Research Opportunities

Intracellular complement (the complosome) emerges as key regulator of key cell metabolic pathways in a range of (immune) cells. In consequence, perturbations in complosome activity contribute to human disease states, including recurrent infections and autoimmunity. Recent data also indicate that high complosome expression is the defining feature of tissue-resident immune cells including T cells and macrophages. In this project, we will combine pertinent mouse models and intravital imaging to address the role of the complosome in maintaining residency and sustaining function crosstalk between immune and parenchymal cells in tissues (lung/kidney/brain?) during normal homeostasis and in disease (which one?).

It is well recognized that acquired genetic mutations are an important cause of cancer, but recent studies have suggested that such somatic mutations are also associated with atherosclerosis. Somatic mutations have been found in blood from 10% of people over 70 years of age and 20% of people over 90 years of age and appear associated with an increased risk of atherosclerotic disease. Although age is a known independent risk factor for atherosclerosis, the basis for this has not been known.  It now appears likely that these mutations, several of which are found in genes known to regulate inflammation and immunity, are either a direct contributor to, or a potential biomarker for, this age-associated risk. The challenge now is to identify molecular mechanisms linking these somatic mutations with atherosclerosis.

This PhD project will investigate the cellular and molecular basis of the association between age associated DNA mutations and atherosclerotic disease risk. To do this will require cross-disciplinary collaboration, so this project brings together two highly complementary groups to address this important new biomedical challenge. At the National Heart, Lung and Blood Institute of the NIH, Chris Hourigan works on these acquired mutations in the context of a blood cancer called acute myeloid leukemia. At Oxford, Chris O’Callaghan works on molecular mechanisms involved in atherosclerosis and the genetic control of those mechanisms, especially in vessel wall inflammation.

This is a very exciting new field and has potential to identify new drug targets and so benefit patients with atherosclerosis. The experience gained by this doctorate will be highly relevant to other fields and will include cellular and molecular biology, high throughput sequencing approaches including single cell approaches and analysis of genetic variation.

*This project is available for the 2021 Oxford-NIH Pilot Programme*

This project would be to extend a long standing and productive collaboration between the Kukura lab at Oxford and the Sellers lab at NIH.  The specialty of the Kukura lab is in the development of light microscopic approaches to study novel biological processes with high temporal and spatial resolution.  The strength of the Sellers lab is in the production and characterization of myosins using various biochemical and biophysical approaches.

Neurons are specially shaped cells that have an extremely polarized structure. They contain protrusions called dendrites and a long axon extending from cell body that connect to neighbouring cells forming a neural network. Axons and dendrites retain a dynamic plasticity throughout the whole lifespan of a neuron to ensure the ability to adjust and adapt neural network connections.  The polarity and plasticity of neurons is maintained by a cytoskeleton of actin filaments and microtubules together with associated motors and other essential proteins.

This PhD project aims to elucidate the molecular organization of axons and dendrites using in situ cryo-electron tomography (cryo-ET) of primary neurons.  We will address how cytoskeletal filaments and motors drive the branching, elongation and neural network formation. To this end we form a strong collaboration between the lab of Andrew Carter at the Laboratory of Molecular Biology (LMB), Cambridge University and Mizuno Naoko at the National Heart, Lung and Blood Institute at NIH. Mizuno’s lab’s expertise is visualizing cell shape formations controlled by remodelling of cytoskeleton and the Carter lab has a long-standing interest in how trafficking is carried out by cytoskeletal motors.

Cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) bridge the resolution gap between light-microscopy and conventional structural methods for gaining information on a molecular level (X-ray crystallography/NMR).  Current technical developments further facilitate in-depth analysis of cells on a molecular level that has not been possible before. The skillset obtained in this PhD project will be highly relevant to the field of newly emerging structural cell biology.

The formation of neural network is essential for building a nerve system and to maintain its dynamic function. Neuronal cells extend their axons to connect to dendrites of partner neurons. The process is facilitated by axonal migration and controlled by the balance of the search for partner neurons vs the locking of axon-dendrite connections. This balance is maintained by two signaling pathways relying on the integrin receptor (mode of neurite migration) and the semaphorin receptor (mode of axon-dendrite locking). The inter-regulation between both pathways is mediated by the intracellular signaling factor Rap1. However, the mechanism of this interconnection is unknown.

This PhD project aims to elucidate the nature of this crosstalk using a bottom-up reconstitution of integrin, semaphorin and Rap1 by developing a cell-surface mimicking membrane system. We aim to establish a functional membrane system that allows us to control the two modes, i.e. attachment/detachment of two neighboring membranes representing dendrite and axon connections. The uniqueness of the project lies in the exact control of communication through membranes by the bottom-up strategy, which would be otherwise extremely challenging to elucidate. Moreover, the system will allow us to probe receptor interactions using biophysical, light microscopic as well as cryo-EM methods to understand the underlying principles of neural network formation and neuronal regeneration.

Our collaborative team has expertise in a wide variety of interdisciplinary techniques to facilitate the proposed PhD research, such as X-ray crystallography, cryo-EM, biophysical analysis, membrane biology and light microscopy. Mizuno lab is leading in the use of cryo-EM in combination with cellular methods to visualize cell shape formations controlled by the integrin signaling pathway and the remodeling of cytoskeleton components. Jones lab has a long-standing interest in axon guidance and structural biology of membrane proteins. Yvonne Jones co-heads the Structural Biology Division of the Wellcome Centre for Human Genetics at the University of Oxford.

This project will give a candidate a tremendous opportunity to apply cutting-edge in vitro reconstitution methods in the field of structural- and neuro- biology.

Hibernation confers extraordinary protection against various forms of stress and insults that would be life-threatening to non-hibernators. However, the mechanisms of such promising protection remain elusive, hindering potential therapeutic applications. One of the hallmarks of hibernation is metabolic regulation, exemplified by modifications in mitochondrial respiration throughout the different stages of hibernation. Nonetheless, the possible link between metabolic regulation and cellular protection is unclear.  This project aims to study the mitochondrial regulations and their roles in metabolic adaptation during hibernation, in the context of neuroprotection.

Age-related macular degeneration (AMD) is one of the leading causes of blindness among the elderly affecting over 30 million individuals world-wide. AMD initiates in the back of the eye because of dysfunctions in the retinal pigment epithelium (RPE), a monolayer of cells that maintains vision through maintenance of photoreceptor healthy and integrity. AMD can lead to severe vision loss and blindness in advanced stages – “dry” and “wet” forms. In the dry stage, the death of RPE cells triggers photoreceptor cell death and atrophy of the choroidal blood supply causing vision loss. It is thought that RPE cell death in AMD is triggered by the formation of sub-RPE protein/lipid deposits called drusen. Our recent work shows that drusen formation is initiated by reduced autophagic flux in RPE cells resulting in reduced ability of RPE cells to process intracellular “debris” that eventually gets secreted as drusen deposits. TFEB, a member of MiT family of transcription factors is a known master regulator of autophagy. Here, we propose to investigate the activity of transcription factor TEFB in our AMD cellular models of iPSC-derived RPE cells. We hypothesize that autophagy downregulation is triggered by post-translational changes in TFEB that affect its sub-cellular localization and reduce its transcriptional activity. Here, we propose to identify those changes in TEFB and discover signaling pathways that lead to its altered activity. Lastly, we will test the ability of our recently discovered FDA-approved drugs that stimulate TEFB activity to reduce drusen formation by increasing autophagy in iPSC-RPE AMD models. This work will lead to a better understanding of AMD pathogenesis and potentially retool existing  drugs to treat AMD patients.

The BL research is organized into four focus areas: a) epidemiology; b) infections; c) genetics, and d) tumor studies. The epidemiological studies seek to characterize the macro- and micro-geographical and spatial-temporal  patterns of endemic Burkitt lymphoma to generate new hypotheses about environmental risk factors. The infection focus seek to discover infection-related biomarkers of risk, focusing on unique serological profiles or discovery of high-risk genetic variants for EBV or Pf infection associated with eBL risk. The genetic studies (GWAS, exome, HLA) provide a powerful approach to complement questionnaire and serological methods with less concern for measurement error, reverse causality, and imperfect correlation with biology to disentangle the genetic architecture of eBL risk.  Finally, BL is a molecular disease with identifiable molecular sub-groups. The EMBLEM study provides an opportunity to collaborate with others on studies to develop a blood-based assay for BL diagnosis and molecular characterization. Students will be given the opportunity to spend time in East Africa with collaborating partners to be involved with data and sample collections.

The primary goals of EMBLEM are to investigate:

a) risk factors of BL in endemic populations in East Africa;

b) EBV and Pf immuno-profiles and other biomarkers associated with BL;

c) molecular characteristics of BL tumor genomes, B-cell receptor, and EBV variants; and

d) germline risk factors of BL using genome-wide association studies (GWAS) and exome sequencing

e) the association between BL and human leukocyte antigen (HLA) class I and II loci.

The tumour suppressor p53 is encoded by the most mutated gene in human cancers and there is extensive knowledge of its vital role in tumour suppression. However, the contribution of p53 to immune surveillance is less well understood. Cancer initiation and progression is influenced by inflammation, and it is increasingly important to understand interactions between inflammatory and tumourigenic pathways to improve cancer prevention and patient responses to immunotherapy. p53 activity is known to intersect with key inflammatory signalling pathways, including NFB, AP1, MAPK and JAK/STAT, suggesting p53 could have a pivotal role in immune surveillance. To expand knowledge in this important area, this project will investigate crosstalk between the p53 pathway and inflammation.

The project will use cutting edge technologies, including ex vivo 3D organoid co-culture models, to study interactions between cancer-initiating epithelial cells and immune cells. It will also harness recent advances in RNA-sequencing, single cell analysis and ChIP-sequencing, as well as a broad range of molecular cell biology techniques, to address the crosstalk between p53 and inflammation. The student will be able to leverage access to expertise and clinical samples in chronic inflammatory conditions – such as Barrett’s Oesophagus – that predispose patients to cancer. Oesophageal cancer and stomach cancer may be used as exemplar cancer types; these cancers have important unmet clinical needs and strong links to inflammation. This project may also extend to crosstalk of p53 with the immune system, such as in the context of immunotherapy for cancer: an emerging therapeutic strategy that is showing great success in some patients. The study will offer exciting opportunities to understand the details of the relationship between p53 and inflammation, which will be crucial for developing new approaches for early intervention to prevent cancer progression and for understanding responses to therapy.

In order to maintain homeostasis in response to environmental changes such as nutrient availability, eukaryotic cells have evolved intricate mechanisms to quickly increase or decrease the activity of fundamental processes such as gene expression, protein expression and degradation. Indeed, several metabolites act as cofactors for important cellular enzymes that regulate e.g. chromatin state and serve as templates for posttranslational modifications flagging proteins for proteolysis via the ubiquitin-proteasome system. Consequently, the identification of metabolites and complementary binding domains has broadened our understanding of human physiology and contributed to the development of new medicines to treat malignant and inflammatory disease. The aim of this project is to systematically map protein-metabolite interactions on a proteome-wide scale by combining the development of specific metabolite-inspired affinity reagents with unbiased approaches such as thermal profiling to dissect metabolite signalling in the context of protein degradation pathways in various cell types. Applicants will have the opportunity to take advantage of a unique combination of synthetic organic chemistry and cell biology techniques to identify new potential drug targets and develop first-in-class ligands for key regulators of protein homeostasis.