection Thrombosis is estimated to contribute to 25% of deaths worldwide, yet our understanding of the mechanisms behind thrombus formation and related inflammation remain poor. This so-called thromboinflammation can occur as a result of severe infection, for example in sepsis and severe COVID-19. We aim to probe the lifecycle of the thrombus, and understand why it differs between different organs. To do this, we will use the well-established mouse models of Salmonella infection to study the composition of thrombi in different organs. We also aim to investigate the response of human platelets (the main component of many thrombi) to different strains of Salmonella, allowing identification of host and bacterial-specific factors that are affecting the thrombotic response after infection.
This research will help further our understanding of the mechanisms behind the dysregulated inflammatory processes that occur upon infection, including during COVID-19, that can lead to fatal consequences.


PhD Studentship (Basic)

Defining pathways of infection induced inflammation in the CNS While the importance of smallest cells in blood, namely platelets, in blood clotting is well understood, there is increasing interest in their role in regulating the inflammatory response. Our preliminary observations have revealed platelet aggregation and recruitment within the meninges following infection with the fungus Cryptococcus neoformans, the main causative agent of cryptococcal meningitis. Meningeal inflammation is one of the main contributors towards death in patients with cryptococcal meningitis, and thus targeting this is a potential therapeutic strategy for a disease which kills over 180,000 people every year. This project aims to understand how platelets and leukocytes (e.g. meningeal macrophages) drive inflammation and disease progression within the central nervous system during fungal meningitis. Using techniques such as flow cytometry and microscopy, we will determine platelet-leukocyte interactions during fungal infection in the CNS and define the molecular mechanisms governing these responses. Previous studies have shown disrupting platelet-macrophage interactions worsens disease outcome in sepsis, thus there is scope for targeting these interactions therapeutically. The results from this project will significantly advance our understanding of the pathology of cryptococcal meningitis, a disease associated with high morbidity and mortality, whilst providing novel insights into the immune functions of platelets which are poorly understood.


PhD Studentship (Basic)

Understanding biotin mediated metformin resistance within Pseudomonas aeruginosa Biotin synthesis deficient mutants of Pseudomonas aeruginosa can be killed by the diabetes drug metformin. I previously hypothesised that metformin disrupts metabolism and energy production, but not enough to kill Pseudomonas. This loss in energy may be compensated for by biotin mediated energy production, and therefore when this is also lost metformin has antimicrobial activity. I aim to understand the mechanism of action of metformin, the resistance mechanism of biotin and to try produce a novel combination therapy using metformin and a biotin production inhibitor. I will test P. aeruginosa growth in different carbon source medias +/- metformin to validate if metformin mechanism of action is metabolism linked. I will also try to elucidate the target of metformin via a suppressor screen and the use of TRADIS. Alternatively, I propose 2D-TPP. To validate if biotin resistance is related to bio-energetic compensation I propose an extracellular ATP accumulation assay. Next, the biotin synthesis enzyme BioA would be purified and an existing drug library will be used to screen for inhibitors. Should time permit, I will elucidate the structure of BioA using x-ray crystallography. These studies will help produce or inform the production of a novel combination therapy for P. aeruginosa infection.


PhD Studentship (Basic)

Defining the role of RND efflux pumps in antibiotic resistance I will investigate the role of efflux pumps in antibiotic resistance by researching two themes. Firstly, by looking at the function, prevalence and impact of plasmid encoded efflux pumps. There have been increasing reports of plasmid encoded RND efflux genes. To our knowledge no one has collated the incidence of RND pumps found on plasmids, their spread or potential roles in antibiotic resistance via the efflux of antibiotics. Using a clinical Acinetobacter pittii isolate, I will define the functional role of RND efflux pump genes in the laboratory for example by using efflux assays to measure export and minimum inhibitory concentration experiments to define the substrate profile.

The second theme will explore two Acinetobacter species: A. baumannii and A. lwoffii. Both species inhabit the same niche (hospitals) and cause high numbers of infections in immunocompromised patients. We wish to understand why A. baumannii is drug resistant and A. lwoffii is drug susceptible. To do this we will look at the variations in the resistance and efflux pump genes in clinical isolates of both species and hypothesise why A. lwoffii has not yet developed drug resistance and if there are any indications that it might in the future.


PhD Studentship (Basic)

Metagenomics for antimicrobial resistance in respiratory diseases Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of morbidity and mortality globally (Quaderi and Hurst, 2018). Worsening of typical daily symptoms (acute exacerbations) are frequently instigated by infection or pollution and are associated with a greater mortality (Toraldo and Conte, 2019). Antibiotic treatment is often used to alleviate exacerbations (NICE guideline, 2018).

The aim of this study is to collect longitudinal respiratory samples from COPD patients at baseline and post-exacerbation, including following antimicrobial treatment, and using the technique of shotgun metagenomics with long read nanopore sequencing, to probe the microbial community structure and investigate the presence and burden of antimicrobial resistance (AMR) genes. Method development will be required as respiratory samples have a significant proportion of human DNA which can make detection and analysis of microbial reads difficult (Hasan et al, 2016).

I will explore different extraction and human DNA depletion methods to enable a greater sequencing depth of microbial reads to be obtained, while minimising bias on community taxon distribution. AMR genes detected will be related to specific organisms and clinical data. This will help inform treatments used in the management of COPD and identify potential biomarkers to predict clinical outcomes (Leitao Filho et al, 2019).


PhD Studentship (Basic)

Does host age affect the emergence and spread of antimicrobial resistance? Antimicrobial resistance (AMR) and population aging are currently two of the greatest threats to the human race. While extensive research has been carried out on each individually, little is known about the impact of aging on AMR. This is somewhat surprising since a decrease in efficacy of antibiotics married with a population-wide increased susceptibility to infection due to aging could be catastrophic. During this project, I aim to characterise the relationship between host age and likelihood of contracting an infection which is resistant to one or more antibiotics, or the rate at which resistance develops during treatment. This will be carried out using electronic health records and meta-analysis. Mechanisms which may give rise to these relationships will then be proposed, tested using mathematical modelling, and further investigated using the model organism Drosophila melanogaster. Understanding the relationship between age and AMR may highlight certain patient groups where AMR interventions should be focussed, or where use of certain antimicrobials should be increased or reduced. Targeting antibiotic interventions in this way is hoped to slow the rapid spread of resistance which may be exacerbated by an aging population and preserve antibiotic efficacy to prevent a dramatic increase in morbidity and mortality.


PhD Studentship (Basic)

Prevention is better than a cure: Novel biomaterials to stop biofilms formation on blood contacting catheters Antimicrobial-resistant pathogens are of increasing concern, and the O’Neill report [https://amr-review.org] predicts that, by 2050, more deaths globally will be caused by antimicrobial-resistant infections than cancer. One solution is reducing antimicrobial dependence. Our approach is preventing formation of biofilms (communities of microbes attached to surfaces) on blood-contacting catheters. The immune system is then able to deal with the infection, preventing antimicrobial treatment (Jeffery and Mundy 2020).

Hook et al (Hook et al. 2012) identified polymers that resist biofilm formation in the absence of blood, now used to coat urinary catheters (Jeffery et al. 2019) with Wellcome Trust funding.

In vitro testing of candidate co-polymer coatings in bacterial culture in blood and the analysis of the adsorption of blood components on their surface will allow optimisation of biofilm resistance and haemocompatibility of the coating. Co-polymerising with protein biofouling resistant monomers will be conducted, leading to materials that perform both anti-protein biofouling and anti-biofilm functions. Determination of mechanical properties will ensure integrity of the coating during mechanical deformation. Once optimised, the coating will be tested in an in vivo foreign body infection model.

This technology has the potential for patients with blood-contacting catheters to experience fewer infections and associated risks.


PhD Studentship (Basic)

Understanding adult human hematopoiesis in ageing and chemotherapy The resilience of the human hematopoietic system declines with age as it becomes more susceptible to age-related disorders or malignancies, produces lower blood counts and is less capable of fighting off infections. When subjected to chemotherapy, it can be severely challenged, but cell counts will usually recover in 2 to 3 weeks. However, in older patients, the recovery can be slower, and individuals over the age of 75 are unable to tolerate more intense regimens.

In my project, I will compare and contrast the clonal composition and functional characteristics of hematopoietic cells from patients before and after receiving chemotherapy. To achieve this, blood samples of consenting patients between the ages of 40 and 90 will be obtained before and after their treatment, and I will grow single-cell derived colonies and then profile their DNA and single-cell RNA. This will allow me to measure how perturbation of the systemic environment affects the clonal composition of blood, how the proliferative capacities of cells are affected and what functional changes occur in their transcriptomes.

This study will help us understand to what extent the fitness of hematopoietic stem cells is environment-dependent and how ageing affects the recovery time after chemotherapy.


PhD Studentship (Basic)

Hydrodynamic interactions in molecular simulations at the biological mesoscale Macromolecules under flow at the biological mesoscale (10 nm  L  t  L  >  1 mum, t  >  1 mus) whereas atomistic scales (L  t


PhD Studentship (Basic)

Characterisation of a novel GBA-L444P BAC transgenic mouse model of Parkinson’s disease. Parkinson’s disease (PD) is the second most common neurodegenerative disorder, currently affecting 145,000 people in the UK. It is known that specific mutations in certain genes can increase the risk of developing Parkinson’s disease. One such gene is GBA, which represents the greatest genetic risk factor for developing PD. Despite this, we still don't fully understand how mutations in GBA increase the risk of developing PD and progress is limited by the lack of relevant animal models of GBA-associated PD. The Wade-Martins lab has therefore developed a new mouse model to study GBA-associated PD. These mice harbour a human GBA gene, which contains a mutation called L444P. My project will use biochemical, electrophysiological and behavioural techniques to investigate how disease in these mice progresses with age. I will also assess the effectiveness of potential therapeutic strategies at restoring the function of GBA. The second phase of my project will characterise pathology in stem cell derived dopaminergic neurons from Parkinson’s patients. These neurons also carry the L444P mutation in GBA, which will allow the translation of pathological findings in the mice into human neurons. This project will contribute to the field’s understanding of the pathology of GBA-associated PD.


PhD Studentship (Basic)

The evaluation of azoreductases as infection specific targets for antimicrobial delivery Bacterial biofilms pose a major threat to global health, due to their ability to evade antibiotics and host defence systems; therefore, leading to the development of chronic infections. The process of biofilm development is regulated by a series of molecular pathways, including cell-to-cell quorum sensing (QS) signalling. The disruption of this QS signalling pathway, through the use of QS inhibitors, shows great potential for the treatment of biofilm infections, while minimizing the selection pressure exerted on the bacteria. The incorporation of nanoparticle drug delivery systems enables the enhancement of antimicrobials delivery, including an increase in drug solubility and prolonged systemic circulation. Furthermore, these materials can be equipped with stimuli-responsive switches enabling a targeted drug delivery. Of particular interest is the use of poly(b-amino esters) (PBAEs) reported to selectively target and accumulate within bacterial biofilms. We hypothesize azoreductase enzymes, released by bacteria, can induce the opening of PBAE nanoparticles equipped with azobenzene moieties. This targeted cleavage of the azo bond would result in the release of encapsulated QS inhibitors, leading to the prevention of biofilm maturation. This delivery pathway has the potential of significantly enhancing the efficiency of antimicrobial delivery to biofilms, enabling the prevention of highly challenging chronic infections.


PhD Studentship (Basic)

Testing the roles of polyamines in predator-prey interactions of B. bacteriovorus Antibiotic resistance is one of the greatest threats to human health faced today. Infections previously treatable with antibiotics no longer respond, and bacteria have emerged that are resistant to all currently available antibiotics (O’Neill, 2016). As such, it is imperative to find novel treatment options including new antibiotics but also to develop alternative methods. One such method is to use other bacteria for our own benefit. Bdellovibrio bacteriovorus is a small, highly motile bacterium with an interesting food - it preys upon other bacteria, eating them from the inside out, including many bacteria that cause harmful infections in humans.  However more must be known about the predatory behaviour of Bdellovibrio before it can used in the clinic. This project focuses on chemical signals (polyamines) produced by Bdellovibrio, its prey, and its potential patient hosts. It asks how these signals alter the predatory ability of Bdellovibrio. This will increase our understanding of how Bdellovibrio senses its prey in host and natural environments and the signals it needs to continue the hunt. More detailed knowledge of this predatory behaviour in vitro will allow us to better predict how Bdellovibrio may behave in vivo inside a patient during future potential therapeutic uses.


PhD Studentship (Basic)

The use of global connectivity estimates in real-time models of international infectious disease spread Human mobility plays an important part in the spread of infectious diseases. Mathematical models can assess the risk that an emerging outbreak will spread internationally, providing decision-makers with information to support early surveillance and control measures. In this project I will aim to improve how well these models capture international mobility patterns by exploring the suitability of different measures of connectivity. I will compare flight passenger data (which is commonly used in international infectious disease spread models) with alternative transport passenger statistics and novel data, such as location data from mobile phones. I will use these data sources (both individually and in combination) in models to make predictions of the risks of imported and exported disease cases, and assess how well these different models can retrospectively predict the global spread of COVID-19. I will use these findings to develop a statistical model and tools that are ready in advance of future outbreaks to make rapid assessments of the risks that they will spread geographically. The project will lead to more realistic models of international infectious disease spread and thus improve the information that is available to support decision-makers in controlling future outbreaks before they become widespread.


PhD Studentship (Basic)

Determinants and consequences of HIV treatment amongst adolescents and young adults in sub-Saharan Africa Adolescents and young adults (10 to 24-year olds) account for a significant proportion of people living with HIV globally. Due to psychosocial and biological changes associated with individuals in this age category, they are more likely to have poorer treatment outcomes compared to younger children and older adults. Two interventions that have shown potential to improve outcomes in this age group include timely disclosure of adolescents’ HIV status to them and inclusion of the highly potent integrase inhibitor 'dolutegravir' into antiretroviral therapy regimens. However, there is limited knowledge on the psychosocial impacts of disclosure, and level of uptake and impact of dolutegravir use among adolescents and young adults in sub-Saharan Africa.

I aim to analyse data from a longitudinal, community-traced cohort study of HIV-positive adolescents in South Africa (Mzantsi Wakho) to assess the effects of timely HIV status disclosure on anxiety, depression, behaviour and suicide. I also aim to analyse routine HIV program data and develop a mathematical model of HIV progression, to estimate the level of uptake and effects of dolutegravir on treatment outcomes among adolescents and young adults.

My findings will help improve current HIV status disclosure guidelines and assess the progress in dolutegravir transition among young individuals.


PhD Studentship (Basic)

Characterising the effect of seasonality on the spatiotemporal transmission dynamics of dengue virus. Dengue virus (DENV) transmission is dependent on the vector capacity of mosquito populations (their ability to carry and transmit DENV), which is influenced by seasonally varying traits such as mosquito lifespan. Novel and effective DENV control measures include the release of mosquitoes infected with Wolbachia bacteria,  which confers reduced vector capacity, and vaccination. The high global economic and health burden of DENV is increasing with growing urbanisation and climate change. To target control measures to areas with the greatest burden of DENV, accurate estimates of where DENV is spreading the most are necessary.

We will develop DENV transmission models which integrate mosquito traits fitted to data describing the number of reported DENV cases over time in South East Asia and South America. The models will be further developed (addition of spatial structure) to explore the impact of population movement on the spread of DENV. In addition, the potential impact of novel control measures will be evaluated, including the release of Wolbachia infected mosquitoes, to explore their impact on DENV transmission. This research is therefore of high relevance to public health and to the DENV research field.

Grants awarded from 1 October 2005 to 30 June 2021


PhD Studentship (Basic)

Developing novel phylodynamic modelling methods for  forecasting infectious disease outbreak detection and transmission dynamics  Phylodynamic methods utilising genetic and epidemiological data, such as contact-tracing, hot-spot identification and modelling of strain-specific transmission dynamics, can provide a useful way for forecasting infectious disease outbreaks and transmission dynamics of interest. However, information from epidemiological investigations and genome sequences are rarely utilised together in current gold-standard methods used for outbreak assessment (2). We propose to develop novel phylodynamic methods for real-time outbreak detection of RNA-viruses (Sars-CovV-2, Influenza) using contact-tracing and predicted hotspot identification, as well as further developing understanding of transmission dynamics at the strain-specific level in a sustained outbreak over time. Sars-CoV-2 sequence data is sourced from COG-UK and linked to epidemiological patient data from PHE (3). Influenza sequence data is sourced from PHE, including strain-specific samples for Influenza A and B, and linked to epidemiological patient data from 2015 to present (4). Methods will be developed into publicly available R packages for application in future RNA-virus outbreaks. We aim to advance methods for incorporating genome sequence data into real-time forecasting of outbreak detection (5–8). Additionally, by increasing understanding of strain-specific transmission dynamics, we will advance understanding of seasonal infectious disease transmission at local, community and national level, and inform annual vaccine development in the UK (9).


PhD Studentship (Basic)

Structure, dynamics and function of OMPs in physiological-like membranes The outer membrane (OM) of gram-negative bacteria is the first line of defence against exogenous threats, and helps confer antibiotic resistance and enable biofilm formation. It is an asymmetric bilayer, consisting of an outer leaflet of lipopolysaccharide (LPS) and an inner leaflet of phospholipids and cardiolipin, and is crowded with outer membrane proteins (OMPs). While much is known about OMPs in symmetric phospholipid membranes, the effects of LPS, membrane asymmetry and protein crowding remain largely unclear – although they have been shown to be important. I will explore the structure, dynamics and function of OMPs in native-like membranes through an interdisciplinary approach combining molecular dynamics simulations, cryo-electron microscopy and biochemical/biophysical approaches. Specifically, I will develop protocols to generate OM-like asymmetric vesicles. Exploiting cryo-electron microscopy and molecular dynamics simulation methodology, I will elucidate the effects of the physiological OM components on FusA (a model OMP) in a broad range of asymmetric membrane contexts. In addition, substrate binding and in vivo function of FusA will be determined. Together, this work will elucidate details of how the OM modulates OMPs, providing clearer pathways to understand gram-negative bacterial biology, the role of the OM in antibiotic resistance and to develop better therapeutics.


PhD Studentship (Basic)

Structural and functional characterisation of E3 ligase complexes involved in inflammation Tissue damage and infection can elicit a specific response in the bone marrow called emergency haematopoiesis, which results in the production of myeloid-type blood cells. This response is mediated by a protein complex signalling hub called the Myddosome. After damage or infection resolution, the termination of emergency haematopoiesis is crucial, as prolonged emergency haematopoiesis may result in chronic inflammation, autoimmune disease and cancer. As such, termination of emergency haematopoiesis is carefully regulated by orchestrating a series of signalling events.
Using a multidisciplinary approach involving structural and cellular biology, this project aims to understand the molecular and functional basis of Myddosome-regulating complexes that participate in termination of emergency haematopoiesis. To achieve this, I will use cryo-electron microscopy to gain high resolution structures and use mutational analysis to probe protein-protein interactions and their functions. Results from this project will provide structural and functional information which will enable us to design potential therapeutics against immune-mediated diseases and hematopoietic cell proliferation.


PhD Studentship (Basic)

Defining the structural mechanism of the cellular response to DNA inter-strand crosslinks: structural characterization and inhibition of SLF1-SLF2 with its interacting partners. Interstrand crosslinks (ICLs) are the most toxic form of DNA damage, forming a blockage to essential cellular processes by preventing separation of the two strands of our DNA.  DNA crosslinking agents that induce this form of damage have been at the frontline of chemotherapy for over 50 years.  However, to protect our genomes from their constant exposure to DNA damage sources, our cells have specialised repair pathways to detect and remove ICLs. Understanding the molecular details of DNA damage repair pathways is therefore essential for advancing cancer research. Using a range of structural techniques and functional assays, including X-Ray crystallography and Cryo-EM, I will focus on a structurally uncharacterised complex involved in recruiting SMC (structural maintenance of chromosome) 5/6 to sites of double strand breaks (DSBs) introduced during the Fanconi Anaemia pathway, a major ICL repair pathway in proliferating cells. This complex, SLF1-SLF2, directly interacts with the E3 ubiquitin ligase, Rad18, which binds sites of DSBs marked by post-translational modifications, appearing to define a linear recruitment pathway for SMC5/6. This study will provide further insight into how toxic ICLs are resolved and could identify novel interactions that can be specifically inhibited for development of new cancer treatments to enhance chemotherapy.

Fanconi Anemia Complementation Group D2 Protein


PhD Studentship (Basic)

Determining the architecture of the HCV replication complex The hepatitis C virus (HCV) infection induces an intracellular rearrangement in the host cell forming many vesicles referred to as replication organelles. In particular, double membrane vesicles (DMVs) are proposed sites for the HCV replication. The HCV polyprotein is composed of structural and non-structural proteins. Five of the non-structural proteins form the replication complex. I aim to determine the ultrastructure of the HCV replication complex by taking a multidisciplinary approach. I will use biochemical, biophysical and structural analyses, including confocal microscopy, super-resolution approaches and cryo-CLEM, to visualise how and where these non-structural proteins form the replication complex. I aim to investigate in detail whether the replication complex is formed inside the DMV or on the surface. I will also determine the topology of nascent HCV RNA which will provide extensive knowledge about HCV replication. These studies will help to explain the concerted action of non-structural proteins and their role in HCV replication.


PhD Studentship (Basic)

Mechanisms of neurodegeneration and repair following demyelination in zebrafish In the neurodegenerative disease multiple sclerosis (MS), the lipid-rich layer surrounding nerve fibres known as myelin is lost, in a process known as demyelination. While this is thought to contribute to neuronal loss seen in MS, it is not clear exactly how neurons respond to demyelination, which prevents targeting key mechanisms that could be responsible for neurodegeneration in disease.
In animal models of demyelination, it has been observed that synapses, the structures that allow neurons to communicate with one another, are lost. Synapses are also affected in MS, which could contribute to clinical disability and cognitive impairment. We expect that synapse loss is an early feature of the neuronal response to demyelination, and if prevented, may protect neurons from degeneration. In this study, we aim to understand mechanisms of synapse loss and neurodegeneration after demyelination, and to determine if they are direct effects of demyelination or mediated by immune cells that respond to demyelination. We will employ zebrafish as a model, because we can follow individual neurons and synapses before, during and after demyelination using live imaging. This research will allow us to investigate the relationship between demyelination and synapse loss and identify strategies to prevent neuronal loss from ocurring.


PhD Studentship (Basic)

Effects of lifestyle and phylogeny on occipital lobe organisation across primate species The way a brain is organised stems from a combination of evolutionary and environmental influences. I aim to understand how these factors have shaped how different primate brains are organised. Specifically, I am interested in how visual experience and evolutionary adaptations have shaped the organisation of the occipital (visual) lobe.

To study occipital lobe organisation, I will reconstruct white matter tracts from MRI scans of primate brains. I will then use computational approaches to compare these tracts, finding which tracts differ between species. Using our knowledge of phylogenetic relationships and different animals’ lifestyles, I can test hypotheses about which tracts diverged at different points in evolutionary history, and about which adaptations are unique to different ecological niches. Afterwards, I will explore how ecological specialisations affect connectivity on a cellular level, in finer-grained detail than MRI can offer, by staining brain slices for axons and their myelin and analysing the innervation patterns of specific white matter tracts.

This work will yield insights into the evolution of the primate visual system and illuminate how it evolved to subserve uniquely human functions like reading. This work will additionally help us understand principles of brain diversity, with implications for evolutionary biology and translational neuroscience.


PhD Studentship (Basic)

The present is saturated with the past and pregnant with the future: continuous temporal integration of past and future events in the brain The environment is continuously changing. Our nervous system is capable of integrating these changes over time, facilitating an adaptive interaction with the world. At any moment, our brains are retaining past experiences and estimating future events. In the words of the philosopher Gottfried Leibniz: the present is saturated with the past and pregnant with the future. For example, when two people are having a conversation, retentions of what has just been said are needed in order to construct what will be said in the immediate future.

During my doctoral research, I will try to answer the question of whether retention of immediately past events and anticipation of future ones influences present perception both in the visual and in the auditory domains. By manipulating task demands, I also hope to explore whether such effects are flexible and context dependent. To explore how different brain regions across the visual and auditory systems allow for retention and anticipation, I will record electrical brain activity of participants while they observe learned and unlearned sequences of stimuli, such that we can manipulate their anticipation of what is coming . This work will advance the understanding of how events in the environment are integrated in time.


PhD Studentship (Basic)

The role of Xist binding partners in Xist localization X chromosome inactivation (XCI) is the mechanism that equalises X-linked gene expression in mammalian XX females relative to XY males. It is triggered by the expression of the 17Kb long non- coding RNA Xist. Upon transcription, Xist spreads in cis ‘coating’ the elected inactive X (Xi) and recruits factors acting in concert to modify the underlying chromatin and repress gene activity. A crucial step for XCI is the limited in cis localization of Xist, ensuring its action is restricted to the Xi elect only. Previous studies revealed Xist to be tightly anchored to the Xi territory through interaction with nuclear matrix proteins, however the mechanisms governing this process remain poorly understood. I will investigate the nature and the single-cell dynamics of Xist interactions with its anchoring factors through the genetic dissection of their functional domains in mouse model systems, using a combination of molecular biology and advanced microscopy approaches, such as live imaging and super resolution microscopy. Our research will elucidate the single-cell interplay between Xist and its localisation factors and their potential role in influencing Xist behaviour, providing insights into the mechanisms governing Xist spreading and retention within the Xi territory.


PhD Studentship (Basic)

Identification, characterisation and therapeutic targeting of gene regulatory complexes and networks in leukaemic stem cells. Transcription factor (TF) networks are cardinally dysregulated in Acute Myeloid Leukaemia (AML), with many of these dysregulated TFs known to have developmental and homeostatic roles in normal haematopoiesis. I will focus on the E-twenty six (ETS) TF Pu.1 that is known to play an important role in myeloid and lymphoid development. Conventionally, Pu.1 is better known as a tumour suppressor during AML development but, more recent studies within the Huntly Lab have suggested an alternative role for Pu.1 in the maintenance of AML.

I will be using an Npm1c/Flt3-ITD double-mutant mouse model, which recapitulates AML, to study Pu.1 in relevant leukaemic cell populations. I propose to study Pu.1 using chromatin-related genomic and proteomic techniques and will integrate these with gene expression analyses across normal-, early AML- and late AML-derived cell types. I will then aim to corroborating my findings from murine systems in AML patient samples. An understanding of changes in gene expression and the 3D chromatin structure caused by the binding of PU.1 and/or its interactors will unveil novel mechanisms of transcriptional regulation in the AML setting. Looking into the future, the combination of these experimental approaches may enable the development of therapeutics to specifically target PU.1-associated pathways AML.


PhD Studentship (Basic)

Examining the use of infectious disease modelling in international outbreak response Infectious disease modelling (IDM) is a branch of epidemiology that uses mathematical models to predict the spread of disease, often through a population. It is especially useful for estimating the impact of prevention and control measures.

After attending recent international conferences, the clear take-home message is that IDM research does not always reach healthcare decision-makers in a usable format, in useful time. ‘Healthcare decision-makers’ include such organisations as the WHO; Centres for Disease Control; International health NGOs; and country-specific Governments and Departments of Health. The bridge between researchers and decision-makers is especially challenging in emergency epidemic-response situations, where crucial action must be taken immediately.

In applied epidemiological research, the goal should be to inform evidence-based healthcare decision-making - answering the policy questions that need an answer. How do we ensure this can be achieved effectively?

This PhD seeks to analyse the use of infectious disease modelling in pandemics and large epidemics, by scrutinizing existing models and working closely with both influential modellers and global healthcare decision-makers on a broad range of outbreak case-studies. We will identify existing challenges on the interface of these two fields and work to develop a document of best practice, implementing change at the international level.


PhD Studentship (Basic)

Promoting an Adult Phenotype in Erythroblasts and Megakaryocytes derived from Human Pluripotent Stem Cells through a Forward Programming Approach Red blood cells (RBCs) and platelets are important cells in the blood required for oxygen delivery and blood clotting, respectively. Having too few of these cells, which can be caused by things such as cancer treatment, can lead to severe health problems. Although this is treatable using voluntary blood donations, in coming years more donations will be needed. Alternative options must therefore be developed. In answer to this, the Ghevaert group has developed a method (known as 'forward programming', or 'FOP') to artificially produce RBCs and platelets from stem cells in the lab. Unfortunately the cells produced by FOP are less functional than the adult cells found in our bodies, meaning that improvements must still be made. Using a computer program, I will redesign FOP so that it produces more functional RBCs and platelets from stem cells. This redesigning will involve changing the core ingredients used to drive FOP, so that FOP is more likely to produce adult cells. I will also investigate why it is so difficult to produce adult RBCs and platelets from stem cells. Consequently this work will guide future research in a more informed direction, and may provide a viable alternative to donated blood products.


PhD Studentship (Basic)

Genetic and non-genetic factors driving the expansion and progression of clonal haematopoiesis Myeloid malignancies are a range of blood cancers caused by specific mutations in blood cells. These mutations cause affected cells to grow more rapidly and make up a greater proportion of our blood over time in a process known as clonal haematopoiesis (CH). Recent studies have shown CH is commonly found in otherwise healthy individuals with some fraction going on to develop myeloid malignancies. We have previously shown that some of these mutations are particularly common in elderly individuals, although how they lead to CH is currently unknown. My research will study human bone marrow samples and mice carrying these mutations to understand how they cause CH and why they are more common in the elderly. In particular, I hope to identify factors present in the bone marrow of elderly people that alters the behaviour of blood cells carrying these mutations and leads to CH. This could be used to determine which individuals carrying these mutations are at high risk of progression to myeloid malignancy and develop treatments to stop or reverse this process.


PhD Studentship (Basic)

Circuit and Molecular Mechanisms of Olfactory Associative Learning To direct behaviour effectively, animals need to constantly update the value and predictions of the sensory stimuli they encounter. To solve this task, all brains have the ability to change sensory processing and behaviour according to previous experiences, a process termed learning. The aim of this project is to identify what changes in sensory processing underlie the integration of conflicting (rewarding and aversive) experiences which produce opposite behaviour. I will use C. elegans because it has small and anatomically well described circuits for associative learning that share functional features with those of more complex brains and can be manipulated with single cell resolution. I will combine behavioural analysis, genetic manipulation of neuronal communication and imaging of neuronal activity to dissect the mechanisms of neural plasticity that underlie a switch in odour preferences after sexual conditioning. This will consist in identifying the neurons within the circuit for odour processing that release a neuromodulator and establishing the changes in information flow arising from neuromodulation.  These studies will provide a mechanistic understanding for integration and resolution of conflict during learning that will illuminate how this process occurs in more complex brains.


PhD Studentship (Basic)

Investigating the role of CTHRC1 in biliary fibrosis Fibrosis (scarring) is a necessary part of regeneration, a stable scaffold around which cells can reorganise themselves to regain function is essential. In the liver, there are different modes in which fibrosis occurs, we need to learn more about what makes them different.

844 million people worldwide have chronic liver disease, with about two million deaths per year. Chronic liver disease can progress to cirrhosis, liver cancer and death. Treatment is limited to removal of the underlying cause or liver transplantation. Importantly, the greater the fibrosis a patient has the poorer the outcomes. Therefore, developing antifibrotic therapies for patients with chronic liver disease will impact significantly on morbidity and mortality. Primary biliary cholangitis (PBC) is a chronic liver disease resulting in destruction of the bile ducts. We have identified a protein called CTHRC1, expressed on scar-forming cells surrounding the duct, in patients with PBC. These cells play a role in fibrosis and disease progression.

To investigate how CTHRC1 contributes to liver fibrosis in PBC I will use liver tissue and cells from PBC patients and mouse models of liver fibrosis to explore whether targeting the function of CTHRC1 could be a new treatment for patients with liver fibrosis.


PhD Studentship (Basic)

The Epicardium as the Conductor of Cardiovascular Cells in Cardiac Regeneration Regenerative cardiovascular medicine is emerging as a novel therapeutic alternative to heart transplantation in patients suffering from chronic heart failure. This approach aims to restore cardiac functionality by exogenous transplantation of stem cell-derived cardiomyocytes. Although promising, challenges to cardiac repair remain, for example with respect to cell maturation and revascularisation. It has recently been shown in rats, that these challenges can be improved by co-transplantation of stem cell-derived epicardial cells. One plausible explanation for these improvements is paracrine-mediated effects. Paracrine signalling involves secretion of signalling factors in cells to alter the behaviour of surrounding cells, often in a gradient-dependent manner. Paracrine signalling factors include secreted proteins and miRNAs. They can be secreted into the extracellular space directly or packed into small extracellular vesicles, called exosomes. I aim to identify and characterise paracrine signalling factors of stem cell-derived epicardial cells, which promote myocardial maturation and vascularisation. Candidate paracrine signalling factors will be selected based on gene, protein, and miRNA expression and functionally characterised in vitro and in vivo. Identification of effective paracrine signalling factors will make it possible to address selected cardiac repair processes, resulting in new approaches to therapy.

Grants awarded from 1 October 2005 to 30 June 2021


PhD Studentship (Basic)

Investigating ancestral structure in the founding populations of modern humans in Africa Current research suggests that homo sapiens originated in numerous subdivided populations, opposing the traditional view that we evolved from a single region/population. Existing methods for detecting the size of ancestral populations are limited by their assumption that populations develop in isolation (without mixing with other populations), therefore necessitating new methods that can detect ancient population mixing.

My approach is to simulate different population ancestries – generally speaking, mixing vs non mixing – and see if any of the current methods for population size estimation hold any information in their model parameters that change in the presence of population mixture. Using these results, I will aim to analyse the extent of mixing in ancestral African populations by examining real genome data of extant peoples, such as the San and Yoruba. The impact of my research will be to shed more light upon the origin of homo-sapiens as we developed in Africa, 150,000 to 400,000 years ago.


DFID-Wellcome Epidemic Preparedness Grant

London School of Hygiene & Tropical Medicine

Yellow fever vaccination- will a booster be needed? A highly effective vaccine against yellow fever (YF) is available and part of the Expanded Program on Immunisation in YF endemic countries. Following a change in WHO guidance in 2014, YF vaccination is now restricted to a single dose given in infancy and expected to provide life-long protection. Recent data have highlighted that this schedule might be insufficient as low antibody titres have been documented in infants who received a primary dose at the age of 9 months. A booster dose of the vaccine might be required in order to ensure long-term protection. Data to support future decisions regarding the ideal timing of  a potential booster dose and its subsequent immunogenicity are now urgently required.

Our Aim is to assess if a YF booster dose is required for children who received a single dose of YF vaccination in infancy and if so, at what age this booster dose might be most effective to administer.

We will enrol three well characterised cohorts of children aged between 15 months and 8 years of age with available data on primary immune response to YF vaccination to determine ideal timing for a booster and examine underlying innate and cellular immune responses related to sero-protection.


PhD Studentship (Basic)

Determining the function of intestinal macrophage subsets in health, inflammation and repair Intestinal macrophages are crucial in maintaining gut homeostasis and, during health powerful regulatory mechanisms exist to maintain intestinal macrophages in an anti-inflammatory state, allowing them to exist in their antigen- and microbe-rich environment. However, macrophages are now also considered key drivers of intestinal pathologies, such as inflammatory bowel disease (IBD). Moreover, proinflammatory macrophages accumulate in the intestine and promote reduced epithelial-barrier integrity in response to distant inflammation, including cerebral ischemia (stroke). How macrophages can play such seemingly paradoxical roles remains unclear. One line of thought is that functionally-distinct macrophages subsets may dominate in certain contexts, i.e. health, inflammation and repair. Recent work from our lab uncovered at least two transcriptionally-distinct intestinal macrophage subsets, however their locations and functions within the gut wall in different contexts remain unclear. I aim to determine the roles of these macrophage subsets in intestinal inflammation caused by local insult or distant injury, as well as tissue repair. I will use immunofluorescence and flow cytometry together with novel genetic depletion models to assess the spatial and functional characteristics macrophage subsets in experimental IBD and intestinal inflammation caused by cerebral ischemia. These studies will determine whether the paradoxical roles of intestinal macrophages are explained by functional heterogeneity.


PhD Studentship (Basic)

Non-distancing: The role of direct cell-cell contact in cancer initiation and early progression Cells must communicate with their neighbours, send, and receive various information as they build and regenerate tissues. This communication is often not well understood, for example during the very first steps of cancer growth. Pre-neoplastic cells (PNCs) (the first cells carrying oncogenic mutations that will lead to cancer) are surrounded by healthy neighbours and contacted by patrolling innate immune cells. I want to know how these interactions between healthy cells of the body and the very first cancer cells may lead to the arrest or support of tumour development.
Evidence from the Feng group shows that neutrophils and macrophages contact emerging PNCs in the skin, and that this interaction results in increased proliferation of cancer-cell colonies (van den Berg et al., 2019). A new synthetic-biology tool called SynNotch allows us to precisely report on direct cell-cell contact at the single cell level (Morsut et al., 2016). I will engineer this tool into the zebrafish, where it will allow us to report on cell-to-cell contact in real-time, and in the living animals. Using this tool, I will study the effects of PNC-immune cell contact.
Additionally, I will study the effects of contact between PNCs and healthy neighbour cells in cell culture.


PhD Studentship (Basic)

Elucidating the functions of Pbx1 during pancreatic cell differentiation  Pbx1 is a TALE homeodomain transcription factor whose diverse regulatory function makes it indispensable for organogenesis (Selleri et al., 2019). Its activity is essential for early pancreatic development as embryos with homozygous deficiency of Pbx1 exhibit pancreatic hypoplasia and cell differentiation defects prior to death in utero at E15.5 (Kim et al., 2002). However, the basic mechanisms underlying the requirements for Pbx in mammalian pancreatic development remain largely unexplored. Using a conditional Cre-Lox system, I will focus on Pbx1 deletion in pancreatic epithelium at various stages of mouse development and in the adult pancreas to determine its role in maintaining pancreatic cell type identity. I will also establish a human induced pluripotent stem cell model to assess whether developmental mechanisms involving Pbx1 observed in mice are also conserved in humans. Here, I will use CRISPRi-Cas9 gene editing to reversibly inhibit Pbx1 at different stages of pancreatic cell differentiation. Lastly, I will construct a gene regulatory network of the pancreatic epithelium using chromatin immunoprecipitation and RNA sequencing data at various developmental stages to test Pbx1 targets both in vivo and in vitro. This project has great potential for advancing the field of diabetes research, disease modelling and cell therapies.

Gene Expression Regulation, Developmental


PhD Studentship (Basic)

Reconstructing a Gene Regulatory Network for cell fate decisions in the sensory nervous system The nervous system is the most complex organ in our body with thousands of different cell types. How is such diversity generated? This remains one of the key questions in developmental biology, which ultimately will inform regenerative medicine and cell reprogramming. Single cell technologies have shed light on how progenitor cells may commit to a particular fate, challenging the long-standing assumptions that cell differentiation is a smooth, continuous process.

This project will dissect the molecular mechanisms controlling how progenitors give rise to different cell types in the sensory nervous system of the vertebrate head. Despite a wealth of information on signalling, cell movements and timing of this process, a mechanistic understanding of how progenitors diversify is still missing. This is therefore an ideal context to apply a systematic, single-cell approach to identify and characterise cell fate decisions.

I will obtain single cell gene expression and chromatin state data from the developing chick embryo and use this to predict developmental trajectories, branchpoints, and candidate transcription factors regulating these branch points. I will then use perturbation analysis to validate these predictions. Together, this will reconstruct the molecular circuitry, the gene regulatory network, that drives cell fate decisions in the sensory nervous system.


PhD Studentship (Basic)

Muscle stem cell function in facioscapulohumeral muscular dystrophy Facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited muscular dystrophy, and involves progressive muscle weakness and wasting, beginning in muscles of the face, shoulder, upper back and lower legs. FSHD is caused by inappropriate expression of a protein called DUX4 in adult tissue. DUX4 is a transcription factor, meaning that it controls expression of other genes. DUX4 upsets the carefully orchestrated pattern of gene expression that allows muscle to function effectively, causing cells to die. However, exactly how DUX4 expression induces muscle cell death/loss are not well understood.

Muscle normally repairs efficiently due to resident stem cells, but loss of muscle in FSHD indicates a compromised repair mechanism. I aim to characterize muscle stem cells in FSHD by examining protein and gene expression in muscle biopsies from FSHD patients. I also aim to explore the dynamics and effects of DUX4 expression on development and function of muscle stem cells, as well as subsequent myofiber formation and regeneration, using induced pluripotent stem cells from FSHD patients and in vivo models. This work will inform whether deficits in muscle stem cell function contribute to the muscle wasting observed in FSHD pathology, and explore potential regenerative therapies.


PhD Studentship (Basic)

Tissue-resident macrophage activation and regulation in injury and recovery In this project, we hypothesise that there exist a tight regulation of macrophage activation following tissue injury to create environments permissive to different stages of tissue repair. Making use of human iPSC-derived macrophages (iMacs), we aim to gain insight into how they become activated after tissue damage, particularly through scavenger receptors in collaboration with other pattern recognition receptors. By studying knockout iMac models, we will then seek to understand how the IL-10/PGE2 axis and regulatory T cells limit excessive activation. Lastly, we aim to deliver in vivo evidence that some of these pathways are involved in promoting either organ inflammation or homeostasis restoration by using carbon tetrachloride (CCl4)-induced acute liver injury mouse model. A full understanding of these mechanisms will guide the development of potential therapeutic targets that harness specific macrophage properties for clinical benefit.


PhD Studentship (Basic)

Obtaining macrophages from induced pluripotent stem cells to investigate the influence of the host genetic background on the outcome of HIV-1 infection The influence of host genetic factors upon HIV-1 infection is still not fully elucidated. As the virus relies on the host cell machinery and proteins to replicate, host genetics are a key determinant not only of the proteins expressed but also of their functional capabilities – therefore dictating the outcome of virus infection. This research aims to link the natural occurring genetic variation found in the human population with the inherent variability in the capacity of cells from different individuals to support HIV-1 growth. The work will employ well characterised cells from a bank of human induced pluripotent stem cells to obtain macrophages, which are natural targets of HIV-1 infection. Experimental procedures will include characterising how the virus infects and replicates in macrophages, and employing a bespoke bioinformatics pipeline to compare the genome sequences and transcriptomes of cells showing extreme infection phenotypes. With this approach, we aim to identify novel host factors that can regulate viral replication. These results will add new insights into the understanding of HIV-1 infection and disease (AIDS) and suggest avenues to explore as potential novel therapeutic strategies to treat and control HIV-1.


PhD Studentship (Basic)

Immune-system dysfunction across major psychiatric disorders Currently, diagnosis of psychiatric disorders is based on symptoms rather than underlying biological cause. However, symptoms can vary within a disorder and are common across many different disorders. Therefore, it is possible there are shared biological causes for overlapping symptoms across disorders. Immune system dysfunction has been suggested as a potential cause of symptoms and altered brain structure common to many disorders.

I aim to identify groups of individuals with psychiatric symptoms and a genetic predisposition to immune dysfunction. To do this, I will analyse multiple large datasets of people with detailed information about their genetics, brain structure (from MRI neuroimaging), mental health and lifestyle. I will then uncover which specific components of the immune system are different in these groups of individuals. Using epidemiological statistical methods, I will test whether immune dysfunction causes psychiatric symptoms and altered brain structure. I also aim to extend this research to include a large dataset of young individuals (9 -11 years), to determine earlier origins of such relationships between immune dysfunction, alterations in brain structure and development of psychiatric symptoms.

These studies will identify shared biological causes common to many psychiatric disorders to help improve diagnosis, prognosis and move towards personalised treatment.


PhD Studentship (Basic)

Discovery and impact of schizophrenia rare genetic variation using next-generation sequencing Schizophrenia is a psychiatric disorder which affects around 1% of the population. There is no one single cause of schizophrenia, but genetics is known to play a substantial role. The genes involved in risk for the disorder span many different genes. Mutations thought to be linked to schizophrenia are often seen in individuals without a schizophrenia diagnosis, and I plan to investigate the impact these mutations have on an individual’s characteristics. I will use large-scale datasets in which every protein-coding base pair has been sequenced, highlighting any mutations. I will use information on an individual’s characteristics along with this genetic data to investigate the impacts of mutations in schizophrenia associated genes in both people with a schizophrenia diagnosis, and in those without. I also aim to discover new genes linked to schizophrenia, which will provide insights into the underlying biology of the disorder.


PhD Studentship (Basic)

Neural and cognitive mechanisms of temporally-extended decision-making, goal pursuit and learning Whether it be catching prey or making dinner, rewards in natural environments take time to pursue. This requires planning into the future, setting goals, and flexibly switching between different strategies when needed. In my PhD I will use computational models alongside fMRI and MEG imaging techniques to explore how humans plan and make decisions in temporally extended environments. In particular, I’m interested in the role of the human frontal lobes in prospective value-based decision-making and goal maintenance.

I will investigate the neural mechanisms by which humans pursue goals and suppress alternative courses of action, versus deciding to abandon goals. In addition, I will examine how individuals differ in this tendency to commit to goals, which may have relevance for our understanding of various psychiatric disorders such as OCD, apathy, and depression. In future projects I will use MEG to investigate the moment-by-moment brain activity responsible for tracking changing rewards, and using this information to make predictions about the future. Finally, I am also interested in how humans weigh up different types of value across time, such as the value of information or increased agency.


Discretionary Award – DSH

Vivli (Centre for Global Clinical Research Data)

Accelerating Access to Individual Participant-Level Data via the Vivli Platform Data repositories (such as IDDO and Vivli) have played a significant role in making research data available for secondary use. However, access to data needs to be further enhanced for accelerated innovations on infectious diseases by addressing the friction in data contribution, discoverability, access, and reuse. There is a strong alignment between Vivli the Wellcome’s visions of improving the discovery and accessibility of Individual Participant Data related to COVID-19 in the short term, and for other infectious diseases in the long term.  With this grant we seek direct support for discoverability and accessibility of data related to COVID-19, and to directly support Vivli to become an effective node in the "FAIR Data Network".

The grant will focus on the following primary objectives:

 Recognition and credit for data contributions,
 Accelerated access to Individual Participant Data (IPD) hosted by Vivli,
 Discoverability of IDDO studies via the Vivli platform, and
 Discoverability of IPD hosted by Vivli and its platform partners (including IDDO) based on rich metadata).


PhD Studentship (Basic)

Computational investigation into the interplay between pro-arrhythmic and mechanical abnormalities
Cardiac electrical activity and contractile output have a complex relationship – electrical activity signals contraction and contractile output can then affect electrical signalling via feedback mechanisms. Computational modelling allows us to understand this relationship further, particularly regarding two important applications.

Cardiac toxicity is a leading reason behind pharmaceuticals being withdrawn during development, but current screening methods centred on animal testing raise concerns with ethics and accuracy. Recent developments have suggested computational testing is a viable alternative, outperforming animal models in predicting risk from dangerous arrhythmias. I will incorporate contractile mechanics into our drug testing pipeline such that we can also assess their effect on contractile output.

Sudden cardiac death (SCD) is a leading cause of mortality worldwide, usually caused by arrhythmias. Various treatments exist to prevent SCD, but accurate risk stratification tools are needed to identify those at high risk for developing arrhythmias causing SCD. Measures of contractile output, such as ejection fraction (EF), are used, but the relationship between them and arrhythmic risk is currently unclear, as most people experiencing SCD have preserved EF. I will use an electromechanical model to investigate the mechanisms underlying this relationship so that we can more effectively identify and treat this high-risk population.


PhD Studentship (Basic)

Decoding heterogeneity and specialisation of interstitial synovial macrophages: what, where and how
Rheumatoid arthritis is an autoinflammatory condition that mainly affects the joints. Increased permeability of the blood vessels and recruitment of immune cells into the joint likely play a role at the onset of this disease. For immune cells to enter the joint, a signal sent by joint tissue-resident cells is required. A specific subtype of tissue-resident immune cells, called synovial macrophages are suspected to be the source of this initial signal. It has been shown that synovial macrophages consist of different macrophage populations with unclear functions within the joint and during arthritis development. Exploration of synovial macrophages via computational methods, namely single-cell RNA sequencing, revealed a subpopulation of macrophages defined by high gene expression of aquaporin 1(AQP1). This population was not previously defined in the literature and the overall role of AQP1 in macrophages is unknown. Furthermore, AQP1-positive macrophages expressed high levels of genes associated with bioactive lipid signalling previously shown to influence the inflammation in animal arthritis models. In my project, I aim to characterize the AQP1-positive macrophages, define their function and position within the joint, and finally identify the contribution of these cells in bioactive lipid signalling and induction of inflammatory arthritis.

Grants awarded from 1 October 2005 to 30 June 2021


PhD Studentship (Basic)

Precision genome editing with tandem autologous transplantation as a therapy for multiple severe immune-mediated diseases.    Immune-mediated diseases (IMDs) affect around 10% of the global population. Treatment of IMDs generally consists of immunomodulatory drugs to suppress active disease, but can have variable efficacy and can be associated with sometimes severe side effects. An alternative treatment for IMDs such as severe multiple sclerosis (MS) and scleroderma, is autologous stem cell transplantation (ASCT), which is emerging as a safe and effective therapeutic approach, although disease recurrence and secondary IMD development can occur.

The objective of our research is to test precision genome editing approaches for the treatment of several different IMDs by editing haemopoietic stem cells (HSCs). Edited HSCs would be for use in an autologous transplant to reconstitute the patient’s immune system with genome-modified cells to both treat and prevent the recurrence and development of IMDs.


PhD Studentship (Basic)

Patient-derived monoclonal antibodies as a precise tool to understand the pathophysiology of Caspr2-antibody encephalitis The production of autoantibodies by our immune system can be protective. In some cases, it can result in brain inflammation with memory disturbances and seizures.

My work aims to understand the basis of these disorders by studying a prototypical condition associated with antibodies against Caspr2. To study Caspr2-antibodies, I clone out patient antibodies from their blood and cerebrospinal fluid and study their characteristics using a suite of biochemical techniques. I will relate this to the properties of the cells which make these antibodies, also isolated from blood and cerebrospinal fluid, to address questions about the underlying immunology such as which cells first make the antibodies and which cells carry the most harmful antibodies.

After cloning, the antibodies will be subjected to in vitro tests to study their effects on nerve cells. Those with most potent effects will be injected into mice to observe their influence on memory, mood and seizures. In addition, real-time recordings of epileptogenic activity in awake animals will be used to investigate how the antibodies can lead to seizures.

These studies will utilise patient-derived antibodies as a powerful tool to decipher their relative contributions to human neurological illness and offer directed future methods to target their production.


PhD Studentship (Basic)

Structure and function of membrane proteins important in synaptic signalling Membrane proteins are integral to synaptic signalling, a process that enables the communication between a neuron and its target cell. Understanding the structure and function of such proteins is key to deciphering the biochemistry of our nervous system, which in turn will aid the development of new therapeutics. In this project, I aim to solve the 3D structure of membrane proteins using either cryo-electron microscopy or x-ray crystallography. The candidate proteins include: a) muscle-type acetylcholine receptor, an ion channel that is implicated in congenital myasthenic syndrome and myasthenia gravis, and b) the SLC1A family of membrane transporters which includes glutamate transporters and neutral amino acid exchangers – members of this family are associated with neurological disorders (Alzheimer’s disease, epilepsy and Huntington’s disease), cancer and other metabolic disorders. I will also test the effects of various compounds on purified proteins. These compounds could become useful tools for future studies or even evolve into therapeutics.


PhD Studentship (Basic)

Determining the structure of Pseudomonas aeruginosa Lipopolysaccharide across spatial scales Pseudomonas aeruginosa (P. aeruginosa) is a major human pathogen, needing urgent development of novel antimicrobials. It lives in bacterial communities called biofilms and severe infections are typical within hospital settings. Due to increased antibiotic tolerance of P. aeruginosa in biofilms, treatment is lacking and infections can be fatal, especially for those who are immunocompromised.

Lipopolysaccharide (LPS) is the main component on the outer membrane of the bacteria, which protects the cell and provides rigidity. LPS is important for bacterial survival as it interacts with our immune signals, protecting bacteria from being killed. LPS also contributes to antibiotic resistance, due to variations of LPS in different bacterial strains. Additionally, it forms part of the physical barrier within the membrane, preventing antibiotics from entering. Using biochemical and structural techniques, including CryoEM and CryoET, I will determine what P. aeruginosa LPS looks like in vitro purified, on the outer membrane of single P. aeruginosa cells and within the biofilm environment.

Accomplishing this will further our understanding of how LPS functions and reveal the structure of this essential drug target. Ultimately, this information will help us understand how to treat P. aeruginosa antibiotic resistant infections more effectively and provide insight for novel antibiotic development.


PhD Studentship (Basic)

Exploring the interdependence between cell cycle dynamics and cellular differentiation at the single-cell level The cell cycle and cellular differentiation, two of the most fundamental biological processes, have been shown to be interdependent in embryonic stem cells, and during the development of blood cells and neurons. I aim to understand whether cell cycle alterations are associated with cellular differentiation in other developmental contexts as well, and how both processes jointly shape the cell’s epigenome and higher-order chromatin structures. To this end, I will establish a murine embryonic stem cell line stably expressing fluorescent cell cycle reporters, which will allow me to jointly quantify cell cycle progression and perform single-cell RNA sequencing and single-cell ATAC-sequencing during cell cycling and cellular differentiation. I will also use a low input chromosome conformation capture technique to study the regulatory genome interactions around cell cycle genes and master transcription factors in the same cells, which will allow me to characterise the regulatory elements governing the expression of these genes. These studies will help us better understand the interdependence between the cell cycle and cellular differentiation, which might have important implications for stem cell research, regenerative medicine, and for our understanding of the fundamental processes governing organismal development.


PhD Studentship (Basic)

Structure-Function Studies of Lipid Transporters Lipid transporters are a class of membrane proteins that perform critical functions in many organisms. These proteins transport lipid molecules from one leaflet of a lipid bilayer to the other leaflet. In bacteria, lipid transporters can confer resistance to antibiotics, whereas in humans, dysregulation of lipid transporters has been implicated in a number of neurological disorders, highlighting the important role these proteins can play in health and disease. However, the mechanism of action of many of these transporters is poorly understood, in part due to the difficulties involved in the structural studies of membrane proteins. Therefore, this project aims to look at two lipid transporters that are implicated in health and disease: the bacterial Multiple Peptide Resistance Factor (MprF) and the human transporter TMEM16K. The focus in both cases will be on structural elucidation using a combination of cryo-EM and crystallography. The information obtained from these structural studies will be used in combination with biophysical assays to advance our fundamental understanding about the function of these proteins, whilst providing the groundwork that could be used to develop future novel therapeutics to target these proteins.


PhD Studentship (Basic)

(Neuro)Immune Regulation of Endocrine Organ Function Building on the identification of macrophages which modulate sympathetic nerve signalling in adipose tissue (AT), our lab has recently also discovered tissue-resident macrophages within other endocrine organs thought to be sympathetically-innervated – including the adrenal glands (AGs). A role has not yet been described for these AG-resident macrophages, which localise to regions of both the adrenal cortex and medulla. Interestingly, a ring of macrophages unique to the female mouse inner-cortex suggests possible sexually-dimorphic immuno-endocrine interactions. Using bulk RNA-sequencing, whole-mount imaging and in vitro assays, I aim to phenotypically and functionally characterise male and female adrenal macrophages. I will compare the transcriptomes of male and female macrophages sorted from either the cortex or medulla, and use differentially-expressed genes between the sexes to find novel markers of female inner-cortical macrophages – which may also allude to their function. In addition I will also confirm the presence or absence of AG sympathetic innervation, as a role for these macrophages in the modulation of adrenal sympathetic nerve signalling similar to AT cannot yet be excluded. This will provide new insights into sexual dimorphism of immuno-adrenal homeostasis, which may underlie the incompletely understood pathologies of sex-biased adrenopathies such as polycystic ovary syndrome or Addison’s disease.


PhD Studentship (Basic)

Efficient embeddings of genealogical processes A central objective of population genetics is finding objects that describe the relatedness structure of a group. For closely related individuals these can be family genealogies. On a larger timescale they can be evolutionary phylogenies. In general, such tree-like structures can be obtained by calculating the smallest number of generations needed to go back in time to find a common ancestor between a pair of individuals, through a mathematical framework known as coalescent theory. However, due to random recombination events that occur in the genome between generations, the most recent common ancestor for a pair of individuals varies along the genome, resulting in different tree structures for the same group on adjacent sites in the genome. Due to the highly structured nature of coalescent trees it has proven very difficult to obtain a precise probabilistic description of these random tree sequences. Our project aims to develop statistical methods that can encode coalescent trees and recombination events into a more amenable mathematical form, thus giving a close approximation to the underlying stochastic process. Efficient representations of the coalescent will facilitate all analyses of population structure and have the potential to increase the accuracy of genetic imputations and disease association models.


PhD Studentship (Basic)

Rational engineering of antibody binding kinetics Therapeutic antibodies – drugs made from defence molecules produced by the body – are becoming increasingly important in treatment of diseases ranging from cancer to hepatitis. These drugs work by binding to the molecules they target called antigens. In order to be effective, an antibody must bind its antigen tightly and this depends in part on how fast it binds the antigen. For example, it has been shown in a set of antibodies against malaria that the ability of antibodies to neutralise the pathogen is highly dependent on the binding rate. Our research will use a multidisciplinary approach to engineer antibodies with the aim of achieving faster binding. Using both computational tools and experiments that characterise the physical properties of antibodies, we aim to identify factors that contribute to the rate of binding. Next, we would like to use this knowledge to generate software to predict changes that can be introduced to an antibody to increase its binding rate. As a way to validate our conclusions, we plan to improve antibodies against malaria. These studies will provide us with insight into the factors that make good therapeutic antibodies and also provide a tool for use by the wider scientific community.


PhD Studentship (Basic)

Exploring the genetic determinants of the portability of GWAS associations and polygenic risk score performance across populations Over the last 10-15 years, large datasets containing genetic, physical and medical information for thousands of people (such as the UK Biobank) have allowed researchers to detect many genetic mutations that increase disease risk or explain variation in other physical traits.

An important limitation of most of the studies conducted so far is that they mainly use data from people of European ancestry. This is significant, because there is increasing evidence that genetic differences between populations limit the validity and applicability of findings from European samples in other populations.

We propose to address one aspect of this problem by exploring genetic variation that affects the accuracy of a set of relevant mutations in predicting a physical trait or disease within a single population. This is an important first step in understanding the causes of the poor portability of findings across populations.

We expect that our work will identify relevant new genetic mutations, or interactions between them, which impact particular traits and diseases (as well as corroborate previous findings) and that this information will then improve our ability to understand the causes of, and predict, disease risk in understudied populations.


PhD Studentship (Basic)

The role of ADAM10 in modulating cell-cell interactions Efficient clearance of dying and dead cells, a process called efferocytosis, is crucial for tissue homeostasis and a healthy, well-regulated organism. Dying/dead cells are cleared by cells called phagocytes, principally macrophages. We recently identified the leukocyte-expressed glycoprotein CD43 as a molecule that acts as a ‘don’t-eat-me’ signal for macrophages, and showed it was rapidly and completely cleaved from the surface of dying T cells. We also demonstrated that ADAM10 (A Desintegrin And Metalloproteinase Domain-containing protein 10) is the enzyme responsible for CD43 cleavage from dying cells, therefore removing the don’t-eat-me signal, triggering phagocytic uptake. CD43 cleavage by ADAM10 is a novel observation that may be more generally applicable to other ‘mucin-like’ glycoproteins with similar don’t-eat-me properties. To explore this, we will take two approaches: i) probe leukocyte surface molecules with similar biophysical properties to CD43 for ADAM10 cleavage; ii) take an unbiased broader approach using mass spectrometry (MS) to reveal other proteins cleaved by ADAM10 during cell death. Once identified, we will analyse their function in regulating efferocytosis of dying leukocytes. This will shed light on how these molecules modulate clearance of dying and dead cells to ensure healthy tissue homeostasis, and will yield insights into immune cell-cell interactions.


PhD Studentship (Basic)

Understanding the molecular basis for the ubiquitin-dependent activation of the TAK1/TAB complex Cells respond and adapt to various stimuli through a variety of detectors, which receive the signal. To ensure that a signal is transmitted, key decision-making hubs that interpret the incoming signal and define the output are required.

I am interested in one signalling hub the TAK1-TAB complex, which is vital for cells to respond to an infection or other external signals and decides cell death or survival. Correct interpretation of the signal by the TAK1-TAB complex is vital: human diseases ranging from inflammatory diseases, certain cancers and neurological disorders arise from defects within these hubs.

I will use a toolkit of biochemical and biophysical techniques to understand how the TAK1-TAB complex is regulated and obtain molecular snapshots that will provide the three-dimensional structure of the complex before and after signal activation.

Understanding the structure of this key signalling hub will, for the first time, provide a glimpse into its regulation. Furthermore, the structure will provide an explanation of how certain genetic mutations in the assembly and architecture of the TAK1-TAB complex leads to certain diseases, notably Crohn's disease and amyotrophic lateral sclerosis.


PhD Studentship (Basic)

Understanding the role of circadian and hypoxic signalling pathways in HIV infection Rhythmicity is fundamental for the existence of life and 24 h circadian rhythms regulate every cell of the body. Synchronizing biological processes to certain times of the day optimizes the host response to invading pathogens and asynchrony can increase the severity of infection. Another basis of human life is oxygen and following infection, viruses can experience environments with variable oxygen tension that can influence their replication and persistence. Previous studies from our laboratory have shown that the circadian system and oxygen signalling pathways can independently influence viral infection. My project will study the interplay between these pathways to understand their role in human immunodeficiency virus (HIV) infection. I will use laboratory models of active or latent HIV replication along with genetic and pharmacological agents that modulate hypoxia and circadian pathways to study their role in the viral life cycle. Our goal is to uncover new therapeutic approaches.


PhD Studentship (Basic)

Structural and biochemical studies on mRNA 3’-end processing and transcription termination in fission yeast  In the cell, genetic information from the DNA is copied into RNA molecules in the nucleus of the cell before being exported to the cytoplasm, where the information they carry is used to make proteins. In eukaryotes, these messenger RNA molecules (mRNA) are modified before they are exported out of the nucleus. An enzyme called the Cleavage and Polyadenylation Factor (CPF) cleaves the mRNA at the end and adds a string of adenosines to create a polyA tail. This polyA tail is important for the stability of the mRNA, and the cleavage process ensures that the enzyme that makes the mRNA, RNA Polymerase II, stops at the end of the gene and goes back to the beginning to repeat the process of making mRNA. The aim of my project is to study how the CPF modifies mRNA and interacts with RNA Polymerase II to ensure functional mRNA are properly produced. I will use techniques such as electron microscopy and x-ray crystallography, as well as biochemical techniques, to look at the structure of CPF to understand how it works. Through this work, we expect to gain a more detailed understanding of this fundamental biological process.

mRNA Cleavage and Polyadenylation Factors


PhD Studentship (Basic)

Characterising HIV-1 infections in East African epidemics: an interdisciplinary approach to analysing network dynamics and transmission clusters using viral phylodynamics and agent-based modelling. With a yearly 1.7 million new people infected with HIV, the HIV/AIDS epidemic remains a major global health threat. Characterising HIV transmissions using phylogenetic tools like phylogeography and phylodynamics aids our understanding of HIV infections, both evolutionarily and epidemiologically, shaping epidemic control measures through increased knowledge on transmission events and thus, their prevention.
Sub-Saharan Africa (SSA) constitutes 59% of all new HIV infections, and phylogenetic studies highlighting HIV transmission dynamics have historically been less common in this region due to limited sequence availability. However, the recent sequencing upscale in SSA will inform the poorly understood structure of transmission networks and HIV epidemic dynamics in the region.
I aim to use viral phylogenetics, epidemiology and mathematical modelling to investigate the evolutionary dynamics of HIV-1 transmission networks in East African epidemics: firstly, using HIV-1 sequences from a trial in rural Uganda and Kenya, I will characterise HIV-1 infections and analyse HIV-1 transmission networks and cluster dynamics; secondly, I will undertake a comparative analysis of HIV-1 phylodynamics amongst different East African study populations; finally, I will model local transmission dynamics and intervention effects in these populations.
Altogether this will ultimately inform the design and evaluation of HIV prevention interventions.


PhD Studentship (Basic)

Defining the transcriptome of the first functional haematopoietic stem cells in the mouse embryo. Despite clinical demand for hematopoietic stem cell (HSC) transplantations for patients with blood cancers or hematologic diseases, little progress has been achieved in in vitro generation or expansion of HSCs. Cellular reprogramming by overexpression of critical transcription factors has been impeded by our incomplete understanding of how HSCs develop in the embryo. The very first HSCs are generated from endothelial cells in the aorta-gonad-mesonephros region in the embryo, with only a few functional stem cells hidden among other blood progenitors. Separating true HSCs from other blood progenitor cells in the embryo has proven challenging because they have similar surface protein expression. Moreover, testing function and then sequencing cells is impossible and HSCs differentiate and alter their transcriptome in expansion. Therefore, new methods of identifying functional HSCs are needed to advance our understanding of these clinically relevant cells. I aim to develop a model that predicts HSC function based on the precise levels of gene expression. I will then test the predictions of the model and determine if narrowing the ranges of gene expression can distinguish HSCs from progenitor cells. Accurate predictions will inform future studies into in vitro generation and expansion as precise required gene expression levels will be uncovered.

Grants awarded from 1 October 2005 to 30 June 2021


PhD Studentship (Basic)

 Predicting the epidemic potential of RNA viruses using viral sequence information and machine learning Among all known emerging pathogens, RNA viruses are overrepresented and pose a particular high risk of emergence. New RNA virus species have been detected steadily since the 1950s and their discovery is projected to continue in the future. Studying the epidemic potential of new RNA viruses is therefore important, however obtaining relevant epidemiological data requires extensive field and/or laboratory studies. These studies could be better directed if a priori predictions about the epidemiology of RNA viruses can be made.

Here, I propose to investigate whether predictions about the epidemiology of RNA viruses can be made using machine learning and genome sequences. Using an existing database containing epidemiological relevant data on all human infective-RNA viruses, I will use multivariate statistical analyses to establish which epidemiological characteristics correlate with genomic biases calculated from genome sequences. Using this information, I will devise machine learning models to make predictions about the epidemic potential of RNA viruses. Lastly, I intend to investigate how genomic biases change over time during an epidemic and link these to changes seen in the epidemiology of RNA viruses. If successful, my research could inform targeted surveillance to combat emerging RNA viruses.


PhD Studentship (Basic)

Telomeric chromatin and VSG allelic exclusion in African trypanosomes Trypanosomes are single-celled parasites that causes lethal diseases in humans and livestock. The parasite is covered in variable surface glycoprotein (VSG) that enables host immune system evasion. VSG is often swapped by ‘antigen switching’, which is central for the parasite’s virulence.
My group found that the active VSG suppresses expression of other VSGs. As VSG genes are located near the ends of chromosomes, we hypothesise that the characteristic and highly repetitive sequences at chromosome ends are important for suppression. To facilitate studying this, I will manipulate the dosage of these sequences using new genome editing tools (CRISPR/Cas9).
Also, I will explore the function of the proteins that package these regions. Again, I will use CRISPR/Cas9 to create parasites with a single copy of each gene encoding these packaging proteins, allowing me to manipulate those genes as well. These proteins impact DNA repair, DNA replication and gene regulation.
This project will provide new insight into how chromosome ‘caps’ function, how VSG genes behave at these locations and may also reveal potential drug targets.


PhD Studentship (Basic)

“Using the force”: An investigation into the perception of stiffness in CTLs and its importance in activation and killing in cancer. Cytotoxic T lymphocytes (CTLs) are important agents of immunity responsible for clearance of infected or malignant cells. The understanding of their activation is incomplete. Recent advances have unveiled their ability to sense the stiffness of the opposing surface, with stiffer surfaces resulting in larger forces being transmitted to the CTL, promoting activation, leading to CTL-mediated killing of the target cell. Furthermore, decreased stiffness of malignant cells has been observed and posited as an avenue for their evasion of the immune system.

I will create cell lines in which intracellular stresses can be visualized with state-of-the-art microscopy via force probes. I will activate CTLs to varying degrees and measure the effect on the force probes. I will knock out cytoskeleton-associated genes in order to screen for genes that are involved in CTL force perception. Interactions between T cells and target cells of manipulated stiffness will also be investigated as a means of understanding the role of target cell stiffness in malignant immune evasion. A final screen will be performed to identify gene mutations associated with this immune evasion in target cells.

This work will broaden our understanding of T cell function and provide us with useful avenues for cancer immunotherapy.


PhD Studentship (Basic)

Dissection of the function of the Plasmodium falciparum protein families EBL and RH during erythrocyte invasion. Plasmodium falciparum causes  > 90% of malaria mortality, killing over 400,000 people annually. To multiply, P. falciparum parasites must invade human erythrocytes. Invasion begins with attachment of the parasite to the erythrocyte, followed by reorientation to position the parasite to invade. These early steps depend on two families of membrane proteins: Erythrocyte Binding Like proteins (EBLs) and Reticulocyte Binding Protein Homologues (RBLs). There are four members of each family in the P. falciparum genome that can individually be deleted without blocking invasion. EBLs and RBLs are therefore believed to be functionally interchangeable, but this has never been systematically investigated and all Plasmodium parasites maintain both families suggesting considerable selection pressure against loss of one family. To determine if the families have distinct roles, this project will characterise invasion of single and double protein knock-outs using advanced video microscopy tools, and visualise the localisation of proteins simultaneously using fluorescence microscopy. New antimalarial therapies are needed as P. falciparum has developed resistance to every antimalarial drug available and the only licensed malaria vaccine is


PhD Studentship (Basic)

Development of artificial oligonucleotide catalysts (XNAzymes) for specific targeting of disease-associated RNA. Nucleic acids (DNA  &  RNA) are commonly known for their ability to store genetic information. However, when single-stranded, nucleic acids can also fold into sophisticated 3D structures including catalysts capable of speeding up chemical transformations. RNA-cutting catalysts can be programmed to target specific RNA sequences in order to turn off harmful mutant genes or destroy viruses. However, catalysts composed of natural DNA and RNA, among other limitations, are rapidly degraded in the blood, hampering their clinical applications. Recently, it has become possible to evolve such catalysts in the test tube using robust, artificial alternatives to DNA known as "xeno nucleic acids" (XNAs). Our aim, therefore, is to explore the use of biologically stable XNA chemistries to evolve novel enzymes ("XNAzymes") capable of degrading disease-associated RNA (aberrant mRNA, microRNA and viral RNA). We will establish systems for engineering XNAzymes using chemistries resistant to degradation and which (unlike protein enzymes) do not trigger unwanted immune responses. Currently, there are few clinically-suitable molecular tools for manipulation of cellular RNAs and they often lack precision, XNAzymes are thus promising alternatives.


PhD Studentship (Basic)

The contribution of T cells to PI3Kδ and Bcl6-dependent B cell lymphomagenesis Non-Hodgkin Lymphoma (NHL) accounts for 4% (14,100) of new cancer cases every year (UK) with a survival rate of 55% (2013-2017). Diffuse Large B Cell Lymphoma (DLBCL) is a common subtype of NHL which arises from high affinity B cells. The lipid signalling enzyme phosphoinositide-3 kinase delta (PI3Kdelta) is critical for the development of these B cells and is often mutated (hyperactive) in DLBCL.
We identified that hyperactive PI3Kdelta cooperates with the oncogene B-cell lymphoma 6 (Bcl6) to drive lymphomagenesis and that this was accelerated in the absence of a functioning immune system. Furthermore, restricting PI3Kdelta hyperactivity to CD4+ T cells was sufficient to drive lymphoma progression. I aim to investigate the cooperativity between PI3Kdelta and Bcl6 in B cell lymphomagenesis by combining flow cytometry and transcriptomic approaches to identify and characterise B and CD4+ T cell populations in our lymphoma models. Transfer of selected populations into immunocompromised mice, followed by tumour analysis by histology, will allow me to identify the cellular origin of the malignant B cells and the CD4+ T cell populations responsible for driving lymphomagenesis upon PI3Kdelta dysregulation. This study will illuminate the cooperation between PI3Kdelta and Bcl6 in B cell lymphoma with important future therapeutic implications.


PhD Studentship (Basic)

Investigating signalling pathways in intraepithelial lymphocytes (IEL) in the small intestine Intraepithelial lymphocytes (IEL) are T cells that reside interspersed between intestinal epithelial cells in the gut. They provide protection to the gut by coordinating immune responses towards pathogens and producing factors which maintain the gut epithelial barrier. However, dysregulated IEL function has been associated with increased gut inflammation promoting inflammatory diseases of the gut including coeliac disease and inflammatory bowel disease. The signals which activate IEL and the intracellular machinery used to communicate these signals to have an effect within the cell are relatively unknown. I propose to investigate the signalling pathways in IEL using techniques such as flow cytometry, mass spectrometry and RNA sequencing. I will stimulate IEL through cell surface receptors to initiate the downstream signalling events. I will compare the IEL response to stimulation with conventional T cell responses to determine similarities and differences in IEL signalling. I will look at proteins which have become phosphorylated upon stimulation and, using a RiboTag mouse, detect which proteins are translated as a result of the activation. I will also investigate IEL signalling in vivo. These studies will increase understanding of how IEL become activated and offer opportunities to manipulate these pathways in the treatment of disease.