Research Opportunities

This collaboration between the Altan-Bonnet (NCI), Buckley and Coles (Oxford) labs addresses how organs generate distinct inflammatory responses despite sharing common components like immune cells, fibroblasts, and the extracellular matrix. In collaboration with additional teams from the Netherlands, and Canada, we aim to uncover the molecular, cellular, and tissue-level rules governing organ-specific inflammation.

We hypothesize that (1) organ context and cellular experience shape the perception of inflammatory signals, and (2) organ-specific hierarchies integrate responses into coordinated outcomes. Using a data-driven approach, we will combine ex vivo and in silico models of mouse and human tissues to explore these mechanisms. High-throughput robotics will generate diverse tissue models with varying sensitivities to infection or immunopathology. Multimodal datasets from these models will be analyzed using machine learning to build computational models, to guide iterative cycles of discovery.

This project will revolutionize tissue biology by creating a unified framework for understanding tissue-specific inflammation, paving the way for new treatments. We are seeking researchers with expertise in bioengineering, computer science, or immunology to join this interdisciplinary effort.

Project keywords: immunology, systems biology, biomedical engineering. 

Population-based cohorts have identified major modifiable risk factors for cardio-metabolic diseases, such as adiposity and physical activity, but the patterns and relevance of these factors varies greatly across populations, and previous evidence is predominantly from high-income countries. There is a high burden of cardio-metabolic diseases in South and Southeast Asian populations. However, the underlying mechanisms are yet to be fully elucidated, with previous evidence suggesting ethnically divergent body fat and muscle mass distribution to be a determining factor. Furthermore, physical activity has a complex relationship with body composition, and different patterns of physical activity between high- and low-/middle-income countries and between urban and rural areas might be an independent or explanatory factor in associations with cardio-metabolic diseases.

The objectives of this DPhil project may be to explore associations between different measures of body composition with objective measures of physical activity between populations and their individual and joint associations with cardio-metabolic diseases across different ethnicities, using data from different large-scale prospective studies. 

This project will use data from three large prospective studies: the Indian Study of Healthy Ageing (ISHA), the Malaysian Cohort, and the South and Southeast Asian participants of the UK Biobank. It will provide unique opportunity for novel insights into disease risks and aetiology to inform global non-communicable disease control and prevention efforts, and the student will have the chance to work collaboratively across the Global Populations Studies Group led by Prof Sarah Lewington, the Oxford Wearables group led by Prof Aiden Doherty, and the Oxford Centre for Diabetes, Endocrinology and Metabolism led by Prof Fredrik Karpe.

Our research group aims to understand unique patterns of hypertensive end organ disease progression of women and their children following a hypertensive pregnancy. This information is used to develop personalised clinical tools to identify, track, and slow end organ disease to prevent early onset cardiac, cerebral and vascular disease in these families.

This project will make use of information from computational modelling to study disease progression related to a hypertensive pregnancy across multiple modalities and organs. The insights into key structural and functional changes at the organ-level that describe stages of disease will be used to help identify potential targeted intervention.

The project will make use of a collection of unique imaging and clinical datasets from clinical trials and observational studies in families with a hypertensive pregnancy history. Furthermore, our clinical trials help us understand how interventions modify the underlying disease development.

Potential areas for a PhD project include: 

• Artificial intelligence - Application of artificial intelligence and machine learning to large research imaging datasets to improve the clinical tools already available to identify those at risk, and to identify next generation imaging and management approaches.
   
• Novel markers of early disease - Using imaging and laboratory studies to identify early cardiac and vascular changes in young people at risk of cardiovascular disease.
   
• Young adult cardiovascular prevention trials - Running trials to understand how novel approaches to lifestyle and clinical management may be able to modify these early risk cardiovascular phenotypes to prevent the development of later disease. 

We are interested in understanding how cellular identity is propagated as cells divide. Using advanced flow cytometry combined with mass spectrometry1,2, we have been able to isolate and purify individual mitotic chromosomes from different species (human, mouse and fly) and comprehensively profile the proteins and RNAs that remain chromosome-associated during mitosis. We have also prospectively isolated the active and inactive X metaphase chromosomes from female cells and identified novel factors likely to be important for maintaining their distinctive states3. Although many proteins are evicted from condensing chromosomes, our studies have shown that approximately 10% remain chromosome-associated throughout mitosis1,4. These include specific DNA-binding factors, chromatin repressor complexes, DNA methylation machinery and SMC family proteins. To assess their importance for chromosome structure and epigenetic inheritance, we are systematically degrading or cleaving individual factors in metaphase and examining the biophysical, structural and molecular consequences of this using optical tweezers and Cryo-ET approaches as well as analysing nascent RNA expression in postmitotic cells. These studies bring together expertise in several fields to decipher, at a mechanistic level, how epigenetic memory is propagated. In addition, as the approaches we are developing enable native (unfixed) human chromosomes to be individually isolated and studied ex vivo, we will investigate how disease-associated chromosomal translocations impact mitotic bookmarking and genome stability.

References

1. Djeghloul et al., 2020 Nat Commun. 11, 4118. 
2. Djeghloul et al., 2023 Nat Struct Mol Biol 30, 489.
3. Djeghloul et al.,Research Square https://doi.org/10.21203/rs.3.rs-4687808/v1
4. Dimond et al.,bioRxiv https://doi.org/10.1101/2024.04.23.590758

Immune surveillance plays a formidable role in eliminating cancer cells. At the centre of this process lies an interaction between the T cell receptor (TCR) in T cells and peptides presented by the major histocompatibility complex (pMHC). The biochemical and structural properties that underpin the TCR/pMHC interaction dictate the fate of infected or cancer cells. However, the rules that govern TCR specificity and sensitivity remain unknown. 

We aim to apply cryoEM and cryo-electron tomography (cryoET) including in situ structural studies to determine the structural fingerprints associated with productive TCR/pMHC interactions. We have recently made crucial technical advances in determining the structures of native unmodified TCR/pMHC complexes derived from SARS-CoV-2 infection, which had been intractable due to their intrinsic flexibility and innate low affinity. A robust cryoEM structure pipeline has thus been established for elucidating tumour-reactive TCRs in complex with natural cancer pMHCs. We will examine conserved features and differences among complexes to understand the observed specificity, sensitivity and binding affinity of TCRs recognising cancer antigens. We will also determine the complete, native TCR/CD3 and pMHC complexes from opposing membranes as they are in the immunological synapse formed between the T cell and target cancer cell using in situ cryoET.

These structures will reveal mechanisms underpinning the specificity and affinity for each TCR/pMHC pair and common shared interfaces. Such structural information will make critical contributions to the selection of TCRs for the deployment of robust and safe TCR-based immunotherapies

Human immunodeficiency virus type 1 (HIV-1) is the causative agent behind acquired immunodeficiency syndrome (AIDS) that currently has no cure or vaccine. While antiviral treatments are effective, the rise of drug-resistant strains has become a growing concern. HIV-1 primarily infects the immune system, targeting CD4+ T cells and macrophages and is a lentivirus known to be able to infect non-dividing cells, requiring it to exploit nuclear import mechanisms. This process is dependent on the viral capsid. The HIV capsid is a conical structure that houses the genomic material of the virus. It needs to be metastable in order to be protective while allowing timely disassembly (termed uncoating) to release its genome. The dynamics of the capsid nuclear import and uncoating are still unknown and are modulated by host dependency and restriction factors.

We aim to apply multi-imaging modalities to investigate uncoating and nuclear import of HIV. These will include super-resolution fluorescence microscopy (including the newest MINFLUX technology), Focused Ion Beam and Scanning electron microscopy (cryoFIB/SEM), cryo-electron microscopy and cryo-electron tomography (cryoEM/ET). The viral core and host factors will be fluorescently tagged, and infection will be monitored from viral attachment to nuclear import. The sample will be cryo-preserved and imaged by cryoEM/ET and cryoFIB/SEM. The combination of these imaging techniques, paired with molecular biology and virology tools, will yield unparalleled knowledge of the HIV infection process within the native cells, providing the framework for development of novel therapeutics targeting HIV infection in the future.

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 mechanosensing 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: 
1) use of imaging and genetic approaches to characterize how mechanosensing affects disease intitiation and progression ; 
2) applying high throughput RNA sequencing and proteomics approaches to globally dissect steps involved in disease aetiology; and 
3) use of bioinformatics and biochemical experimental approaches to understand the role of blood flow forces in cardiovascular disease.

Reference:
Mehta V, Pang K, Rozbesky D, Nather K, Keen A, Lachowski D, Kong Y, Karia D, Ameismeier M, Huang J, Fang Y, Hernandez A, Reader JS, Jones EY, Tzima E. The Guidance Receptor Plexin D1 moonlights as an endothelial mechanosensor.2020 Nature Feb 5. https://pubmed.ncbi.nlm.nih.gov/32025034/

Ribosomes are fascinating protein-making factories. Ribosomes and the entourage of associated factors are responsible for translating the genetic information encoded within mRNA into amino acid sequences joined together to make proteins. Surprisingly, components of the ribosomal machinery have been recently discovered to have additional roles in eukaryotic cells, including regulation of endothelial cell health. Work from our group has identified a strong genetic link between a ribosomal factor and cardiovascular disease but we do not understand how this works. How do ribosomes regulate endothelial cell health and protection from disease? What is the connection between faulty ribosomes and cardiovascular disease? These are some of the fundamental questions that this project will tackle. Our ultimate goal is to identify novel players in cardiovascular disease and design new therapies that target these pathways.

The student will have the opportunity to be exposed to a wide range of techniques based on the student’s individual interests. The student will be supervised on a daily basis by a postdoctoral fellow and will be trained in cell culture, siRNA/CRISPR techniques, protein gels and western blotting, ribosomal and polysome profiling, subcellular fractionation, molecular cloning, confocal microscopy, protein structure analysis, and bioinformatics. 

Understanding eukaryotic replication is important, because during our lifetimes we copy approximately a lightyear’s worth of DNA, and how the different components of the molecular machinery (the replisome) work together to achieve this successfully is an area of highly active research.  In our lab, we take on the exciting challenge of understanding the dynamics of DNA replication of this process by studying the activity of eukaryotic replisome at the single-molecule level on both bare DNA and chromatin.

In this PhD project, you will learn a diverse set of techniques (synthesizing DNA constructs, purifying proteins, state-of-the-art single-molecule microscopy and measurements, in-depth quantitative analysis) and work together with others in an interdisciplinary team comprised of biologists, (bio)physicists, biochemists, and data scientists.  You will be taught how to perform high-quality experiments and then you will be invited to develop new ones of your own, making use of your training and insights! This research, carried out together with collaborators at the University of Oxford, the Francis Crick Institute, the Hubrecht Institute, and elsewhere, should lead to new discoveries and insights that inform our quantitative understanding of DNA replication and advance this exciting field while contributing to the next generation of in vitro single-molecule methods.   

Understanding the role of transposable elements as gene regulators is important, because they make up 50% of the genome, but are relatively understudied in comparison to genes which make up 2% of the genome. In our lab, we take on the exciting challenge of understanding the role of locus-specific Transposable elements as regulators of gene expression in development by studying the activity of transposable elements in single cells using our unique method CELLO-seq using long read sequencing. 

In this PhD project, you will learn a diverse set of techniques (CRISPR, embryonic stem cell cultures, third generation sequencing technologies and in-depth quantitative analysis) and work together with others in an team comprised of molecular biologists, developmental biologists, biochemists, and data scientists.  We will teach you how to perform high-quality science and design your own experiments to develop your own project and make use of the training you received. This research, carried out together with collaborators at the University of Oxford, the University of Edinburgh, and elsewhere, should lead to new discoveries and insights that inform our quantitative understanding of locus-specific transposable elements as new regulators of gene expression in development. These discoveries will advance this novel exciting field while contributing to the next generation of single cell long read methods.   

Asthma is the world’s most common chronic lung disease. It is increasing rapidly in incidence, but it is not known why. It arises from the complex interplay of genetic predispositions and the influence of environmental factors early in life, particularly early life infections with bacteria like haemophilus influenzae and with viruses like respiratory syncytial virus (RSV), and this points strongly to epigenetic changes being induced in the airway epithelium. 

It has been previously hard to decipher these mechanisms, but that is now becoming possible due to the ability to obtain direct airway samples at bronchoscopy and via nasal brushings and importantly the advent of technologies allowing analysis of epigenetics on small tissue samples and even at a single cell level.

We have generated large epigenetic and immunological datasets of airway epithelium and bronchial biopsies at single cell resolution. We also have DNA methylation data from a large paediatric cohort with early life RSV. We have developed a murine model of long-term infection with haemophilus influenzae and so, for the first time, can model the interactions and consequences of early life bacterial / viral coinfection.

We aim to exploit these datasets and models to understand in detail the specific immunoepigenetic changes in asthma and early life infection in mice and humans with a view to developing targeted epigenetic therapies. 

Infections pose a major risk to health globally. Antimicrobial resistance (AMR) threatens effective treatment of infection and healthcare associated infections (HCAIs) impact more than 10% of all hospital patients.

Advances in data availability and new artificial intelligence (AI) methods offer the chance to develop:
 

• More responsive, comprehensive, and automated HCAI/AMR surveillance generating better breadth and depth of intelligence to drive action and changes in practice to protect diverse populations at local, regional, and national levels.
• Predictive tools to improve care of individual patients and combat AMR.
• Methods, infrastructure and skills to optimally use rapidly-evolving electronic healthcare record and patient-contributed data, and emerging AI technologies. 

Several possible projects are available, including:
 

• Developing/testing automated electronic surveillance approaches for rapidly detecting changes in infections and identifying at-risk populations; and deploying these tools in hospitals and national systems
• Extending and piloting in hospitals predictions of personal AMR risk to optimise infection treatment, prevention and control, developing generalisable methods that can update over time/to new locations, and approaches for safely implementing them
• Pre-emptive surveillance, investigating which metrics of hospital processes (e.g. isolation/screening/diagnostic use/cleaning) are associated with HCAI/AMR to inform prevention

Our lab is interested in unconventional and innate-like cells (such as MAIT cells) and what their role is in immune protection and pathology.Tmic cells are one such cell - a recently described subset of T helper cells which are Microbially reactive, Innnate-like and Class II restricted. These cells are abundant in the human colon and marked out by high expression of CD161 – a feature normally associated with unconventional T cells – along with other evolving markers. However, as well as behaving like innate-like cells they bear conventional TCRs and are restricted by MHC Class II. They are also found in mice where they adopt a double negative phenotype over time in response to gut commensals. We think these cells are important in gut homeostasis (also other organs potentially) and we have shown they are involved in inflammation, but there are many questions as to their origin and overall functionality to be answered.

This project would explore the development of these cells using CBIR mice which over-express a commensal-reactive TCR, first by scRNASeq and scATACseq to define the steps along the pathway from conventional tissue memory to Tmic phenotype. Secondly using spatial transcriptomic methods to define their colocalization in the steady state and after challenge. Finally we will use a new in vivo CRISPR screen method (CHIME) to define the critical steps in development of Tmics and explore their functions in vivo. We will aim to compare mouse and human Tmic populations to define this novel conserved cell population and explore its role in health and disease.

Reference: https://www.nature.com/articles/s41467-022-35126-3

Serum Amyloid A-1 (SAA-1), a crucial acute-phase protein, is significantly upregulated during inflammation, associating with high-density lipoprotein (HDL) and modulating immune responses and tissue repair. Elevated SAA-1, however, is implicated in chronic inflammatory diseases and neurodegenerative conditions. This project investigates the role of SAA-1 in neuroinflammation and cognitive deficits following traumatic brain injury (TBI), particularly in Alzheimer’s-like pathology. We will use targeted siRNA within liposomes to selectively inhibit hepatic SAA-1 production, isolating peripheral SAA-1 effects on neuroinflammatory markers and behavior in TBI models. Parallel experiments will use adeno-associated viral vectors to knock down brain-derived SAA-1, assessing neuroinflammation and behavior to differentiate peripheral versus central SAA-1 contributions. Additionally, we will combine both liver and brain-specific knockdowns to evaluate potential synergistic effects in mitigating neuroinflammatory damage. Complementary studies will track exogenous, radiolabelled SAA-1-HDL complexes crossing the blood-brain barrier to elucidate SAA-1’s brain entry mechanisms and impact on neuroinflammation. This project aims to clarify SAA-1’s contributions to delirium post-TBI, potentially guiding targeted interventions to mitigate neurocognitive symptoms.

Radiotherapy (RT) treatment plays a key role in the management of many solid tumours and involves the precise delivery of high energy X-rays to localised tumours. In the curative setting, treatment can be used alone, or in combination with chemotherapy or immunotherapy. Although technological improvements have enabled the ability to deliver novel, highly effective RT treatments such as stereotactic ablative body radiotherapy (SABR), there is no approach that is able to fully spare healthy tissues from receiving some radiotherapy, often leading to significant side-effects. Obtaining greater tumour control by simply increasing the delivered dose is therefore not an adequate solution. A more tractable approach is to develop treatments which selectively render tumours more sensitive to radiation without exerting an effect on normal tissues. Our group have previously conducted high-throughput compound and genetic screens to identify novel, clinically translatable targets and compounds to specifically render tumours more sensitive to radiation. This project aims to characterise these potential therapeutic targets and develop novel therapeutic approaches against these targets. Our ultimate goal is to translate our laboratory findings into clinical trials.