Research Opportunities

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.

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