Research Opportunities

At the National Cancer Institute, we have demonstrated that higher levels of moderate to vigorous intensity physical activity are associated with a lower risk of cancer, including cancer in the breast, colon, endometrium, bladder, kidney, and stomach1. However, due to a reliance on self-reported measures of physical activity, a number of key questions remain unanswered on what overall volume of physical activity, and what types of physical activity, are associated with lower cancer risk. In addition, previous studies are observational by nature and are therefore unable to determine causality due to unmeasured or residual confounding.

At Oxford, our group has shown that wearable sensors such as wrist-worn accelerometers can be used to noninvasively measure physical activity status in large-scale biomedical studies. For example, we have measured physical activity status in 103,712 UK Biobank participants who agreed to wear a wrist-worn accelerometer for seven days2. These measurements are now actively used by health researchers worldwide to demonstrate that simple measures of overall activity are cross-sectionally associated with cancer outcomes3. However, no large study of device measured physical activity has yet taken place to assess associations with incident cancer outcomes with sufficient longitudinal follow-up. Furthermore, activity trackers often capture ~180 million data points/participant/week and therefore have the potential to identify other powerful behavioural signals to detect future cancer risk.

Machine learning methods can help maximise the utility of data from wearable sensors. These methods attempt to automatically detect patterns in data and then use those uncovered patterns to predict future data. Our group has demonstrated the utility of supervised machine learning to identify sleep and functional physical activity behaviours from raw accelerometer data4. However, there is a broad concern around the lack of reproducibility of machine learning models in health data science5. It is therefore important to carefully consider how to promote robust machine learning findings and reject irreproducible ones, to ensure credibility and trustworthiness.

This DPhil project therefore proposes to use the world’s largest available datasets to investigate what types of physical activity are associated with a lower incidence of cancer. Working with colleagues at the University of Oxford and the National Cancer Institute, you will have the opportunity to address the following important questions:

1. What behavioural measurements of physical activity status can be reliably ascertained from accelerometer datasets?
You will have the opportunity to develop reproducible machine learning skills to develop methods to identify physical activity behaviours from raw accelerometer datasets. Specifically, you will develop semi-supervised machine learning methods which seek to combine supervised methods (good quality labels, small datasets) with unsupervised methods (no labels but large datasets which are less prone to sampling bias). This will involve use of the largest available accelerometer datasets with reference measurements for physical activity behaviours in free-living environments (using wearable cameras)6.

2. What physical activity behaviours are associated with incident cancer events?
Here, you will have the opportunity to develop new skills in epidemiological data analysis. You will have the opportunity to use the UK Biobank dataset which has collected wrist worn accelerometer data from 103,712 participants2. This dataset includes information on participants’ first hospital admission or death from cancer, identified from linkages to the national death index, Hospital Episode Statistics, and cancer registries.

3. Are physical activity behaviours potentially causally associated with cancer?
You will have the opportunity to develop genetic epidemiology skills by implementing two-sample Mendelian Randomization7 to assess potential causal effects of accelerometer measured physical activity and cancer. For cancer outcomes, summary genetic association data will be obtained from existing collaborators from International cancer consortia.

Candidates should have a BSc, or ideally MSc, in a discipline with a substantive epidemiological, computational, or quantitative component. We very much welcome prospective candidates to directly contact us to further develop this proposal.

The mortality rate for COVID-19 pandemic has been two-fold higher in men than women. Similar observation extends to susceptibility and outcome of most other infectious diseases. For instance, after initial Hepatitis C Virus infection women are 2-3 times more likely to spontaneously clear the virus without any interventions and in HIV infection females are 5 times more likely to achieve elite control (complete suppression virus without therapy) than men. However, a consequence of the more vigorous immune response observed in females is more immunopathology and auto-immune diseases (such as lupus) in women than men. For the same reasons, females make stronger immune responses to vaccines but suffer more adverse events. Despite large evidence for sex differences in autoimmune diseases and susceptibility and outcome of infectious diseases, data addressing the biological mechanism are remarkably scarce.

In this project you will use computational and experimental methods to probe differences in immune system that lead to sex differences in infectious diseases. We will investigate this question across many infections including HCV, HBV, HIV and COVID-19. You will start with analysing the available RNA-seq and genomic data from our cohorts and other public databases to understand the role of heterogeneity in X chromosome inactivation in female immune cells and the transcriptional consequence and its contribution to better outcome in infectious diseases. In the next stage you will stimulate male and female immune cells with different immunogens and perform single cell RNA-sequencing to evaluate differential responses across distinct cell types and their association with sex. The project will also use samples and data from vaccine clinical trials. The baseline samples will be compared to the post-vaccination samples and differences in immune systems between sexes will be investigated.

Genome-wide association studies (GWAS) aim to identify the genetic basis of phenotypic traits using the variation that exists within natural populations. Uniquely for infectious diseases, the inter-individual heterogeneity in disease phenotype is linked to both host and pathogen genetic variation. Traditionally, genetic studies of infectious diseases have sought to explain between-individual variation in disease phenotypes by assessing genetic factors separately in humans or pathogens, under the assumption that these factors are independent. Although reasonable for some variants, there is strong theoretical and empirical evidence that genetic interactions between host and viruses play a major role in viral disease aetiology.

In this project you will integrate host and viral genomic data from the same patients to better understand viral pathogenesis and between-individual heterogeneity in disease outcomes. By analysis of paired host-virus genomic data from well-characterised cohorts you will gain novel insights on (a) host polymorphisms linked with viral sequence variation, (b) virus sites under strong host genetic selective pressures, (c) host and virus genetic factors independently contributing to disease phenotypes and (d) host-virus genetic interactions contributing to disease phenotypes. The findings have the potential to: (I) revolutionize our understanding of host-virus interactions and human biology; (II) aid in development of more effective vaccines, drug targets and immunotherapies; and (III) permit better use of therapies through patient stratification. In the age of “Big Data” and “Personalised Medicine”, analysis of paired host-pathogen genomic data will become increasingly important to uncover the mechanisms driving pathogen adaptations and heterogeneity of infection outcomes.

The Higgins laboratory are expert in the structural studies of host-parasite interactions in parasitic diseases such as malaria. They study how interactions at the heart of processes such as erythrocyte invasion are mediated. They explore how parasite surface proteins manipulate the human immune system. They examine antibodies produced in response to human vaccination and determine how these function, and they use this information to design improved vaccine components.

To discuss possible projects, contact: matthew.higgins@bioch.ox.ac.uk

Our lab is interested in membrane-bound organelles- how they form and acquire their distinctive proteome essential to carry their specialized functions. In particular, we focus on how organelle function is maintained through quality control processes. Our lab has been particular interested in a quality control process termed ERAD, which targets misfolded membrane proteins in the endoplasmic reticulum (ER). While some of the components of this process have been identified, the mechanisms by which diverse range of misfolded proteins are selected, ubiquitinated, extracted from the ER membrane and targeted for degradation by the proteasome remain elusive. To gain insight on the mechanisms of protein quality control our lab is taking multidisciplinary approaches. We are using CRISPR-based genome-wide genetic screens to delineate the molecular pathways involved in the degradation of disease-relevant misfolded proteins. In parallel, we use biochemical, proteomics and structural approaches to dissect mechanistically the multiple steps of ERAD. These studies will reveal the molecular basis of quality control processes by which misfolded and aggregation-prone proteins are handled by the cell both under normal and pathological situations. We are also interested in inter-organelle communications- which and how molecules are exchanged between organelles, which signals regulate those exchanges, etc.  Although we do mostly basic research, we are interested how these processes are disrupted in human disease.

Patients with neurological diseases often have difficulty in evaluating, planning and initiating actions. This can lead to disorders of motivation, such as apathy and impulsivity. My group studies the cognitive neuroscience of goal-directed action, in the context of disease. Some patients have difficulty  evaluating a particular plan in a given context. For example, they might revert to habitual actions which were previously associated with reward, or may be unable to think beyond their current situation. We take a multimodal approach, with behavioural studies, eye tracking, drug studies in healthy people and patients, EEG and neuroimaging. I have also developed computational models – both in the form of abstract cognitive models, and neural network simulations, to understand what the brain computes when determining actions.

My group has found that dopamine plays an important role in energising goal-appropriate actions. We hypothesise that prefrontal goal representations act through corticostriatal loops, being amplified or attenuated by dopamine.  In this project, the student will study patients with Parkinson’s disease and the effects of dopaminergic drugs on cognition, together with neuroimaging (which can include MEG or fMRI), to understand goal-directed action selection and energisation. The student will design their own behavioural tasks to separate out the component processes involved in maintaining and using goal information to energise actions. The student will test patients on their task, test drug mechanisms using a within-subject neuroimaging design, and  deploy appropriate analysis methods with help from a postdoctoral researcher.   The project will also include the opportunity to learn computational modelling if the student is keen.

Inhibitors of DNA repair have emerged as powerful agents in cancer therapy, either as monotherapies that exploit synthetic lethal interactions between DNA repair pathways, or by increasing the efficacy of chemo- and radiotherapies. Principal in this strategy is inhibition of Poly(ADP-ribose)-polymerases (PARPs), enzymes that regulate DNA strand break repair, and PARP inhibitors (PARPi) are being used to treat tumours with defects in homologous recombination (HR). However, this strategy is restricted to treating ovarian cancers, with limited information on why PARPi are toxic to HR-defective cells, or additional synthetic lethal interactions that will broaden their application to treat other tumours.

By combining our expertise in PARP biology and DNA repair (e.g. Ronson, et al. Nat Commun 9: 746) with cutting edge genome editing, proteomics and cell biology, this project will address this fundamentally important question by characterising novel cancer-related genes that are synthetic lethal with PARP dysfunction. Through a genome-wide CRISPR-Cas9 screen, we identified a novel gene (PASL9) that is synthetic lethal with PARPi. Our data indicate PASL9 is critical to resolve replication-associated DNA damage through a mechanism that is mutated in colorectal cancers. Through multidisciplinary hypothesis-driven research, this research will: a) Define the nature of synthetic lethality between PARPs and PASL9; b) Establish the repair mechanism regulated by PASL9; c) Assess PASL9 as a target to treat colorectal cancer. These studies will define the mechanistic basis of how PARPs and PASL9 maintain genome stability and define novel strategies to exploit PARPi to treat a variety of tumours.

There are few examples of tractable overlaps between the fields of neurodegeneration and neuroimmunology. Yet, an immunological basis for a subset of patients with neurodegeneration would identify a group whose condition may be modified with the use of available immunotherapies. Dr Nath’s group have identified oligoclonal immunoglobulin bands in the cerebrospinal fluid of ~10% of patients with amyotrophic lateral sclerosis (ALS, also termed motor neuron disease). Further, endogenous retroviruses are observed to be activated in about 50% of ALS brains at autopsy. These observations mandate a search for the targets of the cerebrospinal fluid IgGs, to include retroviruses.

To identify antigenic targets, the DPhil candidate will use a variety of immunoassays established in both Dr Irani’s and Nath’s labs. These include B cell immunoglobulin heavy-light chain cloning, single cell RNA sequencing, western blotting, phage display screens and cell based assays.

In addition, these techniques will be applied to the cerebrospinal fluid of patients with Alzheimer’s disease to take an agnostic mass spectrometry based approach to identify antigenic targets of B cells and cerebrospinal fluid IgG in this cohort.

Overall, there will be excellent exposure to neuroimmunology and neuroinfection focused laboratories with the opportunity to learn multiple clinically applicable techniques to link common forms of neurodegeneration with a neuroinflammatory component.

The human brain is astonishing: it is the source of our thoughts, actions, memories, perceptions and emotions. It confers on us the abilities that make us human, while simultaneously making each of us unique. Through deepened knowledge and understanding of how human brain works, we will comprehend ourselves better and treat brain diseases more incisively. Over recent years, neuroscience has advanced to the level that we can envision spanning molecules, cells and neuronal circuits in action. In particular, there is an emerging view that subtle aspects of presynaptic dysfunction are implicated in an increasing number of brain disorders such as neurological and neurodegenerative diseases.

We are particularly interested in exocytosis, a process of vital importance for neuronal cells that is controlled by a set of both positive and negative regulators. While promotors of exocytosis are well studied, negative regulators are poorly understood. We discovered that a small SNARE protein amisyn (STXBP6) acts as a vertebrate-specific competitor of synaptobrevin-2, a key player in exocytosis. Amisyn contains an N-terminal pleckstrin homology domain that mediates its transient association with the plasma membrane by binding to phospholipid PI(4,5)P2. Both the pleckstrin homology and SNARE domains are needed to inhibit exocytosis. Of note, amisyn is poorly studied despite several studies have emphasized its importance for exocytosis and reported the occurrence of amisyn mutations in autism, diabetes and cancer.

This PhD project aims to study mechanisms of exocytosis with a focus on amisyn. The candidate will study how lack or impaired function of amisyn modulates exocytosis, synaptic transmission and behavior. We have generated a mouse model without amisyn to be employed for these studies. In addition, our collaborative team has expertise in a wide variety of interdisciplinary techniques to support and facilitate the proposed PhD project, such as biochemical, (electro)physiologal and life confocal microscopy techniques.

Forces are important in the cardiovascular system, acting as regulators of vascular physiology and pathology. Vascular endothelial cells are constantly exposed to mechanical forces, such as shear stress, due to the flowing blood. Patterns of blood flow depend on blood vessel geometry and type and can range from uniform blood flow (which is protective) to disturbed blood flow (which is pathologic). Although we know that endothelial cells can sense and respond differently to different types of flow, the mechanisms by which they sense and respond to blood flow remain a mystery. Our laboratory has pioneered the studies of endothelial mechano-sensing and has championed the use of a multi-disciplinary approach to this scientific problem. The focus of the proposed studentship is to identify mechanisms by which endothelial cells sense and respond to blood flow.  The student will have the opportunity to be exposed to a wide range of techniques based on the student’s individual interests that include: i) use of imaging and genetic approaches to characterize how mechano-sensing affects disease initiation and progression ; (2) applying high throughput RNA sequencing and proteomics approaches to globally dissect steps involved in disease etiology; 3) use of bioinformatics and biochemical experimental approaches to understand the role of blood flow forces in cardiovascular disease.

Humans and animals adjust their feeding behaviour according to many environmental factors, including the spatial context where food is found and consumed. Such contextual control of food seeking and eating is notably central to the ability to meet future needs and maximise chances of survival to changes in feeding routines, and may also impact abnormal feeding behaviour. However, the underpinning brain network mechanisms and pathways remain unclear. The Dupret laboratory (MRC Brain Network Dynamics Unit at the University of Oxford) investigates how the concerted spiking activity of neurons supports memory and the Krashes laboratory (NIH/NIDDK) investigates homeostatic and non-homeostatic feeding behaviour. An integrated project between the two labs, in collaboration with an NIH OxCam Scholar would be designed to enable the pursuit of a Ph.D. revealing circuit mechanisms of contextual control of feeding behaviour using in vivo large-scale network recordings in behaving rodents, combined with optogenetic and closed-loop manipulations.

This project will investigate mechanisms of assembly, secretion and immune subversion adopted by (+)RNA viruses, with a particular emphasis on Dengue/Zika from the flavivirus and SARS-CoV-2 from the coronavirus families. Current understanding on how small (+)RNA viruses assemble and spread from cell to cell while evading innate and cellular immune responses is limited. Virus-infected cells induce selective autophagy of lipid droplets, which is accompanied by massive reorganisation of the host secretory pathway, but downregulate MHC-I and II restricted antigen presentation and often interferon production.

We have identified host factors that are targeted by viral proteins to induce autophagy-mediated LD hydrolysis (lipophagy) and unconventional secretory processes1,2. Collectively they are crucial for formation of viral replication compartments, assembly and cell-to-cell spread of virus progenies. We will apply CRISPR/Cas9 gene editing technology combined with biochemical and cell biological methods and functional assays to investigate how specific genes affect virus assembly and secretion. 

Infection by Dengue/Zika and SARS-CoV-2 also results in dramatic reduction of MHC-I and II restricted antigen presentation in monocytes and monocyte-derived cells. We will address how these viruses subvert innate and cellular immune responses to drive pathogenesis3,4. We aim to delineate biosynthesis, assembly, transport and turnover of MHC-molecules to define the specific steps targeted by these viruses. We will test E3 ligase candidates that are induced and copurify with MHC-I and II from virus infected cells, that may degrade or mis-sort MHC molecules to evade host immunity. We will combine quantitative mass spectrometry with complementary approaches in biochemistry, cell biology, immunology and virology to investigate the interplay of host cellular pathways such as autophagy, with that of virus biogenesis, and their mode of host immune evasion.

Preeclampsia is a multi-system hypertensive disorder of pregnancy that is caused by placental dysfunction.  The placenta releases extracellular vesicles (EVs) into the maternal circulation from early pregnancy all the way to term as part of its normal function. These EVs have proteins on the surface and contain genetic cargo, capable of altering maternal cellular function. It is known that the release, protein and genetic content of EVs is altered in preeclampsia. We have optimised an ex-vivo placental perfusion technique that permits isolation of trophoblast EVs. We have isolated EVs from normal and preeclampsia subjected these to proteomic and sequencing analysis. It is apparent that there are significant differences in miRNA and other non-coding RNA between EVs from normal and PE placentae. These differences have been validated by RT-PCR. We now wish to investigate the downstream cellular effects of the miRNAs/non-coding sequences, in cell models (endothelial, hepatic etc.) using transfected HEK293 cells. KEK293 cells constitutively produce exosomes. The transfected HEK293 cell will produce exosomes enriched for the RNA species of interest and allow specific miRNA effects to be determined using deep sequencing and proteomics analyses of the target cell. Analysis will require the candidate to be trained in bioinformatics approaches.

Simultaneously, we will interrogate a cohort of clinical samples for circulating miRNAs and investigate their role as a potential biomarker of placental function/disease. The NDWRH sits within the Women’s Centre at the John Radcliffe hospital and delivers 8000 women per year. 

We have been studying the mechanism of gating in the Two-Pore Domain (K2P) family of K+ channels and the way in which their gating can be regulated by lipids and small molecules.  It is now clear these channels use a variety of structural mechanisms to open and close their pores, including changes within the selectivity filter itself.  This mechanism of filter gating is also known to occur in other members of this superfamily of tetrameric cation channels including the BK Calcium-activated K+ channel and Cyclic Nucleotide Gated (CNG) channels.  In the proposed project the student would have the opportunity to combine multiple different biophysical, computational, and functional approaches to investigate the structural mechanisms of filter gating in these channels and investigate what properties might be common amongst these channels.

Maintaining genome integrity through DNA repair is critical for human health and defects in these pathways result in cancer, neurodegeneration and premature ageing. Understanding DNA repair mechanisms will provide insights into the underlying causes of these conditions and strategies for their treatment. For example, inhibitors of Poly(ADP-ribose) polymerases (PARPs), enzymes that regulate DNA strand break repair, are used to treat DNA repair deficient tumours, with the potential to treat other malignancies.

However, despite the use of PARP inhibitors in the clinic, the substrates modified by these enzymes and how they regulate DNA repair are ill-defined. For example, although histones are targets for ADP-ribosylation (ADPr) following DNA damage, how this regulates genome stability either directly, or through competition with other histone post-translational modifications (PTMs) is unclear.  This, in part, is due to the absence of an experimental platform in which PARPs and histone ADPr sites can be manipulated in tandem. These criteria are met in the eukaryotic model organism Dictyostelium and we have identified histone ADPr sites modified in response to DNA damage in this organism. We will exploit the unique ability to introduce site-specific ADPr mutations into endogenous Dictyostelium histone genes to define how ADPr regulates DNA repair either directly, or through influencing other histone PTMs. We will identify novel proteins that specifically interact with ADPr histones and characterise these factors in human cells. Together, this work will uncover how cells maintain genome integrity that will inform novel strategies to refine the use of PARP inhibitors in the clinic.