Research Opportunities

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. 

A crucial aspect of brain development and function is that neurons can structurally and functionally modify themselves and the strength of their connections with other neurons in response to certain stimulus patterns. These changes pertain to three main classes of plasticity: synaptic intrinsic, and structural. In the olfactory circuit, structural plasticity is taken to an extreme: not only neurons can change size and shape of neuronal sub compartments, but quite a few neuronal subpopulations can regenerate throughout life, adding and removing entire elements of the circuit (Lledo et al 2006 PMID: 16495940). Among these regenerating cells are olfactory sensory neurons in the nasal epithelium, dopaminergic cells and granule cells in the olfactory bulb, and interneurons in the olfactory cortex. While adult-born neurons have long been believed to be a like-for-like replacement of embryonic-born ones, recent work focusing on bulbar dopaminergic neurons has challenged this view. Indeed, embryonic and postnatally-born dopaminergic cells differ in morphology, function and activity-dependent plasticity (Galliano et al 2018 PMID: 29676260; Galliano et al 2021 PMID: 33483429).

Using transgenic mouse models, immunohistochemistry, electrophysiology, and behavioural testing, this project wants to expand on these findings. Specifically it wishes to investigate:
(a) whether these differences based on birth date seen in the dopaminergic population can be generalized to the other regenerating populations in the olfactory system, and
(b) what behavioural roles do embryonic and regenerating cells play in olfactory processing.

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.

The placenta is the interface between mother and fetus, integrating signals between the two. There are also a number of pathways linking the placenta to development of the fetal brain, termed the “Placenta Brain Axis”. The placenta releases extra-cellular vesicles (EVs), but the role of these in the placenta brain axis is unknown. EVs are small membrane bound organelles that contain proteins, metabolites and RNA including miRNAs. Placental EV content is regulated in response to the maternal environment and therefore could mediate the known detrimental effects of an in utero obesogenic/diabetic environment on offspring brain development.

This project will explore the underlying mechanisms by which changes in placental EV content can influence the short- and long- term effects on fetal and offspring metabolism via the brain. The project will involve:
(1) profiling of the protein and miRNA content of placental EVs isolated from lean and obese murine pregnancies,
(2) a combination of in vitro and in vivo experiments to establish the functional consequences of the changes in placental EV protein and miRNA content and
(3) labelling of placental EVs to identify the parts of the brain that they fuse with.  

Maternal over-nutrition and obesity during pregnancy is known to have long-term effects on the health of the offspring, including increased risk of obesity. Weight gain in offspring exposed to maternal over-nutrition is at least in part caused by hyperphagia- implicating altered function of hypothalamic energy homeostatic pathways as an underlying cause- but the precise mechanisms by which the in utero environment impacts on hypothalamic development is unclear. Key metabolic hormones such as insulin, leptin and ghrelin have a dual role during brain development as growth factors. These metabolic hormones are altered in an obese pregnancy, providing a direct route by which the maternal nutritional state can impact on offspring hypothalamic development. We will use a combination of in vivo manipulation of hormone levels (e.g. fetal brain injection) and ex vivo neuro-developmental techniques (e.g. neurospheres) to examine the consequences of altered metabolic hormone levels for early hypothalamic development. We will also use immunofluorescence and viral tracing to study hypothalamic architecture in the offspring of obese mothers once they reach adulthood, and correlate the anatomy with functional readouts of complex feeding behaviours using operant and metabolic chambers.  

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.

The human brain is arguably the most complex structure in biology. It’s construction is dependent on a complex cascade of cellular events that include mitotic division, relocation of migrating neurons, and the extension of dendrites and axons. These processes are reliant on a dynamic and functionally diverse microtubule cytoskeleton. Microtubules form the mitotic spindle enabling the separation of sister chromatids, they facilitate translocation of the nucleus and extension of the leading process during neuronal migration, and microtubule polymers extend and maintain large and longstanding axons in mature neurons. Reflecting their importance mutations in genes encoding for tubulin subunits and microtubule associated proteins cause severe neurodevelopmental disorders. For instance, variants in TUBA1A are known to cause lissencephaly and cerebral palsy, mutations in TUBB2A cause cortical malformations, and substitutions in MAST1 cause microcephaly, autism and corpus callosum phenotypes. To study the underlying molecular and cellular mechanisms of these diseases the Keays laboratory is exploiting iPSCs and advanced 2D and 3D neuronal cultures. This project will utilise our recently created biobank of patient derived iPSCs (http://www.tubulinbiobank.org), coupled with CRISPR-cas9 genome engineering to generate isogenic controls. This project with focus on TUBB2A which is known to cause abnormal cortical gyration, microcephaly,  and/or autism. Following the generation of cerebral organoids, the student will study how disease causing mutations influence the properties of the microtubule cytoskeleton, and the cellular events necessary for brain formation.

Hypothesis:
1)    Mutations in TUBB2A act by altering the assembly, stability and/or dynamics of microtubules.
2)    Microtubule dysfunction perturbs the generation and/or the migration of neurons causing neurodevelopmental disease.

Tissue inflammation is a critical response for the front line of infections. However this same inflammatory response within the tissues is also potentially the most damaging – causing destruction to tissue cells and impeding the physiological functions of the tissue. The actions of immunosuppressive cell types, most potently regulatory T cells (Tregs) can counter this destructive inflammation, but the numbers of these cells within the tissues are limiting (Liston and Gray, Nature Reviews Immunology 2014). Through the use of gene therapy vectors we can deliver potent biologics that either enhance the number of immunosuppressive cell types, or replicate their function, within a tissue. We previously used this approach to create an anti-inflammatory pro-repair environment in the brain, protecting against brain inflammation (Yshii et al, Nature Immunology 2022) and aging (Lemaitre et al, EMBO Mol Med 2023). We have developed a novel system of gene delivery that allows an analogous correction of inflammation within the lung, with potential use in respiratory infections, and non-infectious inflammatory diseases. The proposed project will work on identifying the optimal biologics to deliver to the lung to drive repair during inflammation, will test the novel treatment in mouse models of respiratory disease, and will initiate testing in human lung tissue.

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.