PhD Studentship (Basic)

The role of TIGIT in immune regulation of autoimmune diseases The adaptive immune system provides the host with a vast receptor repertoire of immune cells that facilitate protection from a broad range of pathogens1. One consequence of this incredible diversity is the development of immune cells specific for self-tissues, which could lead to the development of autoimmune diseases2. To counteract this auto-reactivity, the immune system uses a number of mechanisms to reinforce the state of tolerance to an individual’s own antigens3. This includes a dominant role for co-inhibitory receptors, such as T cell Ig and ITIM domain (TIGIT), which acts as a brake that determines the balance between activating and inhibitory signals4. While much has been learned recently about which co-inhibitory receptors are expressed in various immunological settings, little is known about how they actually function. We aim to use specific monoclonal antibodies that either block or boost the function of TIGIT and investigate the impact on T cell responses. We will use genetically manipulated mouse models that will provide insight into the role of TIGIT in immune regulation. Data obtained from this study can pave the way for future validation in humans, which will provide novel targets for the treatment of chronic infectious diseases, cancer, allergic and autoimmune diseases.


PhD Studentship (Basic)

Characterising the Role of IN Binding Partners in HTLV Infection and Integration Human T-cell lymphotropic virus type 1 (HTLV-1) is a virus that can cause a range of debilitating and often fatal diseases including neurological disorders and an aggressive form cancer.  There exists no successful therapy to treat these diseases, therefore research into mechanisms of the viral lifecycle is crucial.  For the virus to replicate efficiently it must integrate a DNA copy of its RNA genome into host DNA using the viral enzyme integrase.  Integration site selection is not random but is influenced by interaction with host proteins. The correlation between the site of integration, production of virus, and disease occurrence indicates the integration site as a point of interest. We have identified a number of host proteins that could (directly or indirectly) be involved in targeting the HTLV-1 pre-integration complex to the site of integration. Using a combination of lentiviral shRNA mediated knock-down and expression of chimeric proteins we will investigate whether proteins that co-purify with HTLV-1 IN affect infectivity and integration.  Understanding these mechanisms is a step towards identifying potential drug targets to prevent HTLV-1 infection.

Grants awarded from 1 October 2005 to 30 June 2021

Creative Commons Attribution 4.0 International (CC BY 4.0)


PhD Studentship (Basic)

The role of innate immunity in respiratory viral infection in the elderly With age, there is a decline in immune function, which renders the elderly particularly susceptible to lung infections, such as respiratory syncytial virus (RSV). During ageing there are also significant changes to cellular metabolism. Recent discoveries have shown that the function of cells of the immune system is profoundly influenced by their metabolism. We hypothesise that differences in the immune response to lung infection in the elderly are the results of age-related metabolic changes. In this project we will specifically study age-related changes in alveolar macrophages (AM), immune cells that are an important first line of defence against lung infection.

We will compare AM responses to infection in young and elderly mice. Next, we will evaluate differences in metabolic pathways in these cells. If metabolic differences are detected, we will aim to restore macrophage responses to infection in the elderly by manipulating their metabolism. In addition, we will ask whether transfer of AM from young to elderly mice will protect against infection.

The global population is ageing and lung infection is a growing health burden worldwide. In the long term this project may identify new targets for treatment and/or prevention of severe lung infections in the elderly.


PhD Studentship (Basic)

Investigating the interplay between the Plasmodium oocyst and mosquito vector towards identification of new targets for malaria transmission blocking interventions Malaria is a significant global health burden, causing over 200 million new infections and 400,000 deaths every year. It is caused by Plasmodium parasites that are transmitted between people by Anopheles mosquitoes. Conventional antimalarial therapies aim to clear parasites in already infected humans, but elimination of the disease can only be achieved by blocking parasite transmission through the mosquito vector. Rising insecticide resistance among mosquitoes and increasing drug resistance among Plasmodium parasites have led to a stall in progress towards malaria control and elimination, respectively. It is therefore of vital importance to identify new therapeutic targets and to develop novel intervention strategies to achieve further progress. This project will focus on the interplay between the mosquito and the Plasmodium oocyst, the longest stage of parasite development that results in an explosion in parasite numbers. A high-throughput screen will aim to identify transporters and other key molecules on the oocyst surface required for normal development. Follow-up experiments will genetically and functionally characterise promising candidate genes and assess their potential as transmission blocking targets. This work will therefore help us to further understand the biology of malaria transmission and inform future interventions towards disease elimination.


PhD Studentship (Basic)

Structural and functional analysis of a minor pilin playing a key role in the type IV pilus biology of the opportunistic pathogen Streptococcus sanguinis Long and flexible hair-like filaments, called type IV pili (Tfp), decorate the surface of many bacteria. Tfp confer an impressive variety of properties upon bacteria, ranging from adhesion and motility to electric conductance. Importantly, Tfp play a key role in the development of diseases, caused by many prominent bacterial pathogens. My research focuses on the opportunistic Gram-positive pathogen Streptococcus sanguinis which causes infective endocarditis. S. sanguinis represents a convenient model for studying poorly defined aspects of Tfp biology due to the simplicity of its Tfp machinery. Tfp are composed of small protein subunits, called major and minor (less abundant) pilins which share sequence and structural features. S. sanguinis has two major pilins (PilE1 and PilE2) and three minor pilins (PilA, PilB and PilC). The minor pilin PilA, essential for S. sanguinis piliation, has an unusual sequence and an uncharacteristic structure. Using a combination of molecular genetics, protein biochemistry and structural biology techniques, I aim to characterise how PilA is assembled into pili and what role it plays in Tfp biology.  A better understanding of Tfp assembly mechanisms and their disease-associated functions can help design anti-bacterial drugs that suppress the ability of bacteria to cause disease.


PhD Studentship (Basic)

Investigating the acute and chronic effects of E-cigarettes on human lungs, examining functional and mechanistic outcomes. E-cigarettes vaporise nicotine-containing fluid for inhalation and have become an increasingly popular alternative to tobacco. The effects of e-cigarettes on the human lung are incompletely characterised. Preliminary evidence indicates that healthy vapers and smokers have similarly protease rich lung environments. This supports evidence from our lab, demonstrating that e-cigarette exposed alveolar macrophages(AM) increase protease output.
I aim to understand the effects of e-cigarettes on the cells of the human lung. Lung resection tissue from never smokers/vapers/smokers/ex-smokers will be used to source AM and type-II alveolar cells, as well as precision cut lung slices (PCLS). Effects will be assessed using techniques to assess viability, proinflammatory mediator production/ROS/protease output, wound repair, phagocytosis and efferocytosis. Simple monocultures/co-cultures will provide initial evidence of e-cigarette effects, whilst PCLS and PCLS/AM cultures will allow effects to be examined in the context of the complex cellular architecture of the lung.
In addition, I aim to identify the mechanism(s) of action through which these effects are mediated. Candidate mechanisms will first be tested in co-culture models before validation using our human PCLS model.
These studies will help characterise how and why e-cigarettes affect the lungs. This may help inform regulatory decisions and mitigate risks associated with e-cigarette use.


PhD Studentship (Basic)

Integrated biological and mathematical studies of TTP pathway dynamics Inflammation is a protective response of the body against injury and invading pathogens. However, dysregulation of the inflammatory response, especially if sustained, is associated with devastating diseases, including chronic inflammatory ones, such as rheumatoid arthritis but also less obvious conditions such as neuro-degenerative diseases and cancer, causing an enormous socio-economic burden.

Traditionally, therapeutic approaches focused on inhibiting cellular signal pathways producing pro-inflammatory mediators, with mixed success. For example MAPK p38 inhibitors were viewed as strong candidate anti-inflammatory drugs, but failed expensively in clinical trials. We pursue a complementary strategy, utilizing the Tristetraprolin (TTP) pathway, which comprises a natural cellular mechanism for switching off inflammatory gene expression. Compounds targeting this pathway have been developed and show potential as anti-inflammatory drugs.

We will use a combined mathematical and biological approach to study the dynamic regulation of the TTP pathway in white blood cells during inflammatory responses. We will build a mathematical model of the pathway, based on detailed temporal examination of the biology, and will validate it with cutting edge imaging and analysis techniques. This will allow us to identify new angles in research, drug targets and optimal treatment strategies for chronic inflammatory diseases, improving the lives of many affected patients.


PhD Studentship (Basic)

Immunomodulatory role of platelets ITAM receptors in systemic inflammation and sepsis associated with cardiovascular diseases Sepsis is a dysregulated response to infection that has a high mortality. It is associated with low platelet count, a dysfunctional inflammatory response and multiple organ failure. Patients with cardiovascular disease have a higher risk of developing sepsis with worse outcomes, particularly in the elderly. In this project we will investigate whether cardiovascular diseases and ageing induce a pro-inflammatory and prothrombotic state during sepsis that is mediated by upregulation of platelet activity. We will determine whether this is ameliorated by inhibition of platelet immune receptors GPVI, CLEC-2 and FcgammaRIIa, which modulate inflammation and pathogenic thrombosis but have a minimal role in haemostasis. We will investigate these mechanisms in platelets and immune cells from patients with cardiovascular disease and validate these observations in clinically relevant experimental sepsis models associated with chronic cardiovascular diseases (e.g. atherosclerosis and heart failure). We will inhibit the platelet receptors GPVI, CLEC-2 and FcgammaRIIa using a range of different approaches and determine effects on sepsis progression and outcome. This work will help understanding the influence of cardiovascular disease and age on sepsis and provides a novel approach for targeting platelet-immune cell interactions in sepsis using new drugs that target platelet immune receptors.


PhD Studentship (Basic)

Exploring the function and regulation of surface molecules in the reaction to predation by Gram-negative bacteria during predation by the predatory bacterium Bdellovibrio bacteriovorus in host-appropriate settings.  The number of infections caused by bacteria that are resistant to antibiotic treatment is increasing, potentially threating the treatment of infectious disease and other illnesses. New treatment approaches are therefore desperately needed, one of which involves the application of the predatory bacteria Bdellovibrio bacteriovorus. B. bacteriovorus is a bacterium that is able to prey upon a wide range of these antibiotic resistant organisms, potentially providing an alternative treatment for infections.  This work builds on previous work with other clinically relevant bacteria to further characterise the mechanisms behind the prey recognition and invasion of bacteria by B. bacteriovorus predators and how this interaction is affected by components of the host immune system (1, 2) and prey surface factors (3). By looking at the factors that may prevent or decrease predation and experimentally removing them, we can characterise the mechanisms behind this interaction further and aid the potential application of B. bacteriovorus as a novel antimicrobial therapy in the future.


PhD Studentship (Basic)

Understanding the dynamics of agr expression in vivo and the efficacy of agr pathway inhibitors Staphylococcus aureus is a common cause of hospital acquired infections. Infections caused by S. aureus are difficult to treat due to the emergence of drug resistant strains and growth in biofilms which limits the efficacy of antibiotic drugs. Due to emergence of antibiotic resistant bacteria there is a need for drugs which do not succumb to conventional methods of antibiotic resistance. One method is through attenuation of the virulence of the bacteria. This will reduce the infection with less pressure for resistance to emerge. One promising anti-virulence target is cell-cell communication known as quorum sensing. This PhD will involve investigation of the agr quorum sensing system in S. aureuswhich is known to control virulence. This is temporally expressed during infection and a model using bacteria with NanoLuc/GLuc luminescent reporters linked to the agr system will be developed and used to determine when and where this system is activated in vivo. This model can then be used to screen for inhibitors of the agr system and their efficacy determined in in vivo models.


PhD Studentship (Basic)

Understanding the mechanistic basis of PARG inhibitor sensitivity in the context of high-grade serous ovarian cancer. DNA damage repair (DDR) is frequently activated during normal cellular contexts and is thus instrumental during tumourigenesis when functioning aberrantly. For example, DDR defects are widespread amongst ovarian cancers (1) and thus genomic instability is a defining characteristic of this cancer type (2). Hence, DDR research is extensive, providing insights into mechanisms, therapies and biomarkers. One such research avenue involves the DNA repair enzyme PARG (3), whose inhibitor (PARGi) has shown potential therapeutic usages (4). To widen the opportunities of PARGi as a therapeutic agent, one must first dissect the mechanism of differing PARGi sensitivity. Therefore, a screen identifying genes which, when defective, sensitise cells to PARGi was performed (4), and identified TIMELESS. We aim to decipher the functions of TIMELESS in DDR and PARG dynamics with a focus on TIMELESS’s structure-function relationship. The approach is three-fold: firstly, generation of a series of TIMELESS mutants, with targeted residues spanning the entire gene sequence, followed by characterising the mutants using proliferation and gammaH2AX-production as quantitative outputs. Secondly, hypothesis-driven cell biology-based experiments to focus on the DDR roles of TIMELESS. Finally, an unbiased approach employing mass spectrometry will characterise replication fork modifications upon TIMELESS mutations.


PhD Studentship (Basic)

Control of cortex-wide neural activity maturation by local and long-range GABA signalling  Animal behavior is generated by the collective activity of many neurons, and thus constitutes an emergent property of the brain, which might not be apparent at the individual level of anatomical regions and single cells. Moreover, these collective interactions and patterns of activity across neuronal populations are not fixed but dynamically shaped by many different processes, such as learning, over multiple timescales. These features suggest that the behavior of such complex dynamical system cannot be fully understood by independently analyzing each of its constituents. For this reason, I aim to examine the role and dynamics of two distinct neuronal populations across early brain development, the most critical learning period, by following a whole-brain imaging approach. This will allow me to investigate how the cross-talk between distant brain regions and cell populations influences the formation of a mature brain. Specifically, by simultaneously assessing the spatial and temporal dynamics of excitatory and inhibitory cell activity patterns across the cortex, I would like to study the interplay between both types of neuronal populations during functional maturation of brain circuits, and after senses come online. This is critical to understand normal brain development and subsequently, potential dysfunctions associated with neurodevelopmental disorders.


PhD Studentship (Basic)

Cerebro-cerebellar interactions during learning of cognitive tasks  A substantial part of animal, including human, behaviour is goal directed. Learning how to achieve a defined goal requires the interplay between higher brain centres involved in planning and decision making and subcortical structures that coordinate the desired movements. However, there is growing evidence suggesting that subcortical structures such as the cerebellum play a much wider role by also being directly involved in higher cognitive functions. Although much information exists about the cerebellum and neocortex individually, little is known about how the connections between these areas are involved in complex behaviours. In this project I propose to study how the learning mechanisms in these brain structures support each other to give rise to complex behaviours. First, I will develop a computational model of cerebellar-neocortical interactions based on recent developments from deep learning. Next I will test the predictions of this model using electrophysiological recordings during goal-directed behaviours which require higher cognitive functions. This research will provide a better understanding of the neural mechanisms through which the cerebellum controls high-level, non-motor functions. Ultimately this will be of clinical interest for cognitive pathologies like autism and schizophrenia and will have implications for both cognitive sciences and computer science.


PhD Studentship (Basic)

Understanding behavioral clustering in epidemics An increasingly interconnected world provides a greater opportunity for the emergence of epidemics. In the last decade alone, the World Health Organization (WHO) has announced five Public Health Emergencies of International Concern. Additionally, there has recently been a resurgence in vaccine-preventable diseases. The increasing risk of epidemics necessitates a greater ability to understand how they spread.

Current outbreak models have struggled to reproduce outbreak data across a number of diseases, from Ebola Virus disease in West Africa, to a measles outbreak in Brazil. One reason for this is that current models do not consider how the behavior of individuals in contact with each other is clustered. For example, people who are hesitant to vaccination are more likely to be in contact with each other, and less likely to be in contact with vaccine adherents. This clustering increases the susceptibility of the unvaccinated population to disease.

This PhD will use explore how clustering of individuals affects the spread of outbreaks. I will develop a mathematical model which simulates disease outbreaks through a network of individuals with clustering based on behavior. The work could be applied in a number of disease contexts from Ebola in West Africa to Measles in Latam.


PhD Studentship (Basic)

A global model for the evolutionary dynamics of seasonal influenza  Influenza epidemics infect between 10% and 20% of the global population each year. Infection typically infers a lifetime immunity on an individual, but due to the gradual accumulation of mutations new strains can emerge that evade the host’s immunity and allow repeat infection. This ‘antigenic drift’ of influenza has been well characterised, but the origins of the observations are not well understood. A limited number of models have attempted to explain the observed effects. However, none of the models has included a realistic spatial component or realistic population sizes.

The aim of this project will be to develop a computational model of influenza evolution that incorporates realistic population sizes and spatial spread at a global scale. The model will be based on individuals and allow spatially dependent transmission. The model will include a probability of mutation of a strain upon infection of an individual. By tracking each individual’s immune status based on previous infections evolution will naturally occur in the model to evade population immunity.

This model will lead to a greater understanding on the complex relationship between human ecology and the evolutionary dynamics of influenza. It is possible it may also inform future surveillance and vaccine protocol.


PhD Studentship (Basic)

Addressing the double burden of HIV and cervical cancer: benefits and costs of integrating care in Kenya In Kenya, cervical cancer is the leading cause of cancer deaths among women. The Ministry of Health wants to scale-up preventative screening and treatment to reduce this burden but has limited funds. It has been suggested that providing services for two diseases in one clinic is more cost-effective than providing them in separate clinics, because services share the delivery platform (clinic) and costs of inputs such as diagnostic equipment.  However, joint service provision may also be less cost-effective, because the efficiency gains from sharing delivery platforms only materialize if there is spare capacity to deliver both services; otherwise, one intervention with comparably lower benefits may crowd out another with higher benefits. This means that it is unclear whether the ministry should invest in integrated or separate services for cervical cancer.

Our project will test the hypothesis that integrating services for cervical cancer with services for Human Immunodeficiency Virus (HIV) is more cost-effective than providing the screening separately. We will collect data on the cost of providing care and on the number of patients seen, then compare the cost-effectiveness of integrated services to separate services.

Our findings will be translated into recommendations to the Kenyan Ministry of Health.


PhD Studentship (Basic)

A multifaceted exploration of the dynamics of acute respiratory infections in Denmark using deep learning approaches Acute respiratory infections (ARIs) including bronchitis and pneumonia are common illnesses in children in high-income countries [1]. Childhood adversaries such as death, illness or unemployment in the family, alongside environmental factors such as pollution are thought to increase the chances of someone developing an ARI [2]. Previous studies measured the impact of risk factors for ARIs but focused on a single associated risk and did not factor comorbidities including stroke, cancer, diabetes or mental illness. To our knowledge no study has looked at a multifaceted view of the causes and associations of ARIs. I aim to look at a variety of sociodemographic, environmental and individual specific factors and evaluate the landscape of ARI disease risk. I will use a unique dataset collated from Danish Registers for people born after 1980 [3]. This dataset contains unparalleled information on longitudinal health outcomes and childhood adversaries and, unlike single timepoint surveys, allows the study of risk trajectories for the entire susceptible population. I will study the spatial and temporal influence of risk factors on ARI incidence and develop a modelling framework for predicting disease progression and could be used as an early warning system to identify high risk populations and inform intervention strategies.


PhD Studentship (Basic)

B cell receptor repertoire alterations in immunity and autoimmunity Rheumatoid arthritis (RA) is a chronic, incurable autoimmune condition that affects more than 400,000 people in the UK and can cause severe disability. The contribution of B cells to pathogenesis in RA has long been recognised but the exact mechanisms by which they influence the inflammatory process are incompletely understood. Large-scale next-generation sequencing (NGS) projects have already begun to elevate our knowledge of the role of B cells in a wide range of diseases, by characterising expressed immunoglobulin (Ig) repertoires. New NGS methods focusing on individual cells, including single-cell RNA sequencing, are incredibly powerful at revealing heterogeneity in immune cell populations. A subset of B cells showing a distinct signature of hypomutated antibody, or IgG, has recently been identified in RA. By combining transcriptomic and antigen receptor repertoire data at a single cell level, I aim to understand the origin and role of this cell population. To do so, I will determine the transcriptional heterogeneity of peripheral B cells in RA, characterise gene expression signatures associated with the production of hypomutated IgG, and develop tools to improve analysis pipelines. This work will help clarify the involvement of B cell subsets in RA and may provide targets for more directed therapy.

Grants awarded from 1 October 2005 to 30 June 2021


PhD Studentship (Basic)

Investigating adaptive immune function in ME/CFS patients The underlying cause and the mechanisms driving disease in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are unknown and identifying a marker of disease, even for a subgroup of patients, would open avenues for research into  pathogenesis and better diagnostic tools. B cells in ME/CFS patients have been shown to have unusual features, including an expansion of particular B cell repertoires (BCRs) in the repertoires of a small cohort of ME/CFS patients compared with healthy controls [9]. We will test these initial findings across a large number of patients and examine patterns of diversity or shared responses in the repertoires of patients compared with controls. This will involve sequencing and analysis of B cell samples for approximately 130 severe and moderate ME/CFS patients as well as multiple sclerosis patients and healthy controls. Using machine learning and clustering-based statistical techniques we will stratify individuals based on properties of their B cell repertoires and the available meta-data. Phage display techniques will be used to replicate BCRs in the lab to identify major antigens shaping the repertoires in these patients. This study will generate a comprehensive picture of B cell immune diversity in ME/CFS to improve our understanding of the aetiology and immunopathology of ME/CFS.


PhD Studentship (Basic)

Characterisation of a host receptor for Plasmodium falciparum-infected erythrocyte rosette formation Rosetting, the binding of two or more uninfected erythrocytes to an infected erythrocyte, is associated with severe P. falciparum malaria. Therefore, anti-rosetting therapies that reduce microvascular obstruction may be beneficial as adjunctive therapy to reduce severe malaria deaths. Rosettes are formed by an interaction between parasite-derived Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) and host erythrocyte membrane receptors. PfEMP1 is highly polymorphic and therefore a challenging target for vaccines. Recent work by the Rowe lab suggests that PfEMP1 mediates rosetting by an interaction with the Wrightb antigen formed by Band 3 and Glycophorin A. An antibody targeting Wrightb has disrupted rosettes in all P. falciparum strains tested to date, suggesting that this small antibody fragment (BRIC14) has therapeutic potential. I propose to test BRIC14 across a panel of rosetting P. falciparum strains to determine the efficacy of BRIC14 in severe disease states. I aim to characterise the interaction between PfEMP 1 and Wrightb to determine if BRIC14 reduces rosetting by direct inhibition of a ligand-receptor interaction or by altering erythrocyte deformability. The present study aims to characterise a key receptor-ligand interaction implicated in rosetting and determine if a rosette-disrupting antibody has potential as a therapy against disease-causing P. falciparum strains.


PhD Studentship (Basic)

The role of cell cycle exit in EHT and the haematopoietic niche Haematopoietic stem cells (HSCs) have been used for the treatment of diseases including immune deficiencies and metabolic disorders, as well as bone marrow repair after radiation treatment. In order to harvest their full potential, it is essential that we expand our understanding of HSC development and function. A vital part of HSC generation in the developing embryo is the transition of a subset of endothelial cells into blood cells. This occurs under the control of a multitude of factors within the cell and those present in the surrounding environment, the hematopoietic niche. The cell cycle has been shown to be an important involved in the cellular differentiation process, as some cells need to exit the cell cycle in order to undergo the transcriptional and morphological changes associated with differentiation. In my project I will investigate the impact of various factors as cell cycle regulators in this early differentiation of endothelial cells into haematopoietic cells. These studies will employ genetically modified mice, alongside state-of-the-art in-vitro and transcriptional profiling techniques such as single-cell RNA-sequencing. We expect our research to help elucidate the origin of HSCs and therefore contribute to our understanding of how to generate these cells in-vitro.


PhD Studentship (Basic)

Investigating the female sexual life-cycle of Cryptosporidium, a diarrhoeal pathogen of global significance Cryptosporidiosis is a diarrhoeal disease of global significance caused by the intracellular parasite, Cryptosporidium spp. Infections can cause malnutrition, growth stunting and be fatal in children. Unlike other causes of diarrhoea, cryptosporidiosis lacks effective treatment or vaccine.

Shortcomings in the clinic persist due to the lack of a continuous in vitro culture system. This year, we established and infected mouse intestinal organoids (miniaturized, self organized organs) in our laboratory. Combining these in vitro culture abilities with gene-editing tools, we can now study the complete life-cycle of Cryptosporidium and stages which precede transmission that were not readily observed previously.

I aim to better define the female life cycle stage of Cryptosporidium. It is important to understand how female parasites regulate building environmentally resilient cyst walls, and sporulate new parasites inside this cyst. I aim to generate a female stage-reporter strain of C. parvum and validate Cryptosporidium-organoid co-culture in the first 6 months. Furthermore, isolated females may be further characterized by single cell RNA-sequencing and proteomics. This research will better define the formation of the transmissible stage of Cryptosporidium and provide a basic understanding on which to develop vaccine and drug discovery.


PhD Studentship (Basic)

Investigating the impacts of nutrition on gastrointestinal helminth infection and immunity in a wild mouse model  Gastrointestinal (GI) parasitic helminths, pose a significant threat to the health of humans and animals worldwide. Those affected are continuously exposed and rapidly re-infected post-treatment, however, the level of infection (worm burden) varies among individuals. The underlying drivers of such individual differences are multifaceted; however, host immune and nutritional status influence exposure and susceptibility to helminths. Much of our understanding of GI helminth infections in mammals has derived from lab mouse models that may not reflect real-life scenarios. Instead, using wild hosts and their coevolved wild parasites may provide a more ecologically relevant model of GI helminths for humans and wildlife. Currently, limited research has investigated the relationship between nutrition and immunity in natural host-helminth systems.

We aim to determine the role nutrition plays in immunity and infection within a natural host-helminth system; wood mice (Apodemus sylvaticus) and wild isolates of Heligmosomoides polygyrus. By conducting parallel experiments in the lab and wild, with the same host-parasite system, we can control for variation in parasite exposure and nutritional status to determine the key drivers of susceptibility to infection. We will combine both ecological and immunological data to gain a greater understanding of the interplay between nutrition, immune response and helminth infections.


PhD Studentship (Basic)

A system level approach to identify and validate imprinted genes involved in parental care The neural pathways responsible for parenting behaviours have been well characterised, and the Preoptic Area (POA) is considered a parenting 'hub' in many mammals including mice and rats. Imprinted genes (IG) are a set of ~200 genes that have been clearly associated with the quality of parenting behaviour. Our current work plans to unite these two by investigating the role of IG expression in the neural circuitry for parenting.

Using pre-existing data, we will look for enrichment of IGs in the POA and in specific POA neurons associated with parenting behaviour. We will be guided by this analysis to select an IG to characterise the parenting deficit created from a gene knock-out model. Furthermore, we will utilise RNA-Scope to examine specific gene-expression within the POA of the mouse model looking for the effect that the knock-out model will have on the parenting neurons.

The quality of parenting behaviour is key to the optimal development of offspring in animals, hence the impact of this work will be to further elucidate one of the genetic underpinnings of parenting behaviour, especially valuable since previous work has associated imprinted gene expression with human pregnancy outcomes including prenatal depression and negative infant mood (Creeth, 2018)


PhD Studentship (Basic)

Investigating the effect of colon cancer mutations on human intestinal stem cell dynamics Intestinal stem cells are responsible for the regeneration and maintenance of the intestinal tissue. Due to the high proliferative potential of intestinal stem cells, mutations that disrupt the homeostatic regulatory mechanisms can result in cancer formation. Mouse intestinal stem cell dynamics have been widely studied but our knowledge of human intestinal stem cell dynamics has been lagging behind. Now there is evidence to suggest that mutations in genes driving cancer formation can alter stem cell dynamics to achieve a high mutational burden in the normal human colon but so far only a few cancer-associated genes have been studied. As part of my PhD project I aim to develop an integrative approach by using a three-model system to assess how cancer-driver mutations are affecting human intestinal stem cell dynamics. I will use tissue sections of normal human colon, human intestinal organoids and a conditional knock-out mouse model to address this question. Multiple established methods will be employed including sequencing, immunohistochemistry, genome engineering and lineage tracing. This research will help me explore how stem cells are affected in a diseased context to ultimately understand more about the process of colon cancer initiation.


PhD Studentship (Basic)

Elucidating the functional heterogeneity and fate dynamics of alveolar stem cells in lung regeneration and early oncogenesis Lung cancer, of which adenocarcinoma is the most common subtype, is the leading cause of cancer-related mortality worldwide. Activating mutations in oncogenic KRAS account for approximately 25% of all lung adenocarcinoma cases, and for these tumours in particular, prognosis is poor and effective chemotherapies are severely lacking. Alveolar type II (AT2) cells act as the major stem cell population within the alveoli and are known to be key cells of origin of lung adenocarcinoma, but the molecular mechanisms and early cellular transformation events that drive their tumourigenesis remain elusive. Using a novel, oncogene-associated multi-colour reporter mouse model, I aim to label and track AT2 cells harbouring Kras mutations and compare their behaviour to wildtype AT2 cells. By analysing individual AT2 cell-derived clones over time, I intend to shed physiological insight into the initial steps of tumourigenesis and determine how dynamic cell-to-cell interactions present between mutant AT2 cells and their associated neighbours facilitate tumour propagation. Collectively, this work will help to devise early detection strategies and identify novel therapeutic targets for the treatment of lung adenocarcinoma, whilst simultaneously highlighting the mechanisms by which lung stem cell function can be hijacked during early disease.


PhD Studentship (Basic)

Comparative Analysis of NFE2L-family Stress Responses in Cancer The human NFE2L gene family encodes three proteins that drive expression of a range of genes that protect cells from different forms of stress. Under normal circumstances, these proteins are beneficial and protect cells from potential damage. Unfortunately, high levels of NFE2L activity can also be detrimental. In some cancers, enhanced activity of NFE2L family members allows cells to survive both chemo and radio therapy, leading to poor rates of survival. Therefore, we are keen to know if it is possible to target NFE2L proteins to make tumours more sensitive to treatment. Before we can do this, we need to know how NFE2L proteins work and how they may be controlled in health and disease. Therefore, we plan to show how human NFE2L proteins interact with other proteins, creating ‘molecular maps’ which will shed light on why NFE2L activity is increased in cancer, and how this activity may be inhibited. In addition, we will create genetically modified cell lines which we will use to see if blocking NFE2L proteins can make chemotherapy more effective in different cancer cell lines.


PhD Studentship (Basic)

Investigating how Platelets and Inflammation Impact Cancer Cell Metastasis and Extravasation - Live Imaging in Zebrafish Larvae Metastasis is the process by which cancer cells migrate from a primary to a secondary tumour site, with 95% of cancer deaths attributed to this metastatic spread.  Cancer cells interact with a variety of host cells at the primary tumour location and as they invade other tissues, these interactions increase their survival and metastatic potential.

Platelets are the smallest circulating cell type and are often the first cells to escape blood vessels into a growing tumour. As a cancer cell enters the vasculature it becomes further exposed to circulating platelets. Evidence suggests that platelet:cancer cell interactions mediate interactions with innate immune cells, which are beneficial for the survival and metastasis of cancer cells.

My PhD project will use translucent zebrafish larvae to live image how platelets (thrombocytes in fish) might be pivotal at several stages of cancer metastasis. Specifically:

 Do platelets mediate cancer cell:macrophage/neutrophil interactions at the site of primary tumours and impact tumour angiogenesis?
 How might microclots enable innate immune cells to interact with circulating cancer cells to enable their extravasation to a secondary cancer site?
 What role do other immune cells, including eosinophils and adaptive immune cells, play in each of these plateletmediated steps?


PhD Studentship (Basic)

How are nutrient signalling and membrane trafficking coupled at the lysosome by the Folliculin-FNIP complex? BACKGROUND

Folliculin (FLCN) is a tumour-suppressor protein implicated in control of lysosome-associated nutrient signalling pathways. Loss of FLCN function causes Birt-Hogg-Dubé (BHD) syndrome, a rare genetic disorder associated with an increased risk of kidney cancer. In complex with its interaction partners FNIP1/2, a role is emerging for FLCN as a co-ordinator of small GTPases at the lysosome. FLCN-FNIP can act as a GTPase activating protein for RagC to control lysosomal mTORC1 activity, and regulates lysosome dynamics by acting through several Rab GTPases and their effector protein RILP. Thus, the FLCN-FNIP complex sits at a pivotal position where it couples nutrient signalling and trafficking/transport events at the lysosome.

APPROACH

A clear mechanistic understanding of how these complex activities are carried out is currently lacking. I will integrate structural, biochemical and cellular approaches to study the intact human FLCN-FNIP complex, with the aim of describing its activities in molecular detail. I will particularly focus on its potential role as a co-ordinator of GTPases in relation to nutrient signalling and intracellular transport of the lysosome.

IMPACT

By tying together two branches of lysosome biology we will uncover the normal function of the FLCN-FNIP complex and establish the underlying pathology of BHD syndrome.

Mechanistic Target of Rapamycin Complex 1


PhD Studentship (Basic)

Investigating macrophage behaviour and interactions in normal and pathophysiological erythropoiesis  Macrophages are known to be intrinsically involved in nurturing erythroid cells within the bone marrow. They regulate and enhance erythropoiesis, the production of Red Blood Cells (RBCs), through maintenance of the haematopoietic stem cell (HSC) niche and erythroblastic islands (EBIs). Understanding the cellular interactions involved in EBI formation and maintenance is crucial for investigating disease and improving in vitro erythropoiesis. Polycythemia Vera (PV) is a disease involving increased differentiation of progenitor cells towards the RBC lineage, and subsequent overproduction of RBCs. The genetic component, caused by a single acquired mutation in the tyrosine kinase JAK2, is well established. However, current treatments experience issues with resistance and intolerance, and the involvement of other cell types remains largely under-studied. Importantly, recent studies have implicated a role for macrophages in PV. I aim to further elucidate the molecular basis and cellular interactions that underly the role macrophages play in normal erythropoiesis and PV. CD14+ macrophages from PV and normal patients will be isolated to investigate phenotypic changes, including secreted cytokine profile, proteomic profile and mutations in JAK2. Image analysis will be conducted to probe whether there are changes in interactions between macrophages, progenitors, and erythroblasts within the normal and disease contexts.


PhD Studentship (Basic)

Understanding actin-dependent chromosome cohesion in mammalian eggs Every human life starts when an egg is fertilised by a sperm. For poorly understood reasons, eggs frequently contain an incorrect number of chromosomes. This chromosomal abnormality is a leading cause of embryo deaths in humans – it accounts for nearly 35% of miscarriages. Chromosomal abnormality in embryos also leads to genetic disorders such as Down’s syndrome, which affects about 1 in 1,000 live births worldwide. My PhD project is aimed at understanding which cellular processes protect eggs from having an incorrect number of chromosomes before fertilisation. In this regard, I will investigate a recently discovered and unexpected function of the actin cytoskeleton in preventing chromosomal abnormality in eggs. In the future, knowledge obtained from my research project could be exploited to improve the outcomes of fertility treatments as well as prevent pregnancy loss.


PhD Studentship (Basic)

Mycobacterial drug target deconvolution using Genetic, Phenotypic and Proteomic approaches Mycobacterium tuberculosis is the causative agent of tuberculosis (TB) and leads to 1.8 million deaths per year. Resistance to the currently used anti-TB drugs is growing, which will increase death rates in the future if unchecked, hence there is a high demand for new drugs.
My project aims to identify how novel anti-TB molecules work, to increase our understanding of their targets and how they can be improved to increase their activity and selectivity. The protein targets will be produced and then purified, allowing the drug-protein interactions to be studied. Specific interactions will be identified, providing evidence for alterations to these drugs to increase their potency. Another section will be the identification of new drug targets, which could be taken forward for targeting by studying the protein-protein interactions occurring in the outer membrane and wall of M. tuberculosis.
The main output of my work would be increased knowledge of protein-molecule interactions of novel anti-TB drugs and will allow them to be altered to increase their selectivity and activity. This would hopefully lead to these novel drugs being taken forward as potential drugs for the treatment of TB, expanding treatment options against multi-drug resistant M. tuberculosis strains.


PhD Studentship (Basic)

Investigating the gut colonisation of Intensive Care Unit Patients The spread of antimicrobial resistance (AMR) is a global problem. AMR is a particularly important issue in hospital intensive care settings. Treatment regimes (e.g. broad-spectrum antibiotics) and interventions (e.g. ventilators, feeding tubes) are known to disrupt gut microbiota in adult patients. Opportunistic pathogens (e.g. Escherichia coli) and increased exposure to antimicrobial therapy are more common in critically ill patients. Colonisation with drug-resistant organisms increases risk of developing drug-resistant infections. Understanding the dynamics of colonisation should ultimately help reduce incidence of multi-drug resistant (MDR) infections in high-risk patients. Research is essential to understand how AMR genes move and colonise causing drug resistant infections.

I will use bioinformatics including metagenomics to:

 investigate E.coli diversity and colonisation dynamics in the the intensive care unit (ITU) environment
 Track prevalent E.coli sequence types (STs) including transmission between different areas of the ITU
 Study AMR genes in ITU patients including effects of antibiotic prescribing on the gut microbiota.

This information will show local ITU consultants and microbiologists:

 which E. coli STs  are prevalent in ITU and which are most commonly transmitted
 effects of specific antimicrobial prescribing

so steps can be taken to reduce risks of transmission of colonising organisms and AMR in this high-risk setting.


PhD Studentship (Basic)

Investigating the impact of the local inflammatory environment on CD4+ T cell metabolism and function In inflammatory diseases such as rheumatoid arthritis (RA), T cells (a type of white blood cell) take on multiple different forms. These forms, known as subsets, can contribute to disease or help to resolve it. To develop new drugs for inflammatory diseases, we need to understand how these subsets of T cells are made and maintained. "Metabolism" describes the chemical processes cells use to break down nutrients. It is the basis of all changes in cells, even determining what subset they become. Importantly, metabolism can be targeted with drugs. Whether T cell metabolism changes in inflammatory disease is not yet fully understood. We will investigate this, try to understand the processes involved and test if changing the metabolism of inflammatory T cells influences their subset. To do this, we will compare the metabolism of T cells from RA patients with those from healthy people. We will also investigate the role of cytokines –signals released by immune cells to communicate with each other. These are increased in RA and alter metabolism in other cell types, but their effects on T cells is not known. Together, this research will help us to better understand RA and aid the development of new treatments.

Grants awarded from 1 October 2005 to 30 June 2021


PhD Studentship (Basic)

Probabilistic machine learning for medical applications In recent years, cheaper computing power and higher data availability have prompted a machine learning (ML) explosion. Medicine, however, remains a challenging field of application for ML due to low sample size and overconfidence of traditional models in their predictions. The aim of my project is to tackle these limitations by taking a radically different ML approach, probabilistic ML, that emphasizes uncertainty quantification. I will focus on two systemic diseases that are particularly amenable to the probabilistic ML framework: cancer and type 1 diabetes. Regarding the former, pharma companies are unable to meet the demand of novel anticancer compounds, burdened by the high cost of drug development and the low success rate. I will use probabilistic models such as Gaussian processes (GPs) to predict medically-relevant properties of cancer drug candidates such as the IC50. Then, I will refine the candidates’ structure using Bayesian optimization. On the other hand, type 1 diabetes control is based on a delayed feedback loop between insulin injected and future glucose levels. I will use GPs to better estimate future blood glucose levels and to automatically detect situations that are dangerous to patients such as hypoglycemias, diabetic ketoacedosis and insertion site failure of insulin pumps.


PhD Studentship (Basic)

Regulation of the Translocase of Outer mitochondrial Membrane (TOM) complex by reversible ubiquitylation. Mitochondria are tiny power plants that produce energy for cells in our body. To work properly, mitochondria need to continuously import new parts, mostly proteins, through specialised gates and channels, we call TOM complexes. When mitochondria are damaged and/or proteins get stuck in the gate, TOM complexes are tagged with a protein named ubiquitin. This tag is recognised by the waste disposal machinery in the cell. Diseased mitochondria are wrapped up and safely destroyed through a process we call mitophagy. In people with Parkinson’s disease, mitophagy does not work properly, leading to problems in the brain. We are interested in proteins that remove ubiquitin and can act as a brake on mitophagy. In particular, one of these, USP30, removes ubiquitin from TOM complexes. Interfering with USP30 allows cells to clear away damaged mitochondria more efficiently.

On the mitochondria, a very small amount of USP30 has to survey a large number of TOMs. We want to understand more about the relationship between ubiquitin, USP30 and TOM complexes. In particular, we would like to know what distinguishes those TOM complexes that USP30 works on and how the addition and removal of ubiquitin from these gates affects their function.


Interpreting the microtubule code

PhD Studentship (Basic)

Interpreting the microtubule code All our cells contain mesh-like networks that are formed from tube-shaped protein structures called microtubules. These microtubules help to maintain cell shape, allow cell movement and facilitate cell division. Additionally, they also act as railway tracks in which motors can travel down to transport their cargo to specific areas of the cell. Proteins can bind to microtubules to control their function and determine what is transported along them. Many of these proteins have been identified however the list is still not complete. Identifying and exploring further this collection of proteins using a technique called mass spectrometry may help us discover new functions for microtubule networks. To create even more specific functions, individual railway tracks can be decorated with a variety of different removable groups which distinguishes them from each other. This is known as the tubulin code and allows individual tracks to be recognised by different proteins and alter whether they bind or not. As this tubulin code is not well understood, we will modulate these modifications to identify and explore proteins that bind to specifically decorated railway tracks. This research will help us understand the importance of these removable decorations and how they control the functions of microtubules.


PhD Studentship (Basic)

Investigating the role of mitophagy regulators in neuronal cell and Drosophila models.  Mitochondria are the powerhouses of the cell and are crucial for neuronal function and survival. Disruption of mechanisms governing mitochondrial integrity lead to development and progression of different neurodegenerative disorders (NDs) such as Parkinson’s Disease (PD) and  Alzheimer’s Disease (AD). In fact, the accumulation of defective mitochondria in neurons is a hallmark of NDs. Mutations in genes linked to PD lead to a failure in pathways  designed to rid the cell of low-quality mitochondria. Restoring this pathway offers an attractive therapeutic option.

While this pathway is well characterised in cell models, less is known about this process in living organisms (in vivo). Our laboratory has engineered fruit flies (Drosophila) such that the mitochondria undergoing degradation can be directly visualised. I will develop this model system to characterise the influence of various genetic or pharmacological changes upon the mitochondrial degradation process in flies. I aim to shed light on the interplay between various genes linked to this pathway and discover new factors relevant to the process.


PhD Studentship (Basic)

Investigating how ANCL-causing mutations lead to neurodegeneration  Human neurodegenerative diseases impose a great and increasing social, economic and health burden on society, due to our rapidly expanding ageing population. However, these debilitating and fatal disorders lack effective therapies as the underlying mechanisms remain unclear. A rare neurodegenerative disorder, termed adult onset neuronal ceroid lipofuscinosis (ANCL) is a devastating neurodegenerative condition, rendering sufferers with an average life expectancy of 45 years.  This project will use a combined approach, utilising both roundworms and mice to elucidate the mechanisms behind the disease. The worm and mice genetic makeup will be manipulated to mimic the effects of the ANCL-causing mutations, to generate working models of the disease. Additionally, the cells of the brain, neuronal cells, will be extracted from mice to analyse the impact of the mutations on neuronal survival, connectivity and protein localisation. Furthermore, both the worm models and mice neuronal cells will be used to identify new protein interactions, and how these are impacted by ANCL mutations. Ultimately, this project aims to expand our knowledge on the mechanisms behind ANCL disease processes, to aid in the identification of potential therapies for ANCL, and potentially other neurodegenerative diseases.


PhD Studentship (Basic)

Limited Proteolysis Mass Spectrometry: A Pipeline for Investigating Loss of Proteostasis with Age Cell populations are intrinsically changed by age, reaching a point of senescence (arrested division) that has been associated with misregulation of metabolism, circadian rhythm, the extracellular matrix and signalling to the immune system. Crucially, studies have demonstrated age-related abrogation of protein homeostasis – the maintenance of proteins in their functional, folded states.

Given that the capacity of cells to maintain a correctly folded proteome, and thus functionality, is attenuated in ageing, understanding the biological mechanisms which underlie this loss of protein homeostasis is paramount. In this project, I will use proteomic and bioinformatical techniques to gain a fundamental understanding of the relationship between age and the loss of protein homeostasis.

Limited proteolysis mass spectrometry (LiP-MS) is highly amenable to the study of protein folding, as it facilitates the characterisation of structural changes to the native proteome on both a global and local scale. I will apply LiP-MS to determine the extent of protein unfolding in primary human stem cells. Using replicative senescence as a model of cellular ageing, I will identify a candidate list of proteins whose folding/structure is not maintained at old age and use bioinformatic analyses to predict functional consequences of age-associated protein unfolding.


PhD Studentship (Basic)

Algorithms in a functional genomics study of cichlid fish evolution Epigenetics, or "on top of" genetics, refers to biochemical modifications to the DNA that do not alter the underlying sequence. Such modifications influence the likelihood that individual genes are expressed, allowing many degrees of freedom for the overall gene expression network in an organism. This is believed to underpin how certain organisms exhibit the ability to diversify into a large number of species in short evolutionary time. A famous example is the cichlid adaptive radiation of the East African Great Lakes, which comprises over 2,000 phenotypically diverse species, in terms of their microhabitat, size, morphology, feeding behaviour and colouration.

My PhD project will be a collaboration between myself and Audrey Putman, an experimentalist student from Eric Miska’s lab. Our plan is to explore, characterise and quantify how epigenetic differences can manifest in the cichlid system. I will develop computational and statistical methodologies to analyse epigenomic data, under the guidance of a computational supervisor, Martin Hemberg. The impact of the work include developing efficient algorithms to process large scale datasets, and effectively integrate information from various sequencing technologies, with the ultimate goal of addressing the fundamental biological question of speciation.


PhD Studentship (Basic)

The use of machine learning techniques to assess the quality of mammalian pre-implantation embryos The popularity of in vitro fertilisation (IVF) is growing with techniques improving over the last few decades. Nevertheless, current success rates remain low, which is partly due to difficulty in selecting the best embryos to be used, as we lack a comprehensive understanding of the visual attributes of a healthy embryo. The aim of this PhD is to develop techniques that will improve the chances of selecting a healthy embryo after IVF procedures, based on a video of the first 5 days of its life. We plan to achieve this using machine learning, an artificial intelligence approach that allows computers to learn from available data. We will follow two approaches; 1) attempt to predict the quality of a human embryo using videos provided by an IVF clinic, and 2) create mouse embryos with abnormalities in genetic material, record their development and develop an algorithm capable of identifying the reasons behind developmental failure from image / video data. If we can correctly predict the viability of an embryo and genetic issues impacting on this, it will pave the way for the development of improved detection and diagnosis systems to support human IVF treatment.


PhD Studentship (Basic)

Whole-brain structural and functional connectivity in children treated with therapeutic hypothermia for neonatal encephalopathy Each year 2 per 1000 newborn babies suffer brain injury due to deprivation of oxygen to the brain around birth leading to severe physical disabilities called cerebral palsy and, in severe cases, death. Cooling therapy reduces the risk of severe brain injury, however when the cooled children reach school-age they still perform less well on cognitive and motor tasks than ‘healthy’ controls, even in the absence of cerebral palsy.

Using advanced brain scans (MRI) from a cohort of cooled children, as well as data from controls with no birth complications, I aim to determine the underlying differences in brain structure and function and assess how these differences contribute to cognitive and motor performance. I will apply techniques to investigate tissue microstructure, as well as techniques from graph theory to characterise whole brain wiring. I will develop the statistical methods used in network neuroscience to facilitate more robust and informative analysis of the structural and functional brain networks.

Determining particular brain regions or connections which are affected in cooled children will provide understanding of how the injury affects development and may motivate developing therapeutic interventions. Developing the statistical techniques will allow investigation of the relationship between brain structure and children’s skills.


PhD Studentship (Basic)

Developing a Methodological Framework to Evaluate the Impact of Health Intervention Sequences The goal of my research is to uncover how the sequence of health interventions influences their effects. As an example, should a cancer patient be treated first with the newest and costly drug upon diagnosis, or should such drug be reserved as the last resort, after all other drugs have failed? Typically, it is unclear whether there are any other effective treatments when a new drug fails.

Quitting smoking is another example of where the sequence can matter. We know that e-cigarettes are more effective in helping smokers to quit compared to nicotine replacement therapy (NRT). However, this has been shown mostly in people who have tried NRT and failed before trying e-cigarettes. Therefore, it is unknown whether smokers would have been more successful in quitting if they had used e-cigarettes first. Or would e-cigarettes only work after failed quitting attempts with other methods?

In summary, changing the order of healthcare interventions can result in either positive or negative outcomes. To better understand this phenomenon, I plan to apply novel statistical approaches to existing medical records, surveys and trial data to explore the optimal sequence of interventions and to model the relative cost-effectiveness of different sequences.


PhD Studentship (Basic)

Causal pathways from cognitive function to Alzheimer's disease Findings from observational and genetic studies of modifiable risk factors for Alzheimer’s disease (AD) are inconsistent with studies reporting null, positive or negative findings for the same risk factor. Educational attainment and intelligence are the only risk factors to have been consistently related with AD, with studies using different methodologies reporting greater educational attainment and intelligence to be protective for Alzheimer's disease. Recently, in a genetic study more robust to bias than traditional observational studies, we showed little evidence of an effect of educational attainment of AD once intelligence was accounted for. The aim of the project I am proposing is to investigate how structural brain and physiological (proteins, metabolites) changes, play a role in the relationship between cognitive function and AD.  With the use of birth cohorts, with data on childhood measures such as brain structure, and the use of genetics methods for estimating causal effects, we aim to limit biases associated with adult and observational epidemiological studies. This will allow investigation of the relative importance of anatomical and physiological factors for cognitive function on Alzheimer's disease. This project will contribute to an improved understanding of the causes of AD and highlight potential drug targets and intervention strategies.


PhD Studentship (Basic)

Sensitivity analyses for causal inference Many epidemiological studies are interested in estimating the causal effect of an exposure on an outcome. While experiments in which exposure levels are randomly assigned to participants are the ideal setting for this purpose, it is often infeasible for financial, ethical or logistical reasons. Therefore, we are often limited to analysing observational data in which exposure levels across individuals are determined by many complex and often unmeasured factors. Drawing inferences from such data typically requires making untestable assumptions about the distribution of, or relationships among, the variables under study. Causal inferences which depend on these untestable assumptions are rarely convincing. In the last couple of decades, there has been increasing development of sensitivity analyses, which relax the assumptions and measure the extent to which the estimates change as a result. Estimates which have the same qualitative interpretation even when assumptions have been stripped back are much more persuasive. The aim of my PhD is to continue developing sensitivity analyses for causal inference, with particular focus on selection bias and measurement error, and to promote these methods among non-statistician researchers (e.g. epidemiologists, clinicians).


PhD Studentship (Basic)

Structural investigation into the Tol-Pal transenvelope machine and how it utilises the proton motive force Antibiotic resistance is a global health issue that threatens modern medicine and how we treat bacterial infections. Investigating how bacteria live is important to fight against antibiotic resistance as it can lead to new approaches for dealing with bacterial infections, and new targets for antibiotics. The research project we are proposing aims to further our understanding of a system called Tol-Pal in a class of bacteria called Gram negatives. Tol-Pal has been shown to have a role in cell division and is important for the growth of Gram-negative bacteria. At the moment, we do not fully understand how the components of Tol-Pal work together to carry out this function. In this project we hope to use structural biology techniques to see what a complex of three of the proteins in the Tol-Pal system, TolQRA, look like. We hope that finding out what TolQRA looks like will help us to investigate the mechanism of TolQRA within the Tol-Pal system, and further our understanding of Gram-negative bacteria and how they work.


PhD Studentship (Basic)

Structural Characterization of the Human Endogenous Retrovirus K (HERV-K) Approximately 8% of the human genome consists of Human Endogenous Retroviruses (HERVs) which have been found to be active in several diseases such as cancer and HIV infections. This raises several questions as to why these sequences were retained in the genome and why they become active in such a broad range of diseases. We have decided to study HERV-K (HML-2) as a representative of this class as it is the most recently acquired retrovirus, the most transcriptionally active and encodes all structural and enzymatic proteins to form virus-like particles (VLPs).

We start by studying one polypeptide of the virus which is sufficient to form non-infectious VLPs. We will then include the other proteins step-by-step until we have the structure of the fully formed virus. This gives us the possibility to work up to the more complicated virus on the basis of the earlier results. VLPs can be seen in cryo-electron tomography easily and sub-tomogram averaging of the highly symmetric lattice gives the opportunity to achieve a sub-nanometre structure of HERV-K. These findings lay the basis to find the mechanism of how HERV-K acts and will be tested by in vivo assays to develop compounds for blocking HERV-K.


PhD Studentship (Basic)

Structural and Functional Characterisation of the Very Large G protein-coupled receptor (VLGR1) Very Large G protein-coupled receptor 1 (VLGR1) is an adhesion G Protein-Coupled Receptor (aGPCR/ADGR). ADGRs are cell-surface protein receptors which mediate signal transduction through coupling with G-proteins in the cell and with their characteristic large extracellular domains mediate cell-cell and cell-matrix interactions. VLGR1 is the largest cell-surface protein known and none endogenous ligand for its extracellular domain has been identified yet. It is highly expressed in the central nervous system and mutations in Vlgr1 gene lead to the Usher Syndrome Type 2C which is characterised by hearing loss and progressive retinitis pigmentosa. Mutations are also linked to audiogenic seizures in mice and humans. All these suggest VLGR1’s important role in the central nervous system and despite the importance and the recent research progress, the structure and functions of VLGR1 are not known. During my PhD I will use structural analyses, including X-ray Crystallography and cryo-EM, to characterise the structure of the extracellular domain of the VLGR1 receptor and I will aim to identify its biological binding partners using cellular assays. These studies will shed light on the biology of this poorly understood receptor and may suggest new ways of treating the associated diseases.


PhD Studentship (Basic)

Structural and functional characterisation of the fungal proton pump Pma1 Fungi fuel their nutrient uptake through generating a proton-motive force across their plasma membrane via the membrane protein proton pump Pma1. This proton-motive force is used as an energy source to import nutrients for the cell, and fungi die without the activity of Pma1. To date, knowledge on the molecular structure and function of this protein is limited. I therefore aim to study the structure of Pma1 and understand its molecular function, through the use of structural analyses, including cryoEM and X-ray crystallography and biophysical assays. I will be using protein isolated from the fungus Neurospora crassa and a set of known small molecules that lock the protein in different catalytic conformations to investigate its catalytic cycle. I will also establish a way to produce Pma1 in baker's yeast, allowing me to generate variants of the native protein for functional and structural studies. My findings will broaden our understanding of the structure and function of the protein, opening the possibility of a wide range of secondary research including protein-lipid interaction studies and the possibility of designing novel antifungal agents.


PhD Studentship (Basic)

Investigation of the role of small molecule ligands in Hedgehog signalling using molecular dynamics simulations The hedgehog (HH) signalling pathway is involved in embryonic development, cell patterning and stem cell homeostasis1. Defects in pathway function lead to cancers such as medulloblastoma or developmental defects such as holoprosencephaly2. Several recent observations3–8 have led to the hypothesis that membrane sterols such as cholesterol play a crucial role in the function and regulation of key HH membrane proteins, Patched (PTCH1) and the Class F GPCR Smoothened (SMO).

I will use computer simulations to study the role of sterols in PTCH1 function to inhibit SMO. This will include evaluation of protein dynamics within the cell membrane and calculation of  energy changes along potential sterol transport tunnels within PTCH1 which I have previously identified9. Computer simulations will also be used to investigate how ligands bound within SMO may affect the movement of different regions of the protein. These studies will contribute towards understanding the function and regulation of key HH membrane proteins and how their conformational landscape may be exploited for targeting by drugs.

Grants awarded from 1 October 2005 to 30 June 2021


PhD Studentship (Basic)

Longitudinal studies to investigate adult outcomes of autism and autistic traits Autism is a lifelong condition characterised by difficulties with social interaction, social communication and repetitive behaviours. In recent decades, the number of children and adults diagnosed with autism has increased. As autism is heritable, genetic risk may explain why some individuals with mild autistic traits may not meet the criteria for an autism diagnosis and subsequent treatment or other support requirements. As more children with autism and mild autistic traits reach adulthood, the need for health and other services will likely increase. However, few large, well-conducted studies involving adults with autism exist, representing a research gap.

During my PhD project, I will study how autism and autism traits, including genetic risk for them, may be associated with physical health, social and economic circumstances at different stages of adult life. I will take a longitudinal approach to investigate whether there are periods of vulnerability or change in relation to elements of physical health, such as BMI, and social and economic outcomes, such as employment status and level of education. This research will contribute to better understanding of adult outcomes of autism and, potentially, flag the need for more service provisions to meet health and other support requirements.


PhD Studentship (Basic)

Characterising the regulators of trypanosome development and virulence in selected and natural parasite isolates Trypanosoma brucei, the causative agent of human and animal trypanosomiasis, has two distinct life stages. The proliferative ‘slender’ bloodstream-form morphs into a transmissible ‘stumpy’ form, which is adapted to surviving in its vector’s (Glossina spp.) midgut. The transition occurs in a density-dependent quorum sensing (QS) like process which is initiated by a ‘stumpy induction factor’ (SIF). I propose to use a wide diversity of pleomorphic (capable of morphing from slender to stumpy) field and laboratory strains of T. brucei to generate, via multiple passages, monomorphic cells (unable to become stumpy). I will create genomic, transcriptomic and epigenetic data from these cells at the beginning and end of the selection in an attempt to determine the cause of monomorphism, and therefore, the integral components of the QS process. By performing the study on diverse T. brucei cell lines, it will be possible to establish if the monomorphic phenotype can arise via convergent evolution. Alongside the genomes produced during this project, publicly available trypanosomatid genomes will be collated to identify conserved genes associated with increased virulence and monomorphism.


PhD Studentship (Basic)

Investigating the emerging pathogen Shigella sonnei Bacterial dysentery is a major cause of infant morbidity and mortality. Shigella flexneri and sonnei are responsible for 90% of these cases. Interestingly these bacteria are distributed differently and S. sonneiis the dominant serotype in transitional and high-income countries. Recent work has highlighted key differences between these Shigellaspecies including higher lethality of S. sonneiin an infection model, different interaction with immune cells and an increased ability to survive and persist under low nutrient conditions compared to S. flexneri. I aim to identify and understand the underlying molecular mechanisms behind these differences using a multi-disciplinary approach. I will use a combination of targeted and untargeted metabolite profiling (mass spectrometry, NMR spectroscopy and LC-MS) as analytic platforms in addition to the development of novel assays (to dissect polysaccharide biosynthesis pathways and nucleotide biosynthesis) to test specific hypotheses about nutrient flux in S. sonnei.

Results here would better inform our understanding of Shigella persistence and how this could be mitigated in public health and infrastructure settings. In addition, any new techniques developed could be used to study other bacterial pathogens as polysaccharide biosynthesis is an important aspect of pathogen biology.


PhD Studentship (Basic)

Scaling up effective interventions to reduce maternal hypertensive disorder and gestational diabetes: A return on investment case for Bangladesh Every year over 130 million children are born around the world. Each year 303,000 mothers die in childbirth while over 2 million children die at birth. Ninety nine percent of these deaths take place in low and middle income countries. In Bangladesh, the mother dies in 196 per 100,000 births per year. There is growing interest in the effect of Non-Communicable Diseases(NCDs) on maternal deaths. Almost 14% of deaths are due to high blood pressure during pregnancy and 28% are due to other causes including diabetes. One in 25 women develop diabetes during pregnancy period. Addressing these two conditions can help prevent serious birth outcomes like the death of the baby or mother. Preventing high blood pressure and diabetes during pregnancy will also reduce the risk of development of other health problems among women and their children. I aim to conduct research focusing on addressing these two conditions in the context of Bangladesh. I will identify a number of interventions to be included within the public health services. In doing so, I will review evidence to understand current practices and analyse data in order to identify the best interventions in terms of saving lives, reducing ill-health and saving costs.


PhD Studentship (Basic)

Social tariffs, preference heterogeneity, and collective choice Health economic evaluations are used to compare the costs and (health) benefits of different interventions. Their results often inform policy decisions about the allocation of resources within public health care systems. Since health is, to some extent, a social construct, measuring health requires making value judgments. In the UK, these judgments are supposed to be derived from the general public. To this end, it is established practice to survey a representative sample of individuals and to elicit their preferences over health states. Subsequently, individuals’ preferences are aggregated, using some statistical methods, into a single index of the societal value of health, which is then used to value health outcomes in economic evaluations.

The proposed research project starts from the premise that no scientific method is value free, and that the aggregation of individual preferences into a societal preference is particularly contingent on underlying assumptions. The objective is to critically appraise what value judgments are inherent to the statistical models for health preferences that are commonly used in economic evaluations. Based on work in other fields, namely democratic and social choice theory, alternative conceptual and technical solutions will be developed, and their feasibility and impact will be empirically assessed.


PhD Studentship (Basic)

Modelling mitotic spindle dynamics in stretched epithelial tissue Multicellular organisms are formed by cells dividing multiple times, with the direction of division determining whether tissues expand or new tissues are formed. The mitotic spindle forms during cell division and determines the direction of division. In vertebrates, nuclear and mitotic apparatus protein (NuMA) has been identified as an anchor at the cell periphery which allows motor proteins to apply forces to the spindle and position it appropriately. While current spindle orientation models focus on different characteristics of the shape of the cell as force determinants in single cells and invertebrates, preliminary data from a force-based model shows that spindle orientations best match those seen experimentally when force is amplified at the edges of cells with increased intensity of fluorescently tagged NuMA. We aim to develop this model to include time-dependent NuMA localisation as it accumulates at the periphery and observe the effect on spindle dynamics. We will use in-plane divisions in cells of stretched tissue to investigate whether NuMA localises as a result of the cell shape or applied forces and the subsequent effect on spindle orientation. These studies will go some way to explaining the fundamental process of cell division and its dependence on local and global forces.


PhD Studentship (Basic)

Molecular characterisation of post-translational regulation in offensive Type VI secretion systems The Type VI secretion system (T6SS) is a nanoweapon used by many Gram-negative bacteria to deliver toxic ‘effector’ proteins into neighbouring cells. The targeted cells are most often rival bacteria, but can also include the host or microbial fungi. Understanding what triggers the T6SS weapon to assemble and fire will improve our knowledge of how microbes compete for resources, and how diverse communities of microbes develop. Two T6SS firing ‘strategies’ have been identified: offensive T6SSs assemble and fire pre-emptively, whereas defensive systems only fire in retaliation upon sensing incoming attacks from neighbours. A signalling system of proteins which mediate both strategies has been identified. However, key molecular details of how this is used to orchestrate ‘offensive’ T6SS firing are lacking. In this study, we will elucidate the molecular mechanism of these offensive T6SS protein-protein interactions, using the model T6SS of the opportunistic pathogen, Serratia marcescens. Using a combination of genetic, biochemical and cell biology approaches, we will determine the trigger that activates the pathway, how this signal is transduced to activate the T6SS, and the conservation of this regulation in clinical isolates. Long-term, understanding how bacteria interact in diverse communities will contribute to novel strategies to tackle bacterial infections.


PhD Studentship (Basic)

New approach to identifying epistasis using harmonic mean p-value Epistasis refers to the phenomenon where the effect of one gene in a given trait is dependent on other genes. The effect of such interaction between genes is often ignored in studies that try to identify genetic risk factors in diseases and only the effects of individual genes are considered. Such an approach resulted in missing information and the heritability of genetic risks is only partially explained by these association studies. It is proposed that epistasis might be the missing piece of this puzzle. However, taking epistasis into account would increase the number of candidates dramatically. This presents a statistical challenge as the difficulty to find true signal grows when the number of candidates to be considered increases. In this project, we will leverage a recently published statistical method by Prof Daniel Wilson that can combine numerous signals into one representing signal and thereby reduce the number of candidates to overcome the challenge posts by epistasis. We hope to develop a framework to efficiently and flexibly identify genetic risk factors that includes epistasis in different human diseases.


PhD Studentship (Basic)

Using phased multi-omic techniques to understand the regulatory landscape of the genome Since the completion of the human genome project many genetic studies have discovered variations in our genetic code that are subsequently associated with common diseases. These can be insertions or deletions of genetic code or in-place modifications of the genetic code. Interestingly many of these discovered changes to the genome don't occur within genes but within the so-called non-coding regions of the genome. It is thought that these changes are in fact affecting the regulation of the genes -- switches that control gene activity.

In this research I intend to build upon existing research that aims to understand how these changes are affecting the gene activity, which genes are affected and how. This is often complicated by factors such as these genetic-changes may well be very distal to the genes they affect in our 2-dimensional representations of the human genome. Overcoming these issues will provide clear insights into human diseases and hopefully will lead to improvements in our understanding of human disease and how to treat such diseases.


PhD Studentship (Basic)

Do psychedelic drugs have long-term implications for structural and behavioural plasticity in a mouse model?  Plasticity describes changes at various levels of organisation of the nervous system which result from experience. It is hypothesized that psychedelic drugs can induce plasticity at cellular, structural and functional levels, aiding lasting remission from numerous neuropsychiatric disorders. They offer a unique opportunity to study heightened plasticity as a potential neural pre-requisite of behavioural flexibility. Using a mouse model, I aim to determine whether psychedelics induce long-term anatomical and behavioural plasticity changes and to determine if the context of drug administration affects the quality of on- and off-drug experience. Our approach will be a combination of (1) behavioural investigations of the quality of on-drug psychedelic experience under different contexts and of off-drug effects on cognitive flexibility, (2) longitudinal off-drug structural MRI imaging, and (3) in-vivo microelectrode array electrophysiology to understand single network function and information processing. These studies will elucidate whether the psychedelic-induced structural and functional changes persist after the acute intoxication phase and if they can help explain the lasting behavioural changes that have been observed in human studies.


PhD Studentship (Basic)

A large-scale and comprehensive investigation into the B-cell receptor (BCR) and T-cell receptor (TCR) repertoires during the dynamic immune response to sepsis and recovery  Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to often-unknown pathogens. Following recovery, individuals exhibit long-term immunosuppression. B and T-cells are vital components of the adaptive immune response, each B/T-cell expresses copies of a single, unique surface B cell/T cell receptor (BCR/TCR) respectively, for antigen binding. Diversity in receptors is generated by V(D)J recombination and for BCRs, through somatic hypermutation and class-switching. The pool of BCRs/TCRs within an individual is termed the BCR/TCR repertoire. In healthy individuals this is highly diverse, yielding a complex immune architecture. However, studies suggest abnormalities in the repertoires of septic shock patients.

I will generate the first comprehensive analysis of the BCR/TCR repertoire in sepsis using high-throughput BCR/TCR sequencing at multiple timepoints over the course of disease/recovery; one of the largest studies of this kind. Reactivation of Epstein Barr Virus (EBV) is common during sepsis and EBV induces B-cell somatic hypermutation. Therefore, I will use single-cell RNA sequencing to investigate the B-cell transcriptional profile associated with EBV reactivation in sepsis and relate to prognosis. Finally, I will investigate the effect of immunomodulatory therapies (steroids, anti-TNF) on the BCR/TCR repertoire, thus improving our understanding of how therapies can be combined in sepsis.


PhD Studentship (Basic)

Functional and evolutionary characterisation of chromatin organisation in endometrial cancer Endometrial, or uterine, cancer affects roughly 9,000 women each year in the UK and has become considerably more common during the past two decades. Although more than 80% of affected women are cured by surgery and post-operative treatments, the prognosis for certain disease subgroups is considerably poorer. Improving this requires a better understanding of the evolution of this disease at a molecular level. We propose to do this by a detailed study of genetic (changes in DNA sequence) and epigenetic (changes other than DNA sequence) perturbations in endometrial cancers of different stages. Using a combination of human tumours, cell lines and experimental models (such as organoids - 3D cell cultures derived from the mouse uterus), we will apply advanced machine learning techniques and state-of-the-art experimental methods to understand the key events in tumour evolution and the underlying biology driving this process. In doing so we ultimately hope to improve prognostication and therapies for patients.


PhD Studentship (Basic)

Structure learning with grid-like and axis-aligned codes Recent theories of how people comprehend and learn about the world around them have emphasised a distinction between content (i.e. what things are there?) and structure (i.e. how are those things related?). One theory puts forward that "grid-like" activity – a pattern originally discovered in rodent navigation experiments – is used to organise structural information in the brain. Other work has focused on "axis-aligned" codes that organise information along a single axis of ‘magnitude’ – such as number (low to high), time (soon to later), and probability (unlikely to likely). We will investigate the relative contributions of these two types of neural activity in structure learning tasks.
We will use a combination of human behavioural experiments, functional neuroimaging, and computational modelling. We will record brain activity in humans performing tasks that test specific predictions made by the use of the two neural coding strategies, and design versions of these tasks that can be performed by neural network algorithms, allowing us to make functional predictions about the human neural data.
Delineating the circumstances under which the brain uses these two types of activity will constrain or unify theories of structure learning and help understand the neural underpinnings of flexible human thought.


Dynamics in the regulatory genome.

PhD Studentship (Basic)

Dynamics in the regulatory genome. The human genome comprises multiple layers of information, from the basic DNA sequence, to the complex folding of DNA into 3D structures in different cell types.  We have an extensive knowledge of the coding genome, and are beginning to build a better picture of how non-coding regions regulate gene expression.  I am interested in the dynamic process of protein localisation and recruitment within the context of gene regulation.  Pre-established techniques  give a steady state, population view of which proteins and regions of DNA interact with one another. However, such processes are highly dynamic, occurring at different rates across the genome.  A method that could demonstrate how interactions form dynamically and which genomic regions employ particular regulatory activities would further advance our understanding of genome regulation. My project will utilise a newly developed technique, called RAPID-release, that enables rapid induction of protein localisation which can be visually traced over time. I will integrate this with time-course Chromatin Immuno Precipitation Sequencing (ChIP-seq). I will use the combination of these techniques to generate genomic data from which a model for protein dynamics can be developed within the context of the regulatory genome.


PhD Studentship (Basic)

Genetic and Molecular Characterisation of Postprandial Insulin Resistance  Diabetes is a health concern currently affecting approximately 451 million individuals worldwide. Ninety per cent of individuals with diabetes are diagnosed with type 2 diabetes (T2D), typically in late adulthood. T2D is characterised by an inability of the body to control blood sugar levels. In part, this is due to cells of the body being unable to optimally respond to insulin, a hormone required to regulate blood sugar levels; a condition known as insulin resistance. There have been many efforts to understand how genetic changes result in an individual’s increased risk of T2D in adulthood, however, the mechanism by which these changes result in increased risk are largely poorly understood.

This research aims to understand the genetic contribution to insulin resistance, using an interdisciplinary approach. Using large population studies we aim to identify novel changes in DNA which are associated with insulin resistance.  In addition, we will identify rare mutations in genes thought to be involved in insulin action, and examine using cellular models the molecular impact of these. This will enable a better understanding of the genetic contribution to insulin resistance and how this contributes to T2D, as well as potentially highlighting novel targets for treatment and prevention.


PhD Studentship (Basic)

Prognostic proteomic signatures of type 2 diabetes and related metabolic traits Molecules that can be measured in the blood, such as proteins, show differences in people who will develop T2D, even years before being diagnosed. Recent improvements in technologies, now allow us to measure thousands of proteins (so called proteomics) from a single blood sample. We propose that proteomics can provide information on the causes of T2D and on a person’s risk to develop this disease. In two large studies, we will look for proteins that have different levels between people who will develop T2D and those who won’t. We will use this information to: 1) identify those proteins that can help predict which people will develop T2D and related complications, and can help to classify patients into subgroups with similar characteristics. 2) To evaluate which proteins can cause T2D when altered, and which proteins are altered as a result of developing T2D. This project will improve our understanding of the mechanisms causing T2D and help identify proteins that could be used as treatment targets. Additionally, it could improve how we treat patients by identifying individuals at high risk of T2D and related complications and by identifying subgroups of patients with specific characteristics and risks for complications.


PhD Studentship (Basic)

The microbiota-gut-brain axis in preterm infants Around 11% of infants are born preterm (

First, we will characterise gut microbial composition in infant stool samples and investigate which perinatal factors (e.g. mode of delivery, exposure to breast milk) influence gut microbiota. Second, we will use brain MRI to evaluate how variations in gut microbial composition relate to the integrity of developing brain connections. Third, we will investigate the associations between gut microbial composition and neurobehavioural outcomes (e.g. attention, social cognition, anxiety) in these children at 2 years.

These studies will determine whether the gut microbiota modifies risk or resilience for healthy brain development in preterm children. If it does, it may inform novel therapeutic strategies to improve neurocognitive outcomes.

Grants awarded from 1 October 2005 to 30 June 2021


PhD Studentship (Basic)

Relationship between anticholinergic drug use, brain health outcomes, and biomarkers of ageing Many medicines, including some diuretics, vasodilators, antidepressants, anxiolytics, and antihistamines have anticholinergic properties. Such drugs have been linked with impairments in cognition and dementia. Older people are more likely to take multiple drugs and are more susceptible to their side-effects. Thus, there is a need to better understand prescribing and the biology of anticholinergic drugs in this population.

I aim to understand the prevalence of anticholinergic drug use in the Scottish population, their relationship with cognition and with the underlying biology.

I will use data from large and well-characterised cohorts of people and utilise information on their use of prescription drugs to investigate whether individuals with a higher childhood IQ show different patterns of medicine use and how that relates to mortality. Then I will model the ways in which physical function and cognition change in old age as a result of the use of anticholinergic drugs. Finally, I will explore the possible link between these drugs and changes in the brain and the epigenome.

These studies will help us to better understand the prevalence of anticholinergic drug use, the biological underpinnings of its link to cognitive function, and offer insights into improved management of prescribing in older adults.


PhD Studentship (Basic)

Circuit mechanisms underlying spatial navigation deficits in early Alzheimer's disease Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects millions worldwide. AD can only be diagnosed late in its progression, when cognitive symptoms such as memory loss are prominent. Many years before this, the pathological AD processes are active and damaging the brain, but the symptoms at this early stage are subtle, making diagnosis challenging. Focusing on early affected areas in AD could hold the key to early diagnosis.

An early affected area is the entorhinal cortex (EC), which supports spatial navigation. Damage here causes spatial navigation deficits. In early AD, these deficits are subtle and require the development of sensitive tests. Our goal is to help inform the development of these tests by understanding how the EC carries out spatial computations, and how they are altered in AD. To do this, we will reverse engineer the EC circuitry using optogenetics and electrophysiology during navigation tasks performed by healthy and AD mice. In conjunction, we will build computational models (virtual EC circuits) that simulate AD pathology and task performance. These studies will help explain how the EC carries out computations that underlie spatial navigation, and how they go wrong during AD, informing the development of sensitive tests for AD.


Open Access Award 2019/20

Not available

Open Access Award

Open Access Award 2019/20  Not available


Open Access Award 2019/20

Not available

Open Access Award


MicroRNAs in Branchial Arch Development

PhD Studentship (Basic)

MicroRNAs in Branchial Arch Development Embryonic development of the face and neck is a complex process. In vertebrates it begins with the formation of temporary segments called branchial arches. Within these segments, cells must express the correct genes to properly form various structures and tissues, such as the jawbone. Furthermore, these genes need to be expressed at the correct time and in the correct segment. This requires precise regulation, and one mechanism by which cells can accomplish this tight control is using microRNAs. MicroRNAs are known to be involved in important developmental processes, but no studies have profiled the full collection of microRNAs expressed in developing branchial arches. In this project we aim to identify key microRNAs that function during mouse branchial arch development. We will achieve this using a technology called small RNA-sequencing, which will allow us to determine the abundance of all microRNAs expressed in each stage and time. Following this, we will use computational programs to predict the genes they may regulate and later validate these predictions in the lab. This project will identify new contexts for which microRNAs function in and increase our understanding of the precise regulation in place during facial development.

Gene Expression Regulation, Developmental