Research Opportunities

This collaboration will provide the opportunity to work on malignant brain tumors in the laboratories of these three investigators with complementary expertise. The Zhuang laboratory (NIH) has an interest in the investigation of hypoxia (HIF-2a) signaling and tumor development as well as the pathogenesis of brain tumors and development of therapeutics. The Bulstrode laboratory (Cambridge) has an interest in neural stem cell identity and microenvironment interactions in brain development and in brain tumors. The Lathia laboratory (Cleveland Clinic) has an interest in cancer stem cells, tumor microenvironment interactions, immune suppression, and sex differences in brain tumors. The prospective student will have access to mentorship, infrastructure, and resources across all three laboratories. 

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. 

All viruses deliver or generate RNA in the cytosol. Cytosolic double-stranded RNA (dsRNA) is recognized by the innate immune sensors MDA5, LGP2 and RIG-I. Our group has shown that MDA5 forms filaments and cooperates with LGP2, TRIM14 and TRIM65 to recognize viral dsRNAs. Protein-RNA complexes containing both MDA5 and LGP2 activate the signaling hub protein MAVS to induce a potent antiviral interferon response. TRIM14 and TRIM65 are thought to promote crosslinking of filamentous MDA5/LGP2 complex. However, key aspects of how LGP2, TRIM14 and TRIM65 contribute to RNA sensing remain unclear. MDA5 and LGP2 are both known to bind dsRNA but whether the two proteins interact directly with each other to activate signaling is unknown. We used AlphaFold-Multimer to generate a molecular model of an MDA5-LGP2 heterodimer with high confidence metrics, but this model has not been tested experimentally. How TRIM-dependent filament crosslinking enhances signaling is also not understood.  The aims of this project are to use biochemical, structural, and cell-based approaches to obtain a detailed mechanistic understanding of the contributions of LGP2, TRIM14 and TRIM65 to viral RNA sensing by MDA5. The first aim of this project to test our AlphaFold model of the MDA5-LGP2 complex using structure-based mutations and functional assays. The second aim is to determine the structure of the MDA5 signaling holocomplex containing LGP2, TRIM14, and TRM65 using state-of-the-art cryo-EM image reconstruction approaches. These studies will provide important insights on the mechanism of RNA sensing by MDA5.  

References:

Rahul Singh, Yuan Wu, Alba Herrero del Valle, Kendra E. Leigh, Mark Cheng, Brian J. Ferguson & Yorgo Modis (2023) Contrasting functions of ATP hydrolysis by MDA5 and LGP2 in viral RNA sensing. DOI:10.1101/2023.05.25.542247  

Qin Yu, Alba Herrero del Valle, Rahul Singh & Yorgo Modis (2021) MDA5 autoimmune disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA. Nat. Commun., 12, 6668. DOI:10.1038/s41467-021-27062-5 

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.