Studentship closed: we are no longer accepting new applications for this funding opportunity.
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Maria P. Alcolea
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Mapping a blueprint of ageing across tissue scales This PhD project aims at investigating how specific cancer-associated mutations impact cell fate, both in tumour bearing cells as well as neighbouring cells. The aim is to understand how mutations present in our tissues synergise/compete in the early events leading to carcinogenesis, offering a window of opportunity to develop new strategies to prevent or reduce cancer incidence. This represents an interdisciplinary project, where the student will combine genetic tracing approaches to map the fate of mutant clones in vivo, a new long-term 3D culture approach, single-cell molecular profiling, and mathematical network analysis in order to dissect the cellular and molecular mechanisms underlying mutant clonal dynamics. In particular, this project will use genetic mouse models to investigate how specific mutant clones or combinations of those promote early tumour formation from the most incipient stages of the disease. Additionally, we will expand our understanding of how mutations impact cell fate trajectories both in healthy tissues (i.e. with no tumours) and in those tissues where tumours start to emerge. We are interested in understanding why under certain conditions some mutations are able to develop cancers, while in other they do not contribute to this process. To this end, the candidate will develop computational expertise by working on quantitative lineage tracing data, i.e. data generated in vivo using mouse genetic models bearing cancer mutations, as well as multiomic datasets to decipher cellular and molecular regulatory networks associated with mutant cells. |
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Maria P. Alcolea
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Mapping a blueprint of ageing across tissue scales The ability of epithelial cells to rewire their programme of cell fate in response to tissue perturbations has emerged as a new paradigm in stem cell biology. This plasticity improves the efficiency of tissue repair by enabling differentiated (non-dividing) cells to reacquire stem/progenitor cell-like behaviour in response to damage. However, despite obvious implications for regenerative medicine, we still know virtually nothing about the processes that regulate promiscuous cell fate programmes, how they impact on tissue physiology, and whether this contributes to age-related complications. We are seeking candidates with background in Computational Biology to work in a multi-disciplinary PhD project focused on studying epithelial cell fate reprogramming and plasticity during ageing. We are looking for a highly motivated and enthusiastic individual interested in the underlying biological/disease processes and a passion for data driven science. The ultimate aim of this research programme is to identify potential targets to partially reduce/reverse age-related complications. In this dry lab project, we will combine our interdisciplinary approach to model epithelial cell fate dynamics during ageing. This will be achieved through single-cell multiomics, gene regulatory network analysis, and quantitative lineage tracing analysis. |
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Mechanisms of development and age-dependent regeneration in the brain 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 (PMIDs: 28805814, 30091706, 34878841). 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. Our lab is interested in answering two overarching questions: 1) What are the cellular and molecular mechanisms that enable regeneration in neonates and inhibit it 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. The student will benefit from our multidisciplinary approach and participate in our collaborative work locally and internationally. |
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Riccardo Beltramo
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How does the brain represent the spatial location of others? A critical requirement for survival is the ability to navigate the environment while identifying and localising potential predators and conspecifics (1). Internal spatial maps of the surroundings are found in the hippocampus and entorhinal cortices. How does the brain represent the spatial location of others? How is visual information transformed into these spatial representations? Mammals have two coexisting brain structures that process visual information: the ancient “superior colliculus” and the phylogenetically newer “visual cortex”. This Ph.D. project aims to determine the roles played by these parallel visual systems in spatial navigation. The “primary visual cortex” (V1), the first entry point of visual information in the cerebral cortex, is thought to provide crucial input for the generation of spatial representations. However, even with complete lesions of V1, clinically blind patients are still able to navigate the environment and respond to threatening moving stimuli. This phenomenon, referred to as “blindsight”, is believed to depend on parallel visual pathways, independent of V1, that relay visual input from the eye to the navigation system. We have recently discovered that the superior colliculus has a dedicated space in the visual cortex: the postrhinal area (POR) (2-3). POR, whose responses rely on collicular activity and are critically involved in spatial navigation, is perfectly placed at the interface between the cortical and collicular visual streams and the hippocampal formation. Combining electrophysiological, 2photon imaging, and opto/chemogenetic approaches, we will study the interactions between ancient and modern visual pathways in sensory processing and spatial navigation. |
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Riccardo Beltramo
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Sensory processing and fear overgeneralisation in stress-induced anxiety, across the visual system Anxiety disorders stem from dysfunctions in the circuits that process aversive stimuli1. When confronted with potential dangers, animals must select the appropriate behavioral response. In an environment full of complex stimuli, sometimes threat cues are ambiguous, making it challenging to distinguish dangerous from irrelevant stimuli. The ability to generalise across similar stimuli is an adaptive strategy that protects animals from fatally missing a potentially deadly environmental cue. In other words, “better safe than sorry”. However, an exaggerated generalisation of fear to harmless stimuli (i.e. “fear overgeneralisation”) is maladaptive and considered a hallmark of numerous anxiety disorders(1). The cellular and circuit mechanisms mediating fear overgeneralisation are largely unknown. This PhD project investigates the development of fear overgeneralisation at the level of the sensory circuits that process aversive information. Using the mouse visual system as a model, we will focus on a visual cortex selectively activated by innately fearful stimuli(2), targeted by the amygdala(3), and driven by a midbrain center that triggers avoidance behaviors(2). We will determine how changes in the neural sensory representations of dangerous and safe visual stimuli affect the animals’ ability to discriminate them. Given the critical role of preexisting stress in the pathogenesis of numerous anxiety disorders, we will test the hypothesis that emotional distress changes how sensory stimuli are encoded during learning, leading to fear overgeneralisation. Through chronic 2photon imaging, large-scale electrophysiology, and innovative behavioral tasks, we will determine the effects of severe stressors on early sensory processing, during the development of stress-induced anxiety. |
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Thorsten Boroviak
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Pioneering a marmoset in vitro implantation-platform to unravel the mechanisms regulating human embryo invasion depth. In this project we aim to develop an in vitro model to explore how implantation depth is regulated in human and marmoset embryos. Humans have deep (interstitial) implantation, while marmosets undergo shallow (superficial) implantation, suggesting species-specific regulatory mechanisms. We hypothesize that the endometrium primarily controls implantation depth, though the embryo may also contribute to this process. We will derive and characterise marmoset endometrial glandular and stromal cells and assess their ability to replicate endometrial cycles. Moreover, we will validate these cells using our spatial transcriptome map of marmoset implantation. Next, we will create a marmoset-specific implantation platform by integrating endometrial cells in a hydrogel-based transwell model with endothelial cells for vascularisation to simulate the tissue environment necessary for implantation. By culturing human blastoids on both human and marmoset platforms, we aim to compare implantation depths: shallow implantation on marmoset endometrium would indicate endometrial control, while deep implantation would suggest embryo-led regulation. Overall, this PhD project will reveal mechanisms of implantation depth regulation across species and potentially inform therapeutic approaches to implantation-related disorders. |
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Albert Cardona
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Brain connectomes and sex The neural circuit wiring diagram varies across sexes. In the adult fly, the gene fruitless has been associated with prominent changes across the nervous system between males and females. In the larva, we know that the female nervous system has about 1,000 more neurons than the male, but we don’t know which ones, nor whether neural circuits are the same or significantly different. In this project, the student will image whole central nervous systems of larval Drosophila melanogaster for males and females, map their connectomes with automated methods, and compare the two to identify what is common and what is different across their brains. An enterprising student will see to then test any differing circuits with behavioural experiments using single-neuron genetic driver lines and optogenetics. |
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Angeleen Fleming
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Investigating the role of extracellular vesicles (EVs) and unconventional protein secretion (UPS) in the pathogenesis and spreading of aggregate-prone proteins in neurodegenerative diseases Cell-to-cell communication by extracellular vesicles (EVs) is a growing field of investigation in basic cell biology research, biomarker discovery and therapeutic drug delivery. Our lab is investigating how different cargoes are loaded into EVs and the pathways that regulate EV biogenesis, release and uptake. We are particularly interested in the aggregate-prone proteins that are associated with different neurodegenerative diseases (e.g. alpha-synuclein, SOD1, TDP-43, tau and huntingtin) and have shown that these proteins can be loaded into EVs and secreted from cells. We have recently identified that members of the small heat shock protein (sHSP) family can interact with various aggregate-prone proteins to facilitate their loading into EVs and their intercellular spreading. This project will use a range of cell-based and in vivo assays to investigate how signalling proteins regulate the unconventional secretion by EVs and determine how this affects the accumulation and spreading of neurodegenerative disease-causing proteins. The first part of the project will involve over-expression and knockdown of these signalling proteins in vitro (in cell-based assays), where a range of biochemical and microscopy techniques will be deployed to look at protein interactions, localisation and spreading of these proteins. These findings will be then validated in vivo using a combination of zebrafish fluorescent reporter lines and neurodegenerative disease models. Finally, by using genetic and pharmacological activation and inhibition of signalling pathways, we will monitor EVs in vivo and characterise how perturbation of unconventional secretion can impact the disease progression. |
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Elisa Galliano
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Activity-dependent neuronal plasticity in the mouse olfactory bulb The ability to sense and respond to the environment is critical for the survival of all organisms. This process involves gathering sensory information and using it to generate appropriate behaviors, a feat achieved through neuronal plasticity. This includes structural, synaptic, and intrinsic changes in neurons. However, these mechanisms are often studied in isolation, and their collective impact on behavior remains unclear. In our lab, we seek to bridge this knowledge gap by examining how mice adapt to olfactory stimuli. For this project we will manipulate their olfactory environment, subjecting them to sensory deprivation (similar to a mild cold) or olfactory enrichment (resembling exposure to a perfume shop). Using advanced genetic tools, we label neurons responsive to specific odors. Our approach combines immunohistochemistry and patch-clamp electrophysiology to investigate how olfactory bulb neurons adapt their synaptic connections, morphology, and intrinsic properties in response to different durations of sensory changes. We complement these cellular investigations with automated behavioral testing to assess the mice's ability to detect and differentiate odors and to understand the influence of adaptive plasticity on the learning process. Our comprehensive studies aim to provide deeper insights into the complex neural mechanisms that underlie behavioral adaptability in response to changing olfactory stimuli. |
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Elisa Galliano
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Embryonic and adult neurogenesis: do different birth dates lead to functional diversity? An essential aspect of brain development and function is the ability of neurons to adapt structurally and functionally in response to specific stimuli. This adaptation involves changes in the strength of connections, morphology, and intrinsic properties and falls under three main categories: synaptic, intrinsic, and structural plasticity. In the olfactory system, structural plasticity is particularly striking, with several neuron subpopulations regenerating throughout an organism's lifespan. This includes olfactory sensory neurons, dopaminergic cells, and granule cells. Recent research has unveiled differences between embryonic and postnatally-born dopaminergic cells, challenging the notion that they are like-for-like replacements. Using transgenic mouse models, immunohistochemistry, electrophysiology, and behavioral testing, our project aims to expand on these findings. Specifically, we investigate whether the distinctions based on birth date seen in dopaminergic neurons extend to other regenerating populations in the olfactory system. Additionally, we seek to unravel the behavioral roles played by embryonic and regenerating cells in olfactory processing. By addressing these questions, our research contributes to a more comprehensive understanding of the intricate dynamics within the olfactory circuit and the broader implications of neuronal plasticity for brain function and behavior. |
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Dino A. Giussani Second Supervisor: Andrew Murray
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Placenta-related pregnancy complications and future female heart disease risk Despite heart disease being one of the leading killers of women in the world, women continue to be underdiagnosed, undertreated, and underrepresented in cardiovascular science, with research failing to sufficiently address factors that uniquely affect a woman’s risk (1). One sex-specific condition that increases cardiovascular risk in women is pregnancy. Women who develop a complicated pregnancy, such as fetal growth restriction, are at greater risk of cardiometabolic dysfunction during pregnancy and more susceptible to heart disease long after birth (2). However, it is unclear whether this is due to some women having a genetic predisposition to cardiometabolic dysfunction that is brought to the surface by pregnancy, or something about the complicated pregnancy that alters the susceptibility of genetically non-predisposed women to cardiac pathology. Our work has reported that hypoxic pregnancy in sheep without prior cardiovascular risk mimics the utero-placental pathology associated with obstetric syndromes, such as preeclampsia and fetal growth restriction (3). However, whether these ewes develop cardiovascular complications during pregnancy and long after birth remains unknown. In particular, how altered mitochondrial substrate utilisation and respiratory capacity contribute to (patho)physiological changes in cardiac structure and function is completely unknown. This is critical, as there is an established link between cardiac bioenergetics and function, which ultimately determines disease risk and outcome. This PhD studentship will link cardiac mitochondrial bioenergetic mechanisms to echocardiographic cardiac functional and geometric data at term and 6 months after birth in different cohorts of sheep which have experienced control or hypoxic pregnancy. |
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Courtney Hanna Second Supervisor: Naomi McGovern
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Molecular features and function of placental cell types during pregnancy The placenta forms the maternal-fetal interface during pregnancy, mediating oxygen and nutrient exchange, providing a protective barrier against infection, and producing essential pregnancy-supporting hormones. The human placenta is comprised of several cell lineages, including trophoblast cell types, fetal vasculature, fetal macrophages (Hofbauer cells). Each of these cell types show distinct differences in epigenetic and transcriptional signatures across pregnancy, but whether this is linked to changes in cell function, localisation or developmental events, such as oxygenation, remains unclear. This project aims to use various omics datasets, including DNA methylation, chromatin accessibility, transcriptomics (from bulk and single-cell RNA-sequencing), to perform comparative analyses to understand the molecular changes that occur across cell types throughout pregnancy and to determine whether these changes are linked to difference in cell function. |
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Sepiedeh Keshavarzi
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The Brain’s Gyroscope: Investigating Cortical Circuits and Computations Underlying Self-motion Perception Accurate perception of heading direction and speed is crucial for navigation and understanding the dynamic world around us. Neurons encoding angular head velocity (AHV) are thought to play an integral role in this process. Recent studies in the retrosplenial cortex (RSC), a core component of the brain's navigation system, have shown that cortical AHV cells integrate vestibular and visual information to enhance the accuracy of head motion signalling. While both inhibitory and excitatory neurons in the RSC appear to encode AHV, the specific contributions of different cell types to the integration of vestibular and visual information and AHV computation remain unclear. Additionally, the function of these AHV cells and their role in self-motion perception are still open questions. This project aims to address these knowledge gaps by examining the contributions of different RSC interneurons and projection cell types to AHV coding, as well as their roles in behavioural performance during a self-motion estimation task. The study will employ advanced methodologies using the mouse model, including in vivo two-photon imaging, optogenetic manipulations, and a highly controlled quantitative behavioural paradigm. This project offers PhD candidates an opportunity to engage in cutting-edge neuroscience research, advancing our understanding of self-motion perception and spatial cognition. |
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Sepiedeh Keshavarzi
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The Brain’s Compass: Dissecting Thalamocortical Circuits for Spatial Orientation Spatial navigation fundamentally relies on sensing one's orientation relative to the environment and goal locations. While cells encoding head direction and angular head velocity are believed to form the brain's compass, their precise role in navigation and the circuits through which they influence spatial behaviour remain unclear. These gaps largely stem from a lack of high-throughput paradigms that specifically test the sense of direction while controlling environmental cues. This project addresses these gaps using a novel spatial orientation task for mice, where performance depends on tracking heading with or without reference to the environment. This design dissociates internal and external reference frames, allowing us to study different navigational strategies. By recording from large neuronal populations across core areas of the head direction system, including the anterior thalamus, retrosplenial cortex, and postsubiculum, we aim to identify the neural compass's contribution to spatial orientation under these distinct navigational strategies. Furthermore, we will investigate how thalamocortical circuits connecting these areas contribute to spatial orientation using circuit-specific neuronal manipulations during the task. These approaches will help understand how head direction information is processed and used in goal-directed navigation. Prospective PhD students will have the opportunity to work with cutting-edge neuroscience techniques, including large-scale electrophysiological recordings with Neuropixels probes and targeted circuit manipulations using chemogenetic and optogenetic methods, while addressing fundamental questions about spatial cognition and navigation. |
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Andrew Murray
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Pregnancy at high altitude: understanding the links between placental metabolism and infant health Healthy fetal growth and development are associated with better health outcomes throughout life. Conversely, common complications of pregnancy, such as preeclampsia, can result in fetal growth restriction (FGR), posing a major risk to the mother and developing child. Fetal hypoxia (low oxygen) is a common cause of FGR, and can arise during preeclampsia as a result of altered uterine blood flow. High-altitude pregnancy represents an important experiment in nature. Whilst FGR and preeclampsia are more common at altitude, native highlander populations show relative protection. This might be explained by enhanced uterine blood flow, which is ~2-fold greater in pregnant Andean women at high altitude than Europeans. Yet, in all human pregnancies, uterine oxygen delivery outstrips fetal demand. We propose a critical role for placental metabolism, with the enhanced uterine blood flow supporting oxygen diffusion to the mitochondria. The placenta transports nutrients, oxygen and waste between maternal and fetal circulations. As such, it supports fetal metabolism, but also requires oxygen and nutrients for its own demands. We have shown that placental respiration is suppressed at altitude, which may protect fetal oxygen delivery, but at the cost of impaired energetics. We hypothesize a link between uterine blood flow, placental mitochondria and relative protection against FGR in Andeans. Understanding genetic and metabolic mechanisms underlying this protection could reveal therapeutic targets for the treatment of complicated pregnancies at sea level. Collaborating with researchers in Colorado, USA and La Paz, Bolivia, we study uterine artery perfusion, transplacental oxygen and nutrient transport and placental metabolism in high-altitude pregnancy, and the impact on fetal growth. |
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Understanding the molecular mechanisms that regulate early human development The goal of the Niakan Laboratory is to understand the molecular mechanisms that regulate early human development. The mechanisms that regulate early cell fate decisions in human development remain poorly understood, despite their fundamental biological importance and wide-reaching clinical implications. While our laboratory has identified molecular mechanisms regulating initiation of placental progenitor cell differentiation and divergence of the epiblast from yolk sac progenitor cells in human embryos, the mechanisms regulating the establishment and maturation of human embryonic and extraembryonic cells remain largely unknown. The PhD project will use genetic analysis and multi-modal -omics and high-resolution imaging analysis to investigate when and how cells of the human embryo become specialized to form the pluripotent epiblast that eventually gives rise to the body. Insights into early cell fate specification and gene function will provide foundational knowledge about human biology. The knowledge gained will inform strategies to establish optimised human pluripotent stem cell lines, organoids and stem cell-based embryo models that more closely recapitulate in vivo counterparts. Research techniques used in the laboratory include: advanced live embryo imaging, preimplantation embryo culture and micromanipulation (human, mouse and cow) proteomics, genome modification, TRIM-Away, genome-wide techniques (i.e. single-cell multi-omics), derivation of stem cell and stem cell embryo models.
Candidate background This project would suit a candidate who is curious and passionate to understand the molecular mechanisms that regulate the first cell fate decisions in human embryos. We also seek candidates who have a desire to work in a collaborative research environment. |
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A retrospective cognitive map in the mouse hippocampus The mammalian hippocampus generates a cognitive map of the environment through the location-specific firing of hippocampal neurons known as place cells (O’Keefe and Recce, 1978). These cells have place fields that accumulate at salient locations in the environment, for example at the location of a reward. Whereas cognitive maps were previously thought to be updated by prospective reward prediction errors, it was recently suggested that cognitive maps can also be retrospective, with updating of cognitive maps only on the occurrence of a salient event (Namboodiri and Stuber, 2021). In this project, you will test three specific predictions that are different between prospective and retrospective models of the cognitive map by observing mouse spatial behaviour on the ‘cheeseboard’ maze apparatus, and recording the associated neuronal activity in the hippocampus. The two models would make different experimentally testable predictions relating to (1) the initial learning of a cognitive map, (2) the speed of extinction in the absence of reward, and (3) the effect of new reward locations on previously encoded ones. To test these predictions, you will use a combination of multi-electrode recording, calcium imaging and optogenetics in behaving mice engaged in a cheeseboard maze task (Jarzebowski et al., 2022). Interested students are encouraged to contact the supervisor for more detailed discussion of a potential PhD project in this area. |
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Spatial memory and state-dependent synaptic plasticity in the mouse hippocampus Synaptic plasticity is a leading cellular model to explain behavioural learning and memory. However, the relationship between the fast timescale of induction of plasticity and the much slower timescale of behavioural learning is not well understood. It has been suggested that neuromodulation might serve as a bridge between synaptic and behavioural timescales. There is strong experimental evidence that synaptic plasticity is under control by neuromodulators, including acetylcholine and dopamine, which may alter synaptic learning rules both prospectively and retrospectively (Brzosko et al., 2019). This project would test the idea that the neuromodulatory state of the network at different phases of memory encoding could help explain how memories are bound together at different timescales. To this end, you would use whole-cell patch-clamp recording in brain slices (Fuchsberger et al., 2022), complemented by multi electrode recording, calcium imaging and optogenetics in behaving animals (Jarzebowski et al., 2022), to understand hippocampal encoding of reward-location in a reward-based spatial memory task. Interested students are encouraged to contact the supervisor for more detailed discussion of a potential PhD project in this area. |
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Dr. Jasper Poort
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The role of different inhibitory cell types in visual and decision-making brain regions during visual learning. Our brain is constantly overloaded with visual information. Learning to selectively process visual features relevant for behaviour is therefore crucial for optimal decision-making and linked to activity of GABAergic inhibitory interneuron cell types. Altered inhibition is linked to perceptual and learning impairments and associated with neurodevelopmental disorders including schizophrenia and autism. However, the computational roles in visual learning of neurons in low-level brain areas, specialized in processing specific visual features, and neurons in higher-level brain regions, more closely linked to visual decision-making, are not yet understood. The aim of this project is to understand the precise role in visual learning of different cortical cell types in low- and high-level visual brain areas and their projections. Mice have a similarly hierarchically organized visual system and show complex decision-making behaviours. Mouse brain circuits can be measured and manipulated during behaviour in ways not possible in humans. Our approach is to train head-fixed and freely moving mice, including pharmacological and genetic mouse models of neurodevelopmental disorders and healthy controls, in visual decision-making tasks. We measure activity at the bottom (e.g. primary visual cortex) and top (e.g. posterior parietal cortex) of the hierarchy in specific cell types using 2-photon imaging and electrophysiology, use optogenetics to activate/inactivate specific cell types and computational modelling to build neuronal circuit models of learning. The PhD is associated with a Wellcome Trust funded cross-disciplinary international research programme to investigate the role of inhibition in mice and humans at different scales, from local circuits to global brain networks. |
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Eleanor Raffan
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Genetic and molecular underpinnings of obesity - using veterinary models for insight into human disease Why are some individuals prone to obesity and yet others stay lean in an obesogenic environment? Obesity is highly heritable as are related metabolic traits. We study the genetics of metabolic disease 'in the round' starting with genetic discovery using GWAS and other epidemiological approaches to molecular studies of gene function via physiological and behavioural studies in companion animal species. Capitalising on my background as a vet, we start with animal genetics – dogs, horses and farm animals are excellent models because selective breeding means they show phenotypes of interest and their genomes are conducive to gene mapping. We interrogate large human genomic data sets to focus on genes of greatest interest to both humans and animals which are further investigated with cellular and molecular biology to understand mechanism, focussing on neuronal development, cell signalling and adipocyte biology. We also study whole body physiology in pet dogs volunteered by their owners. Our lab is supportive and collaborative and we welcome students with diverse backgrounds to apply. A bioinformatics background is not required, but a willingness to engage with statistics and 'big data' is a must for most students in the group. We have strong links to the Institute of Metabolic Science. If this appeals to you, please get in touch with your CV, explaining why you are interested and why you think you would be a strong candidate - I am happy to design projects for this studentship that suit the interests and skills of a student. |
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Asymmetry in dorsolateral prefrontal function The dorsolateral prefrontal cortex (dlPFC) has become a target region for transcranial magnetic stimulation of treatment resistant depression (trMDD). Activation of the left hemisphere or inhibition of the right hemisphere have both been effective, although the former is more commonly used. However, concrete evidence for asymmetry in dlPFC function is lacking. Recently, we have shown asymmetry in the effects of area 46 interventions within dlPFC (dlPFC-46) upon appetitive motivation in common marmosets, with acute inactivation of the left, but not the right, hemisphere reducing motivated responding for reward. This hemispheric specialised effect was replicated using chemogenetics to target specifically the pathway from dlPFC-46 to perigenual area 32 within medial PFC. The PhD will explore these hemispheric functional differences further, extending the range of functions studied to include working memory and decision making. The project will involve a range of experimental techniques including chemogenetics to allow pathway specific targeting, computerised behavioural testing and analysis, alongside computational modelling to dissect out the underlying psychological variables and analysis of resting state fMRI for investigating functional connectivity. An additional research strand on studying the neurobiological substrates of treatment strategies for MDD within this circuitry may also be undertaken. |
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Supracellular actomyosin networks sculpting tissues How organ shape is genetically encoded remains a major unresolved question in biology. All tissues arise from simple primordia that become patterned through transcriptional changes within individual cells. Despite much progress untangling relevant developmental gene networks, how cellular patterning is turned into physical changes at tissue scale is poorly understood. The Röper lab studies the formation of tubular organs, the salivary glands in Drosophila embryos and the formation of the nephron tube in human renal organoids in culture. In this project, we want to understand the role that supracellular cytoskeletal networks built from actomyosin play in driving tissue shape changes and coordinating tissue morphogenesis. These supracellular networks are built in individual cells but coordinated between many neighbouring cells, leading to important emergent properties at the tissue scale. Supracellular actomyosin assemblies are conserved across evolution, and so this analysis will uncover mechanisms not restricted to flies, but in a genetically highly tractable model. For this project, you will use a combination of fly genetics, advanced imaging methods including live, super-resolution, laser ablations, as well as genomic and biochemical approaches to identify components and roles of these intriguing assemblies. |
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Mechanisms and mechanics of cell polarisation in human renal organoids In the Röper lab, we want to understand how a transcriptional blueprint is transformed into physical changes at the cell and tissue scale. We focus on the formation of tubular organs, as tubular organs make up most of our own internal organs, and capitalise on the recent advances in organoid culture systems that allow us to derive human tissue organoids in culture from iPSCs, and in our case renal organoids that recapitulate the formation of the nephron tube. All nephrons are formed prenatally and nephron number and health is a key predictor of later kidney health, with chronic kidney disease representing a major health burden world-wide. We are particularly interested in the earliest steps of nephron formation, where mesenchymal cells group together and become polarised into epithelial cells that then begins to form the nephron tube in a process termed mesenchymal-to-epithelial transition (MET). We have generated multi-ome data that allowed us to define the early transcriptional control of this process in humans and have indications of the cell biological mechanisms that operate to drive the polarisation. In this project, we want to identify the morphogenetic effectors downstream of the key transcription factor for MET that we uncovered, PAX8, to illuminate how cells polarise, how junctions to neighbouring cells and the ECM are established and how the MET programme then drives the formation of a healthy narrow-lumen tube, rather than a cyst-like structure that would be a marker of kidney disease. To address these questions, you will use a combination of techniques including iPSC culture and differentiation to organoids, advanced microscopy of live and fixed samples, quantitative approaches, CRISP-mediated knock-down and overexpression and biochemical approaches. |
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Reprogramming the migratory patterns of inflammatory cells Inflammation is a physiological response to injury or harmful agents that ensures tissue defence. A hallmark of inflammation is the accumulation of leukocytes, among which neutrophils have a prominent role as early infiltrators and innate immune effectors. Beyond infection, neutrophil accumulation occurs in tumors and can influence tumor evolution. As neutrophils represent the most abundant leukocyte type, their manipulation can be an attractive route for tumor immunotherapies. However, it remains unclear how to reprogramme neutrophil trafficking. A general premise has been that leukocytes must interpret gradients generated by heterologous tissue cells upon inflammation. Yet, it is increasingly appreciated that many types of migrating cells can generate gradients that they respond to, providing a means of self-organisation. Building on this, preliminary evidence from our lab indicates that genetic engineering of neutrophils to enhance self-generation of chemoattractant gradients is sufficient to boost neutrophil infiltration of infected loci and bacterial clearance. The objective of this project is to explore the role of such neutrophil reprogramming in cancer. The first aim is to establish a tractable tumor model in zebrafish, whereby neutrophil migration and tumor evolution can be easily visualised over time. The second aim is to establish whether reprogrammed neutrophils (with enhanced self-guidance) have altered migration patterns in tumors and how this affects tumor evolution. The third aim would be to build on this model by co-expressing chimeric antigen receptors to enhance tumor recognition and killing. Thus, this project will build new knowledge on how to orient neutrophil recruitment and function towards desirable disease outcomes. |
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Other supervisor: Ewa Paluch Relevant References:
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Cell division and cortex dynamics in in vivo confined microenvironment In vivo, cells migrate through tight spaces and may undergo division in crowded environments, both in physiological and pathological contexts, for example during immune cells diapedesis or cancer cell dissemination. These phenomena are difficult to observe in vivo, especially in mammalian models. Key studies in the field have largely exploited in vitro systems, for example culturing cells in 3D collagen matrices or microfabrication of PDMS microchannels, to mimic interstitial confining environments. From this wealth of work, it has become clear that cells experiencing physical confinement during cell migration suffer mechanical stress. When cells in culture undergo mitosis under mechanical compression, they show extensive cortical blebbing and suffer division defects. Together, these findings show that mechanical stress negatively impacts the integrity of the genome and this has been proposed to underlie cancer initiation and progression. However, the consequences of mechanical compression on cells during in vivo cell division events remain so far unexplored. Here, we will use Zebrafish trunk neural crest cell migration as a novel, physiological model to understand cell division during in vivo physical confinement. The Scarpa lab have preliminary data showing that leaders and followers dividing in the narrow migratory path take significantly longer than premigratory cells, which divide unconfined, to pass through metaphase, and have altered cortex dynamics with prolonged metaphase blebbing. This suggests that in vivo physical confinement may cause delay in passing the anaphase spindle checkpoint.This project will provide a timely opportunity to test the contribution of mechanical stress to genome instability in vivo. |
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Other supervisor: Ewa Paluch
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Investigating nuclear envelope rupture and repair during cell migration under mechanical compression in vivo Does compression compromise nucleus integrity of the TNCs? Cells dividing or migrating in tissues must push against other cells or squeeze through tight spaces. In vitro studies on single cells have shown that physical compression causes mechanical stress, leading to DNA damage because of deformation or rupture of the nuclear lamina. However, whether compressive forces also cause stress in a physiological in vivo setting has not yet been investigated. This project overcomes these challenges by using Zebrafish. Zebrafish embryos are translucent, enabling visualisation of migrating cells in an intact animal. We investigate a population of well characterized embryonic multipotent stem cells, neural crest cells. In the trunk of the Zebrafish embryo, trunk neural crest cells (TNCs) move through narrow spaces, squeezing between the neural tube, notochord and somites. In this project, we will ask whether the compression experienced by TNCs during their physiological developmental migration causes DNA damage during their in vivo physiological migration in this cell population. To characterize location and timings of nuclear envelope openings, we will carry out live imaging of the cytoplasmic DNA reporter cGAS-EGFP using a recently generated transgenic Zebrafish line. To ask whether TNCs experience DNA damage upon nuclear deformations in vivo we will use a novel Zebrafish transgenic line to image 53BP1-emGFP, a live reporter for DNA double-strand breaks and validate this by immunostaining for phosphorylated histone gammaH2AX. Taken together, these experiments w dissect whether physiological mechanical compression can cause lasting DNA damage in migrating cells within a developing vertebrate context. |
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Amanda Sferruzzi-Perri
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Lasting impacts of the placenta on maternal health and aging This PhD project aims to revolutionize our understanding of the significance of placental endocrine function for maternal health both during and after pregnancy. While the effects of placental hormones in establishing pregnancy are well-established, their wider role in functional adaptation of maternal organs to support pregnancy and the mechanism by which they act are poorly understood. Nor is it known how placental hormones are implicated in pregnancy complications and later life multi-morbidity. To address these knowledge gaps, this project will use newly developed tools in protein labelling and quantitative proteomics to assess the secretome of the placenta during pregnancy. Using loss and gain-of-function genetic models and robust physiological testing and imaging, we will establish the importance of newly-identified placenta hormones in adapting maternal metabolic organs during pregnancy, and in determining metabolic health and aging post-pregnancy. The underlying signalling mechanisms involved will be assessed by using state-of-the-art transcriptomic and epigenetic analyses of maternal metabolic tissues. In identifying key placental hormones indicative of pregnancy success and maternal health, the study offers potential diagnostic and therapeutic avenues to prevent complications and lifelong impacts of pregnancy in women globally. It also offers fundamental understanding of female health and aging. |
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The Interplay Between Host and Microorganisms in Developing a Keystone Symbiotic Relationship Symbiotic relationships, the close long-term physical association between two different species, regulate key biological functions. The closest symbioses occur when single-celled microorganisms are internalised into host cells, a partnership that drives the evolution of novel biological adaptations. This form of symbiosis is exemplified in the relationship between Cnidarians, including corals and sea anemones, and their algal symbionts, with nutrient transfer from algae to their hosts sustaining coral reef ecosystems. Intriguingly, the development of this relationship coincides with host morphogenesis and spans biological scales of organisation. At the cell level, large algal symbionts get taken into host endoderm cells. At the tissue level, symbiont-occupied cells are patterned through an unknown mechanism to specific regions of the host during its morphogenesis into a polyp. How the host-symbiont relationship alters cell and tissue properties to regulate symbiont patterning and host morphogenesis remains unclear. Our preliminary data show that host cells expand by ~5 fold following symbiont uptake and that symbiont-dense tissues show a more solid-like behaviour. In this PhD project, the student will use interdisciplinary approaches to elucidate the mechanisms responsible for the development of this ecologically crucial symbiotic relationship, including: 1) 4D cellular resolution imaging of cnidarian morphogenesis combined with AI-assisted morphology analysis, 2) tissue mechanics measurement and perturbation, and 3) functional genetics perturbations. The student will work closely with Dr. Susie McLaren and acquire a variety of skillsets in a highly interdisciplinary group. |
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