Research Opportunities

Radiation therapy is a common treatment modality for cancer patients that eliminates malignant cells through the delivery of high-energy photons. Despite advancements in radiation therapy technologies, factors such as the presence of tumour hypoxia or cell-intrinsic mechanisms of radioresistance limit the effectiveness of this treatment modality. This project aims to investigate the potential of novel drugs to enhance tumour radiosensitivity without causing toxicity to normal tissues. The research plan includes conducting in vitro and in vivo experiments using a broad panel of cancer cells to evaluate the radiosensitising effects of novel compounds which are currently being investigated in Geoff Higgins’ lab (Department of Oncology, University of Oxford). The radiosensiting capacity of these drugs and their mechanisms of action will be determined using a broad range of cell & molecular biology techniques, like colony formation assays, tumour growth delay assays, the analysis of DNA damage repair pathways by fluorescence microscopy and reporter assays, cell cycle determination by flow cytometry, gene silencing, cytogenetics assays, or protein biochemistry, amongst other techniques.

The skin epidermis provides a protective barrier against external insults. To ensure its maintenance, specialised cells located in its basal layer, known as stem cells, divide and differentiate to replace cells lost through exhaustion and damage. However, the mechanisms that control stem cell renewal and the pathways that lead to their dysregulation in disease remain controversial.

While studies have highlighted the role of stochastic renewal programs where stem cells are constantly lost and replaced by neighbouring cells, the underlying biological and physical mechanisms governing stochastic cell fate decisions remain poorly understood. Recent investigations in skin inflammatory diseases, such as psoriasis or atopic dermatitis, where the balance between proliferation and differentiation is typically disrupted have emphasized the influence of tissue mechanics in priming stem cells for renewal or differentiation and the crucial role niche signals from immune, stromal, and neuro-glial cells in modulating stem cell self-renewal and tissue dynamics.

In this project, you will use the latest spatial transcriptomics methods combined with machine learning to characterise simultaneously the mechanical, biochemical and cellular niches of epidermal stem cells, and how their composition, properties and spatial organisation might be altered in inflammatory skin diseases. You will also have the opportunity to contribute to follow-up experiments and hypothesis testing using mouse models and human epithelial organoids co-cultures, combined with advanced live imaging, AFM, mathematical modelling, genetic lineage tracing and functional genomics approaches such as CRISPR-based gene editing.

Ultimately, the results of this interdisciplinary project will transform our understanding of the mechanisms regulating epithelial tissue dynamics, and lay the foundation for the development of more effective therapeutic interventions targeting the causes, rather than the symptoms, of skin inflammatory diseases.

Sex differences often represent the most dramatic intraspecific variations seen in nature. Although males and females share the same genome and have similar nervous systems, they differ profoundly in reproductive investments and require distinct morphological, physiological, and behavioural adaptations. Animals determine sex early in development, which initiates many irreversible differentiation events that influence how the genome and environment interact to produce sex-specific behaviours. Across taxa, these events converge to regulate sexually dimorphic gene expression, which specifies sex-typical development and neural circuit function. However, the molecular programs that act during development remain largely unknown. 

We aim to understand the gene regulatory networks underlying sexually dimorphic neuronal development in the brain of the genetically tractable vinegar fly Drosophila melanogaster. We are using single-cell technologies to compare the molecular profiles of both males and females in the developing central brain to understand the mechanisms underlying sexual dimorphism in the nervous system. The fly's central brain is a remarkably complex tissue composed of approximately 100,000 interconnected neurons, forming the intricate networks necessary to coordinate complex cognitive and motor functions. Tightly regulated molecular programs act over a broad developmental window leading to the diversity of cell types found in the brain. The proposed experiments will paint a detailed picture of cellular and molecular diversity in a developing central nervous system. Our data will answer the longstanding question: How are neuron types associated with sexual behaviours born and wired?

Lab website: 
http://www.oxfordcircuits.com/

Contact: Stephen F. Goodwin stephen.goodwin@cncb.ox.ac.uk 

Sympathetic neurons have a wide range of physiological functions and their hypoactivity contributes to obesity and diabetes, among other syndromes. Sympathomimemic drugs rescue this deficiency but this drug class, mostly composed of brain-penetrant amphetamines and adrenergic agonists, is both cardiotoxic and highly controlled. Our recent publication puts forward new class of drugs  named Sympathofacilitators that do not enter the brain and have an anti-obesity and cardio-neutral effect in vivo. The first-in-class was published in Mahu I et al Domingos, Cell Metabolism 2020; Fig. 3C of this paper demonstrated a neuro-facilitatory effect, rather than neuro-excitatory one. 

This new class is in needed of novel chemical entities which can be screened in vitro on cultured iPSC-derived sympathetic neurones. The screen would be based on fluorescent readouts of calcium activity reporter, screening for a facilitation of responses to acetylcholine (similar to Fig. 3C of Mahu I et al).

The prospect of identifying natural compounds that have a Sympathofacilitatory effect is tangible when performed in collaboration with the laboratory of Barry O’Keefe. The student will learn lab how to grow and scale-up iPSC-derived sympathetic neurones in Domingos lab, and optimize an in vitro assay based on Fig. 3C. The student will then transfer this knowledge to the lab of Barry O’Keefe where the screen will be performed using a fluorescent plate reader, robotic liquid handling, and a library of natural compounds.

The sensory nervous system is a target for recognition by various immune factors after painful nerve injury (Davies et al., 2020; PMID: 32153361). While we know a great deal about immune mechanisms causing pain, we are only just beginning to understand the role it plays in its resolution. We have previously shown that nerve injury upregulates the stress ligand RAET1 that signals to natural killer (NK) cells via the immune receptor NKG2D. This neuro-immune interaction results in the pruning of intact primary sensory axons within the injured nerve (Davies et al., 2019; PMID: 30712871), that are otherwise a significant risk factor in neuropathic hypersensitivity (Kim et al., 2023a; PMID: 37366595). This neuro-immune interaction raises the possibility of an immune-based therapy for the treatment of neuropathic pain (Kim et al., 2023b; PMID: 37385878).

We use a combination of cell culture and mouse models to interrogate the receptor-ligand interactions between the peripheral nerve and killer immune cells injury and disease. We work closely with clinicians to collect and analyse relevant human samples and perform translational mechanistic studies using humanised cell culture models. Students will have the opportunity to learn animal behaviour, stem cell technology, live-imaging and high-dimensional flow cytometry, among other techniques, to understand the cellular and molecular interactions involved in cytotoxic neuro-immunity and its consequences for neuronal function and pain.

We are at an exciting turning point in neuroscience. New technologies now allow us to measure and control neural activity and behaviour with unprecedented detail (Landhuis et al. Nature 2017, Lauer et al. Nature Methods 2022). At the same time, new theoretical frameworks are starting to reveal how rich behaviours arise from synaptic, circuit, and systems computations (Richards et al. Nature Neuroscience 2019). We are contributing directly to the latter by aiming to understand how we learn. To this end, we are developing a new generation of computational models of brain function guided by deep learning principles. We focus on understanding how a given behavioural outcome ultimately leads to credit being assigned to trillions of synapses across multiple brain areas – the credit assignment problem. To survive and adapt to dynamic and complex environments animals and humans must assign credit efficiently. Recently, we have shown that the brain can approximate deep learning algorithms (Sacramento et al. NeurIPS 2018, Blake et al. Nature Neuroscience 2019, Greedy et al. NeurIPS 2022, Boven et al. Nature Comms 2023). In this project, you will build on our state-of-the-art computational models of AI-like credit assignment in the brain and contrast it with recent experimental observations at the behavioural, systems, and circuit levels.

Accumulation of misfolded proteins and aberrant protein aggregates are hallmarks of a wide range of pathologies such as neurodegenerative diseases and cancer. Under normal conditions, these potentially toxic protein species are kept at low levels due to a variety of quality control mechanisms that detect and selectively promote their degradation. Our lab investigates these protein quality control processes with a particular focus on ER-associated degradation (ERAD), that looks after membrane and secreted proteins. The ERAD pathway is evolutionarily conserved and in mammals, targets thousands of proteins influencing a wide range of cellular processes, from lipid homeostasis and stress responses to cell signaling and communication.

We investigate the mechanisms of ERAD using multidisciplinary approaches both in human and yeast cells. Using CRISPR-based genome-wide genetic screens and light microscopy experiments we identify and characterize molecular components involved in the degradation of disease-relevant toxic proteins. In parallel, we use biochemical tools to dissect mechanistically the various steps of the ERAD pathways. In this collaborative project with the Lea lab we will use structural approaches such as cryo-electron microscopy to gain insight into the molecular mechanisms of ERAD.

These studies, by providing mechanistic understanding of the ERAD process, may shed light on human diseases impacting ER function and may ultimately contribute to better therapeutics. 

The spinocerebellar ataxias (SCAs) are a complex group of neurodegenerative diseases that affect the cerebellum and result in the loss of motor coordination. No effective treatments exist for the SCAs, and there is a pressing need for better models in which to study the underlying disease-causing mechanisms and to identify potential therapies.

The aim of this project will be to develop novel stem cell-derived models to identify common pathological mechanisms in SCA that could be targeted therapeutically. The Becker group has identified several novel SCA mutations that highlight mGluR1-TRPC3-IP3R1 signaling as a key pathway affected in disease. Both research groups have developed complementary stem cell-derived and primary cerebellar models that provide unique systems to investigate the functional consequences of disease gene mutations in cerebellar Purkinje cells, which are the neurons that are primarily affected in SCA. 

The project will employ human induced pluripotent stem cells (iPSCs) that will be differentiated into cerebellar neurons and three-dimensional organoids and deeply phenotyped using a combination of functional experiments including calcium imaging, super-resolution imaging, and morphological analyses. In addition, functional analyses will be carried out in primary Purkinje cells. Identified disease phenotypes will subsequently be screened for potential therapeutics.

Becker Group website: 
https://www.ndcn.ox.ac.uk/research/cerebellar-disease-group

Hammer Group website: 
https://irp.nih.gov/pi/john-hammer 

The formation of high-quality germinal centres (GCs) is paramount to developing antibody responses central to resolving disease. How these antibodies are generated in such an efficient and well-regulated manner relies on a controlled and compartmentalised immune-regulatory environment to prevent the production of self-reactive autoantibodies. Reduced GC function has been widely reported in infection, autoimmune diseases, and ageing. Advancing our understanding of the cellular processes curtailing the host immune-regulatory environment modulating GCs could have a clinical impact.

Over the last couple of years, evidence has emerged revealing the presence of T-cell-B-cell-rich tertiary lymphoid structures (TLS) close to tumour cells have been associated with overall survival and better response to immunotherapy in cancer, suggesting an immune benefit. Yet, their interindividual variation in cellular composition, spatial organisation, and the immune mechanisms regulating humoral responses remain unclear. 

With more than ten years of expertise in the HIV field with a focus on the biological processes underpinning the regulation of humoral responses, the Functional Immunology lab led by Dr Pedroza-Pacheco aims to translate their established methodologies to systematically quantify the functional relationship between tumour-intrinsic molecular processes, and the formation, cellular composition, and spatial distribution of CD4-B-cell-rich TLS within the tumour microenvironment. Understanding how CD4 Tfh and B cells contribute to anti-tumour responses provides an exciting opportunity for their translation into precision immunotherapies, non-invasive biomarkers, and cancer vaccines. 

The student will explore a fundamental question in cognitive neuroscience, inspired by state of the art computational models of episodic memory. Their project will include collection of new empirical data, modelling the data computationally, and then testing a joint neural-cognitive model of memory recall using fMRI, where analysis will use RSA techniques.

Over the last 10 years, genome wide association studies (GWAS), exome and short-read genomic sequencing have enabled a revolution in our understanding of the genetic basis of neurodegenerative diseases, their progression and disease pathways. Despite this progress, our molecular understanding of the genes and loci that cause neurodegeneration remain limited, evidenced by the near absence of disease-modifying treatments for these diseases. In part this is because we have lacked the technology to fully characterise these important genomic regions. Short reads cannot fully assemble complex genomic rearrangements especially repetitive sequences, nor can they accurately and unambiguously identify or quantify different expressed isoforms. Therefore, the hypothesis underlying this PhD project is that significant inaccuracies in our knowledge of the genomic structure and transcript annotations at neurodegenerative disease loci have limited our understanding of disease pathogenesis.

To address this knowledge gap, the student will generate and analyse high quality paired long-read DNA and RNA-sequencing data to accurately investigate and annotate loci of interest in human brain samples, and in purified cell populations, across a range of neurodegenerative diseases. The student will use this new genomic and transcriptomic map to re-assess both GWAS risk SNPs at these loci and the pathogenicity of rare variants identified through WGS of patients with hereditary forms of neurodegeneration, so leveraging data generated within this project and that already available publicly. Thus, the student will help generate a core resource of annotated pathogenic loci to drive the identification of novel disease mechanisms, genetic causes and therapeutic targets in neurodegeneration.

The Paluch lab investigates how cells control their shape and the underlying cellular mechanical properties. The project will focus on the actomyosin cortex, a thin cytoskeletal network that supports the plasma membrane. Myosin-generated contractility at the cell cortex controls cell surface mechanics and drives cellular deformations. Recently, through super-resolution microscopy approaches, we have shown that in interphase cells, myosin minifilaments are positioned at the cytoplasmic side of the actomyosin cortex. Upon mitotic entry, myosin minifilaments penetrate the actin cortex as cortical tension drastically increases. How this increase, crucial for the success of cell division, is controlled is not understood. We hypothesize that the cortex is structurally poised for rapid tension changes, and that tuning actin network nanoscale architecture can lead to abrupt changes in the overlap of actin and myosin at the cortex. Myosin entry into the cortex upon mitosis entry would thus be akin to a phase transition in cortex organisation.

To address this hypothesis, we will explore the 3D nanoscale architecture of myosin minifilaments at the cortex. Using Structured Illumination Microscopy, we aim to gain a single molecule understanding of the dynamic behaviour of myosin minifilaments at the onset of mitosis. We will then use Electron Microscopy to interrogate the ultrastructure of the actomyosin cortex, which together with our light microscopy data, will uncover how nanoscale processes control global cell mechanics.  

Key reference: 
Truong Quang BA, Peters R, Cassani DAD, Chugh P, Clark AG, Agnew M, Charras G, Paluch EK. Extent of myosin penetration into the actin cortex regulates cell surface mechanics. (2021) Nat Comm. 12:6511.

Autism is diagnosed in males more often than in females, even after accounting for postnatal social factors, such as underdiagnosis, misdiagnosis, camouflaging and masking in females. This suggests that biological factors contribute to sex differences in autism likelihood.   Several lines of evidence support the case that prenatal sex steroid synthesis is altered in pregnancies that result in a later autism diagnosis. Mothers of autistic children also have significantly elevated rates of conditions and pregnancy complications linked to the endocrine system (e.g. polycystic ovary syndrome and gestational diabetes). However, the potential causes of prenatal endocrine disruption and their effects on brain development, remain unclear.   The placenta may be of particular significance in neurodevelopment, as it maintains endocrine homeostasis prenatally and regulates nutrient transfer to the fetus. Placental function is also sexually dimorphic, with placentas of male fetuses producing more steroid hormones, fewer vascular protective factors and adapting differently to prenatal complications. Thus, the placenta could act as a mediator of various autism likelihood factors.  

To investigate how placental biology contributes to autism in a sexually-dimorphic manner, the Autism Research Centre is in the process of creating the first Autism Placenta Biobank, in collaboration with two specialist institutions: the Centre for Trophoblast Research in Cambridge (CTR), and the Tommy's Maternal Health network of the University of Manchester. This entails actively recruiting pregnant women with a first degree relative or child with autism, assessed through a screening questionnaire during pregnancy and asking them to donate their placentas to research. These are then compared to placentas from typical male and female pregnancies, where the pregnant woman has no first degree relative with an autism diagnosis.  

A successful PhD candidate will be included in this team of researchers and assist with:
1.    Recruiting participating women in Manchester and arranging for tissue transfer in Cambridge and the affiliated laboratories for testing and analysis.
2.    Helping analyse tissue morphology and protein distribution differences in the placentas.
3.    Helping analyse genomic data from the placentas (both methylome and transcriptome) and integrating findings with existing resources regarding brain development (e.g. post-mortem brain transcriptome) and autism (e.g. lists of autism candidate genes, derived from sequencing or genotyping studies).
4.    Locating additional sources for placental tissue and establish research collaborations, in order to add to the Biobank and replicate findings.  

This PhD will be part of a wider, multi-disciplinary research initiative that aims to understand the role of sex differences in neurodevelopment and autism likelihood.

Life thrives on collaboration – this extends to the molecular scale, where life is fueled by the chemical processes collectively called metabolism. Microorganisms exchange nutrients through cross-feeding, and multicellular organisms are made up of cells with different metabolic roles and needs. These collaborations allow for division of labour, for example between germline and soma.  Social insects provide an ideal study system to understand metabolic division of labour for two reasons:
1. They subvert the classic life-history trade-off between longevity and fecundity with long-lived highly fertile queens and small short-lived sterile workers, and
2. Many ant colonies engage in frequent mouth-to-mouth social exchanges of experimentally accessible fluids that contain endogenously produced materials.

These exchanges are so frequent that they form a social circulatory system that distributes material across the colony, allowing metabolic costs to be allocated locally while benefits are distributed across the collective.  Our lab has done ample groundwork on this system in charactering the proteins that are socially transferred between individuals, where they are produced, when and by whom.

This project has two parts. One will focus on tracking protein flow between individuals using stable-isotope proteomics and quantitative feeding measures. The second will quantify the metabolic costs of production for the producers and the longevity benefits for receivers using RNAi, artificial diets, and measurements of physiology, oxidative stress, and metabolic rate.  Disentangling metabolic division of labour in ant colonies, where we can monitor exchanges easily, will hopefully allow us to better understand how some of our tissues lighten the load of others and how to better extend life- and health-span.

Negroni & LeBoeuf. Metabolic division of labor in social insects. 2023 COIS https://doi.org/10.1016/j.cois.2023.101085

Hakala SM, Meurville MP, Stumpe M, LeBoeuf AC. 2021. Biomarkers in a socially exchanged fluid reflect colony maturity, behavior, and distributed metabolism. Elife 10. doi:10.7554/eLife.74005

Kramer BH, Nehring V, Buttstedt A, Heinze J, Korb J, Libbrecht R, Meusemann K, Paxton RJ, Séguret A, Schaub F and Bernadou A. (2021) Oxidative stress and senescence in social insects: a significant but inconsistent link? Philosophical Transactions of the Royal Society B, 376(1823), 20190732. 

Germline genomes are immortal. Their genetic information is transmitted to the next generation and ensures that continuation of life. To protect the integrity of their genomic information, germ cells employ a specialized small RNA-based defense system, PIWI-interacting small RNAs (piRNAs) and their PIWI protein partners. The interest of the Karam Teixera lab in germ cell biology and evolution and the focus of the Haase lab on mechanisms of small silencing RNAs converge on piRNA-guided surveillance of genome integrity. The collaborative project of an NIH OxCam Scholar is designed to combine strength of both labs in genetics, biochemistry and genomics, and offers training in experimental techniques and basic computational analyses of next-generation sequencing data. Results from this graduate study will further our understanding of how germ cells ensure genome integrity and the survival of future generations.