Research Opportunities

Synaptic plasticity is fundamental to nervous system development and function.  Our labs have been studying BMP and reactive oxygen species (ROS) signalling as key regulators of synapse development, growth and plasticity. For example, during critical periods of nervous system development, metabolic ROS generated in mitochondria specify the functional ‘baseline’, including through setting the size and composition of synaptic terminals. The mechanisms by which this is achieved can now be explored. Specifically, we are now investigating:
 -    novel facets of BMP signalling, and their roles in regulating synapse size, composition and transmission properties;
 -    how transient critical period experiences in the late embryo lead to dramatic, lasting changes in gene expression and neuronal function.  

This project will combine biochemical and genetic approaches with electrophysiology and methods for high-end imaging. We expect this project to redefine our understanding of how multiple signalling pathways, working at different time scales and regulating distinct elements of plasticity, integrate at the synapse.

Potential subprojects include: Extending methods for pangenome annotation and analysis to eukaryotic pathogens (e.g. https://www.biorxiv.org/content/10.1101/2023.01.24.524926v1).

Developing adaptive sampling and hybrid enrichment techniques for pathogen/bacteria/host sequencing (see https://www.nature.com/articles/s41587-022-01580-z.)  

Linking strain/variant transmission with pathogen
genetic determinants and host epidemiology. (see: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8552050/ and https://www.science.org/doi/full/10.1126/scitranslmed.abg4262)

There is an unmet need for repair following injury in humans, particularly in the brain where endogenous stem cell activity is minimal. An understanding of neural progenitor diversity and flexibility in their fate choices is crucial for understanding how complex organs like the brain are generated or undergo repair. The neonatal mouse cerebellum is a powerful model system to uncover regenerative responses due to its high regenerative potential.   We have previously shown that the cerebellum can recover from the loss of at least two types of neurons via distinct regenerative mechanisms (Wojcinski, 2017; Bayin, 2018; Bayin, 2021). In one case, a subpopulation of the nestin-expressing progenitors (NEPs) that normally generate astroglia undergoes adaptive reprogramming and replenishes the lost neurons. However, the molecular and cellular mechanisms that regulate neonatal cerebellar development and adaptive reprogramming of NEPs upon injury are unknown.   Interestingly, the regenerative potential of the cerebellum decreases once development ends, despite the presence of NEP-like cells in the adult cerebellum that respond to cerebellar injury by increasing their numbers. However, neuron production is blocked. We hypothesize that the lack of regeneration is due to a lack of pro-regenerative developmental signals in the adult brain in addition to epigenetic silencing of stem cell differentiation programs and inhibitory cellular mechanisms as development is completed.  

Our lab is interested in answering two overarching questions:  
1)    What are the cellular and molecular mechanisms that enable regeneration in the neonates and inhibit in the adult?
2)    Can we facilitate regeneration in the brain?  

This project involves interdisciplinary approaches ranging from in vivo mouse genetics, in vitro modelling and stem cell assays, and single cell and other genomics technologies. Our system allows us to interrogate fundamental stem cell biology questions in a systematic manner and unravel the molecular mechanisms that govern neural stem cells during development, homeostasis and upon injury. The student taking on this project benefit from our multidisciplinary approach and participate in our collaborative work locally and internationally.

The student will take a clinical informatics or bioinformatics approach to investigate causes and/or outcomes in mental disorder and/or related brain phenotypes. This could involve using GWAS summary statistics for metabolomics, genomics and proteomics and relating these to mental disorder and /or brain phenotypes, using techniques such as statistical genomics and mendelian randomisation. It could also or alternatively involve clinical data from electronic health records, in combination with biomarker data,, with a focus on psychosis and/or depression and possible relation to physical health (cardio-metabolic or immune mechanisms).

Extensive work from the Blouet lab has recently characterised the high level of myelin plasticity in the median eminence (ME), with rapid local turnover of myelin in healthy adult rodents. The ME is a region of the hypothalamus essential for various homeostatic functions, neuroendocrine output and energy balance regulation. Both weight loss, achieved through caloric restriction, and weight gain, obtained by feeding with a high fat diet, reduce ME myelin turnover, leading to local hypo- or hypermyelination, respectively. However, the contribution of changes in ME myelin plasticity and myelination to the behavioural, metabolic, or neuroendocrine adaptations engaged during energetic challenges remains unclear and how these adaptations might be impaired in aging is unknown. Investigating whether similar changes occur in humans requires novel strategies to image ME myelin in vivo in humans with high resolution and sensitivity. In this project, we propose to develop advanced magnetic resonance imaging (MRI) methodologies to perform longitudinal quantifications of ME myelination in young or aged rodents exposed to a variety of genetic or environmental perturbations modifying energy balance and adult myelin plasticity. We will also translate protocols to image and quantify ME myelin in human participants and determine the effect of age and variations across the spectrum of body mass index on ME myelin density. This project will benefit from the expertise available in Dr. Bouhrara in myelin imaging using advanced MRI methodologies to quantify ME myelination in the rodent brain in vivo and in human participants with high neuroanatomical resolution and sensitivity. These optimized protocols will be used in the Blouet lab to investigate long term changes in myelination during homeostatic and metabolic challenges. This is a unique opportunity to bridge the gap between molecular neuroscience and MR physics to address outstanding mechanistic questions regarding metabolic dysfunctions and myelination patterns. We expect that this synergetic work will form the basis for further preclinical investigations and clinical trials of targeted metabolic interventions. 

This project will focus on the use of blood plasma biomarkers of neurodegeneration and their role in the early and differential diagnosis of dementia. Blood biomarkers of neurodegeneration such as Phospho-tau (ptau)-181 and 217, glial fibrillary acidic protein (GFAP), amyloid beta (Αβ) 42/40 and neurofilament light (ΝfL) have shown high performance for the early diagnosis of Alzheimer’s disease (AD) pathology. However, their use for the diagnosis of non-AD dementias requires further development and likely additional research. Our group has previously shown that Ptau181 and GFAP plasma markers show excellent potential in differentiating AD from controls, frontotemporal lobe degeneration as well as progressive supranuclear palsy but do not perform as well in differentiating AD from Lewy Body Dementia (LBD). Furthermore these markers are not able to detect AD co-pathology in LBD.  This project aims to build up on ongoing work and test the accuracy and performance of blood biomarkers of neurodegeneration for the differential diagnosis of dementia. Building up to previous work will test novel biomarkers , such as ptau-217  and ptau-231 as well as markers of brain derived tau and synaptic function in cohorts from the Cambridge Centre for Parkinson’ plus disorders. It also aims to test whether such biomarkers can be used to detect AD co-pathology in LBD. It will also aim to test the associations between plasma biomarkers and brain imaging such as PET markers of synaptic function and neuroinflammation in AD and LBD using various statistical models including mixed linear models, area under the curve statistics and more advanced methods such as machine learning. The project will also test multimodal models and test whether addition of genetic information can improve the diagnostic accuracy of biomarkers. This post will ideally suit a clinically qualified candidate as their role will involve assessment and recruitment of research participants, collaborative work on the processing and analysis of plasma biomarkers, brain imaging data analysis and interpretation and publication of findings. 

Recent work in the Nitschke group has produced cages potentially capable of encapsulating proteins or nucleic acids. This project will develop the encapsulation of these biomolecules, and study their properties and potential therapeutic applications.

CADASIL is a hereditary cerebral small vessel disease caused by mutations in the NOTCH3 gene. Small vessel diseases affect the small penetrating arteries and brain capillaries and patients often suffer of migraine, ischaemic stroke, and cognitive decline. Despite its severity, no disease-modifying treatments are available to date. Classical pathogenic mechanisms are associated with cysteine gain or loss in NOTCH3 extracellular domain, but recent studies suggest that mutation site and other polygenic influences may affect disease severity.  In the lab, we have developed a human in vitro model using induced pluripotent stem cells (iPSC) from CADASIL patients to identify new modifying factors which can be targeted therapeutically. The main aim of the project is to establish iPSC models of CADASIL patients with mild and severe phenotype recruited at the Cambridge Stroke clinic and use these models for omics analysis, mechanistic studies, and drugs screening. The project includes a number of techniques: 2D and 3D iPSC-based neurovascular unit models, transcriptomic, proteomic, phenotypic and functional cell assays and high-throughput screening.

We have recently identified a human airway epithelial progenitor cell expressing high levels of the pioneer transcription factor ASCL1. Our data suggest that these cells are key progenitors during lung development, and we hypothesize that ASCL1 plays an important functional role. We have recently constructed a single cell RNAseq atlas for the developing human lung and predicted the differentiation trajectories (He et al. 2022), many of which differ to those seen in mice. We have also established a human foetal lung organoid system in which the progenitor cells generate heterogeneous progeny (Lim et al., 2023). This organoid system provides an ideal, dynamic model to test hypotheses regarding lineage relationships and progenitor cell function during human lung development.   We will test the hypothesis ASCL1 is necessary for efficient airway differentiation. We propose to use our lung organoid systems, in conjunction with an effective genetic toolbox recently established in our lab for human organoids (Sun et al. 2021) to knock-down ASCL1 transcription. We will also use targeted damID (Southall et al., 2013; Sun et al., 2022) to assess the binding targets of ASCL1 in progenitor cells and during the differentiation of specific lineages.    

He et al., 2022. “A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates.” Cell 185: 4841-4860, doi.org/10.1016/j.cell.2022.11.005  

Lim et al., 2023 “Organoid modelling of human fetal lung alveolar development reveals mechanisms of cell fate patterning and neonatal respiratory disease.” Cell Stem Cell, 30: 20-37, doi.org/10.1016/j.stem.2022.11.013

Southall et al., 2013. “Cell-type-specific profiling of gene expression and chromatin binding without cell isolation: assaying RNA Pol II occupancy in neural stem cells.” Dev Cell, 26: 101-112, doi.org/10.1016/j.devcel.2013.05.020

Sun et al. 2021. “A Functional Genetic Toolbox for Human Tissue-Derived Organoids.” ELife 10 (October). https://doi.org/10.7554/eLife.67886  Sun et al., 2022. “SOX9 maintains human foetal lung tip progenitor state by enhancing WNT and RTK signalling.” EMBO J, 41, e111338, doi.org/10.15252/embj.2022111338

Mitochondria are present in every nucleated cell and perform many essential functions. Their primary role is the efficient generation of adenosine triphosphate (ATP) which is required for all active cellular processes including protein synthesis, cell growth and repair. Mitochondrial dysfunction is seen in many common and rare diseases, but given their central role in cell homeostasis, it remains puzzling why this targets some cell-types and not others. We have developed new single-cell methods allowing us to address this question by studying tens of thousands of cells in the brain over the life course. This will cast light on the role of mitochondria in human ageing and neurodegenerative diseases.

There is a need for new drugs to combat viruses that threaten our health. Most existing antivirals inhibit virus attachment/entry or target critical enzymes, and new antiviral targets are needed to develop novel treatments and counter antiviral resistance. One key process in the life cycle of many viruses is the formation of dynamic organelles called viral factories. There is increasing evidence that some viral factories form via liquid-liquid phase separation (LLPS), including SARS-CoV-2, influenza, and measles virus. These compartments concentrate viral replication enzymes and sequester replication intermediates from the immune sensors. Targeting the physicochemical process of phase separation is an emerging paradigm that may underlie the discovery of novel, broad-spectrum antivirals, but this can only be realised by first understanding how viral factories form. This research project will focus on dissecting the physicochemical properties of these viral condensates to understand how their dynamic conformations and posttranslational modifications that affect charge mediate assembly of viral factories, and in doing so, identify targets for future therapeutic intervention. To quantitatively describe the formation of these condensates, we will examine the observed phase transitions of binary and tertiary mixtures of recombinantly produced viral proteins, as well as viral RNAs in vitro using the recently developed high-throughput microfluidics platform PhaseScan. These findings will lead us to define a new model of viral replicative condensate formation that addresses protein-specific attributes (posttranslational modifications, conformation), and their highly selective RNA composition (partitioning of cognate viral transcripts and exclusion of non-viral RNAs). The insights gained from these approaches will underlie the search for compounds that could serve as drug templates for prospective therapies for RNA viruses and improve our fundamental understanding of the synergistic interactions of viral proteins that spontaneously form complex condensates that are involved in viral replication.

This project will provide an excellent research environment that will foster the future development of the PhD candidate through extensive multi-disciplinary training in
i) microfluidics;
ii) protein biochemistry;
iii) biophysics of condensates;
iv) machine learning approaches required for bespoke data analyses.

This project will provide a unique training environment required for training next-generation biochemists interested in exploring biomolecular condensates and their roles in viral replication and assembly, with an ultimate goal of identifying new druggable antiviral targets.

This team is interested in the development and repair of musculoskeletal tissues. Diseases of the musculoskeletal system include those that arise during development, including inherited connective tissue diseases such as Marfan Syndrome and chondrodysplasias, as well as the highly prevalent age-related disease of joints, osteoarthritis. The team uses model systems as well as large human datasets to explore molecular drivers of disease and mechanisms that underly chondrogenesis and cartilage repair, including stem cell biology and deciphering intrinsic cartilage repair mechanisms.

Burkitt lymphoma (BL) is an aggressive cancer of germinal centre B cells that largely affects children globally. In sub-Saharan Africa, Burkitt lymphoma is an endemic disease associated with Epstein-Barr Vius (EBV) and Plasmodium falciparum infection. Unfortunately, children in sub-Saharan Africa have a far worse outcome with about 40% of children surviving compared to greater than 90% elsewhere, particularly in high income countries in Europe and North America. This is due to low access to reliable pathology diagnosis, limited access to specialized oncology centres, where the effective cytotoxic treatments and necessary life support can be given to patients during care. However, there might be biological factors that contribute as well to differences in outcome> For example, Burkitt lymphoma in sub-Saharan Africa is associated with EBV and Plasmodium falciparum infection, which may mediate a different tumour landscape (predominated by action of mutator enzyme adenosine-induced cytosine deaminase), whereas elsewhere these factors are lacking and the tumour landscape is influenced by accumulation of mutations in genes influencing apoptosis. In Cambridge, Prof. Turner has developed in vivo models of both sporadic and endemic Burkitt lymphoma that facilitate comparative research into disease mechanisms. In this project, these will be employed to understand the clonal heterogeneity of these malignancies using a combination of in vivo CRISPR screens and lineage tracing. Data will be validated using a large resource of primary patient specimens available within the EMBLEM study coordinated by the National Cancer Institute. Ultimately, data will be analysed with a view to developing biomarkers of disease prognosis as well as novel therapeutic approaches. In both cases the resource settings of sub-Saharan Africa will be considered towards sustainable and achievable approaches. The student will have the opportunity to travel to Uganda during the course of their studies.

Globally, HIV and schistosomiasis are leading causes of death due to infectious diseases. Despite available interventions, the infections remain uncontrolled in low-income settings causing acute and chronic morbidities. Intestinal schistosomiasis is caused by a parasitic blood fluke, most commonly of the species Schistosoma mansoni, and is predominantly found in sub-Saharan Africa. Chronic infections lead to advanced disease including liver fibrosis, portal hypertension, upper gastrointestinal tract bleeding, and severe anaemia. In the context of coinfections, severe clinical outcomes including death may be likely due to immune failure, interactions related to general fibrosis, and responses to starting antiretroviral therapy. In this project, you will have the opportunity to work with cutting-edge statistical and big data approaches alongside state-of-the art immunology to examine disease progression in the context of schistosome and HIV coinfections in arguably some of the poorest settings worldwide.

The group of Associate Prof. Chami studies schistosomiasis evaluating transmission, clinical outcomes, and treatment strategies, especially for liver fibrosis, in the SchistoTrack Cohort with the Uganda Ministry of Health. This Cohort is the largest individual-based cohort tracking individuals prospectively in the context of schistosomiasis. At Oxford, students can get exposure to computational, big data approaches to clinical epidemiology and field experience in global health research.

The group of Dr. Sereti studies HIV immune pathogenesis with a focus on inflammatory complications related to HIV and coinfections. Studies on biomarkers and how they may assist in identifying early people with HIV who may develop inflammatory and other adverse complications is currently an active area of investigation in the lab as they can also inform disease pathogenesis and new targeted interventions.

At the NIH, students can get experience in immunology research (wet lab) with optional exposure to complicated cases within a clinical setting.

Globally, HIV and schistosomiasis are leading causes of death due to infectious diseases. Despite available interventions, the infections remain uncontrolled in low-income settings causing acute and chronic morbidities. Intestinal schistosomiasis is caused by a parasitic blood fluke, most commonly of the species Schistosoma mansoni, and is predominantly found in sub-Saharan Africa. Chronic infections lead to advanced disease including liver fibrosis, portal hypertension, upper gastrointestinal tract bleeding, and severe anaemia. In the context of coinfections, severe clinical outcomes including death may be likely due to immune failure, interactions related to general fibrosis, and responses to starting antiretroviral therapy. In this project, you will have the opportunity to work with cutting-edge statistical and big data approaches alongside state-of-the art immunology to examine disease progression in the context of schistosome and HIV coinfections in arguably some of the poorest settings worldwide.

The group of Associate Prof. Chami studies schistosomiasis evaluating transmission, clinical outcomes, and treatment strategies, especially for liver fibrosis, in the SchistoTrack Cohort with the Uganda Ministry of Health. This Cohort is the largest individual-based cohort tracking individuals prospectively in the context of schistosomiasis. At Oxford, students can get exposure to computational, big data approaches to clinical epidemiology and field experience in global health research.

The group of Dr. Sereti studies HIV immune pathogenesis with a focus on inflammatory complications related to HIV and coinfections. Studies on biomarkers and how they may assist in identifying early people with HIV who may develop inflammatory and other adverse complications is currently an active area of investigation in the lab as they can also inform disease pathogenesis and new targeted interventions.

At the NIH, students can get experience in immunology research (wet lab) with optional exposure to complicated cases within a clinical setting.