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Molly Stevens - Bionanoscience 'Guiding Brain Organoids: Advanced Scaffolds for Neural Growth'
The human brain and its function are one of the big mysteries of humankind. Many strategies are helping to gain a fundamental understanding of the development and function of the central nervous system: imaging of the human brain, post-mortem analysis, animal models, and – since only a few years – advanced three-dimensional neural structures which reassemble aspects of the human brain, called brain organoids. Brain organoids have been used to model brain development, diseases and neural circuit formation and function. However, to date the lack of directional control over neurogenesis, as well as the limited capability to support larger tissue structures with sufficient nutrition, limit the potential of these human stem cell derived tissues. In this project we aim to develop a scaffold to support directional neurogenesis and perfusion of large brain organoids. The student will learn a range of methodologies, which will include (but are not limited to) stem cell culture, neural differentiation, 3D printing, confocal microscopy and live imaging. Furthermore, the student will be involved in the fabrication and functionalisation of biomaterials.
Ana Domingos - Metabolism and endocrinology 'Fundamental biological mechanisms in Sympathetic Neurocircuitry underlying body weight'
Effective obesity management medications that elevate energy expenditure, such as brain-acting sympathomimetics, lead to descending widespread sympathetic activity that raises the heart rate1. These adverse cardiovascular side effects have repeatedly resulted in their market withdrawal or rejection by regulatory agencies despite their potency in reducing body weight. Consequently, treatment options have been limited to suppressing appetite, for instance, with Glucagon-like peptide-1 (GLP-1) mimetic drugs, which lead to a compensatory decrease in energy expenditure, increasing the risk of recurrent weight gain2,3. While reducing food intake is crucial for treating obesity, sustaining a higher energy expenditure is necessary for therapies to be durable. This could be achieved by directly manipulating subpopulation of sympathetic neurons as they release factors within metabolic tissues that trigger anti-obesity actions beyond appetite control4–6, and without cardiac side effects1,7.
Pawel Swietach - Cell physiology Metabolism & Endocrinology 'Break the Acid Cycle: Targeted Collapse of Tumour Adaptation'
Break the Acid Cycle: Targeted Collapse of Tumour Adaptation DPAG Supervisor: Pawel Swietach
Mootaz Salman - Neuroscience - 'Advanced 3D brain-on-a-chip platforms to study molecular mechanisms of neurodegeneration'
The brain microenvironment is tightly regulated by the blood–brain barrier (BBB) which maintains the central nervous system internal milieu. BBB leakage following neuroinflammation (or systemic inflammation) has recently been described early in the occurrence and development of neurodegenerative disorders including Parkinson’s, Alzheimer's, and cerebral small vessel disease. Dynamic 3D models of the BBB represent a major advance on traditional static 2D models allowing cells to be in a physiologically realistic native-like 3D environment that faithfully recapitulate the complexity of an in vivo system without artificial support membranes. We seek highly motivated DPhil students with either a scientific or medical background to join our group to work on the molecular mechanisms of BBB (dys)function in neurodegeneration. In this project, you will combine the use of patient-derived induced pluripotent stem cells (iPSCs) together with novel brain-on-a-chip platforms, advanced microscopy, microfluidics, and molecular assays. This project will advance our ability to understand how does inflammation-mediated BBB dysfunction lead to the development of neurodegeneration and dementia. It will establish a framework to address fundamental questions about the role of the BBB in health and neurodegeneration.
Black History Month 2023 - Saluting Our Sisters: Mary Logan Reddick
Mary Logan Reddick (31 December 1914 - 1 October 1966)
Black History Month 2023 - Saluting Our Sisters: Marie Daly
Marie Daly (April 16th, 1921 – October 28th, 2003)
Black History Month 2023 - Saluting Our Sisters: Dolores Cooper Shockley
Dolores Cooper Shockley (21 April 1930-10 October 2020)
Damian Tyler - Cardiac Sciences / Metabolism & Endocrinology - 'Assessment of Cardiac Metabolism Using Hyperpolarized Magnetic Resonance Imaging'
The role of abnormal cardiac substrate metabolism in the development of many cardiovascular diseases and the therapeutic potential of interventions targeting cardiac substrate metabolism are unclear. Magnetic Resonance Imaging and Spectroscopy (MRI/MRS) have long been used to monitor cardiac structure and function. However, the application of MRI/MRS for metabolic imaging has been limited by an intrinsically low sensitivity. Hyperpolarized Magnetic Resonance (hp-MR) is a new technique that yields greater than 10,000-fold signal increases in MR images and enables unprecedented real-time visualization of the biochemical mechanisms of abnormal metabolism. This allows measurement of instantaneous rates of substrate uptake and enzymatic transformation in vivo, providing a sensitive assessment of disease and a new means to monitor treatment response. This project will explore the application of hp-MR in the study of cardiovascular disease, enabling the assessment of pyruvate metabolism through the key metabolic enzyme, pyruvate dehydrogenase, and how it can be modulated as a therapeutic target.
Clive Wilson - Metabolism & Endocrinology - 'Regulation of microcarriers: new messengers of cell-cell and reproductive signalling in higher organisms'
Cell-cell communication controls almost all physiological processes in multicellular organisms and is defective in many diseases. Our group has developed the male reproductive accessory gland in the fruit fly Drosophila melanogaster as a new genetic model to study the fundamental processes involved in secretion and signalling. Employing this system, we discovered that multiple secreted signals, including Sex Peptide, the central regulator of female post-mating responses, are packaged into lipophilic structures that we call microcarriers, which stabilise these proteins in the gland and then permit their rapid release when deposited in the female uterus. We have now found that evolutionarily conserved derivatives of the lipid ceramide and the enzymes that produce them have multiple roles in generating microcarriers. In humans, components of this microcarrier biogenesis pathway are required for several biological processes in humans. They are highly upregulated in cancer and implicated in metabolic disease and obesity. In this project, additional new evolutionarily conserved regulators of microcarriers that we have recently identified will be characterised using advanced genetic and imaging technologies to determine their functions. We anticipate that this work could provide the stepping stone to extend our studies into human cells and assess the relevance of microcarriers to human health and disease.
Clive Wilson - Development & Cell Biology - 'Dissecting the conserved in vivo regulation of Rab11-exosomes in Drosophila'
Exosomes are nano-sized vesicles secreted from the endosomal compartments of cells. They carry a multitude of different bioactive cargos, including proteins, RNAs and lipids that can reprogramme target cells. Exosomes have been implicated in many pathologies, in particular cancer, where they can prime pre-metastatic sites, induce drug resistance and suppress the immune system. However, they are also involved in complex physiological cell-cell signalling events. For example, we found that exosomes secreted into seminal fluid in the male accessory gland of the fruit fly reprogramme female behaviour, so she rejects other males that try to mate with her. Using this fly model in which exosomes are made inside unusually large intracellular compartments that can be imaged in real-time, we identified a novel evolutionarily conserved exosome subtype, called Rab11-exosomes, which is the primary mediator of key physiological and cancer-relevant exosome functions, despite representing a small fraction of all secreted vesicles. We recently identified multiple new conserved regulators of Rab11-exosomes by combining human Rab11-exosome proteomics with fly genetic analysis. This project will involve analysing these regulators further, focusing on how they shape Rab11-exosomes, coat these exosomes with extravesicular proteins and traffic them to the cell surface, mechanisms that are all potential targets for future exosome subtype-specific therapies. See https://www.biorxiv.org/content/10.1101/2024.03.28.586966v2 for recent developments.
Richard Wade-Martins - Neuroscience - 'Human stem cell models of neurological disease'
We seek highly motivated DPhil students with either a scientific or medical background to join our laboratory to work on the molecular mechanisms of neurological and neurodegenerative diseases. Techniques in molecular genetics have allowed the identification of genes and proteins with an important function in both familial and sporadic forms of Parkinson’s disease and Alzheimer’s disease. Our laboratory focusses on following up these genes and proteins to better understand disease mechanisms to identify potential therapeutic targets for further translational studies. To undertake this, we work with induced pluripotent stem cells (iPSCs) generated from patients with Parkinson’s, Alzheimer’s and related disorders. iPSC-derived patient models promise to revolutionize the study of neurodegenerative diseases in which the critical cell type has been previously inaccessible. The capability to generate, engineer, differentiate and phenotype iPSC-derived neurons and glia from patients with neurodegeneration allows for the study of highly physiological human models of disease. We have undertaken a detailed phenotypic analysis of patient and control iPSC-derived neurons and glia and identified and published strong cellular phenotypes using robust assays suitable for studying disease mechanisms across a range of new projects.
Clive Wilson - Neuroscience - 'Regulation of physiological and pathological amyloidogenesis in Alzheimer’s disease and beyond'
Amyloidogenesis, the aggregation of soluble proteins into insoluble fibrils, has multiple biological functions in health and disease, eg, in Alzheimer’s Disease (AD), aggregations of A-beta peptides, cleaved products of Amyloid Precursor Protein (APP), form plaques, while peptide hormones naturally condense into insoluble, dense-core granules (DCGs), stored within secretory vesicles until release. However, in vivo assays to analyse how amyloidogenesis is initiated are lacking. We have developed a new cellular model for DCG biogenesis, the Drosophila prostate-like secondary cell (SC). These cells have highly enlarged (5 micron diameter) DCG compartments, permitting the rapid process of DCG assembly to be followed by light and fluorescence microscopy in real-time. We find DCG formation requires the fly homologues of APP, called APPL, and another amyloidogenic protein, TGF-beta-induced, as well as intraluminal vesicles that are secreted as so-called Rab11-exosomes. Genetic dissection of the DCG biogenesis process in SCs shows that it is disrupted by mutant proteins linked to AD, including A-beta peptides and Tau, producing several AD-like phenotypes, and strongly suggests that these previously unappreciated defects are key triggers in pathology. This project will characterise this process further in flies and investigate how pathological defects can be suppressed by genetic manipulations, drugs and dietary changes. See https://www.biorxiv.org/content/10.1101/2024.03.28.586966v2 for recent developments.
Manuela Zaccolo - Cardiac Sciences - 'Nanodomain signalling in the heart'
cAMP and its effector PKA are key regulators of cardiac function and defective cAMP/PKA signalling is a hallmark of heart failure (HF) and genetic cardiomyopathies. This signalling pathway is also at the core of current therapies, which however remain unsatisfactory and need improvement. Current therapeutic strategies largely ignore signalling processes occurring in cardiomyocytes at the subcellular level. We use FRET-based imaging approaches to measure cAMP/PKA signalling in real-time and with high spatio-temporal resolution. Using this approach we were able to directly show that cAMP/PKA signalling is highly compartmentalised within subcellular nanodomains (1, 2), with different sites affecting different functions (2). In a recent study we found that adrenergic stimulation generates pools of cAMP with different amplitude and kinetics at the plasmalemma and at the myofilaments and that such local regulation is disrupted in HF (2). Local PKA activity is dictated by local [cAMP], controlled at each specific site by particular adenylyl cyclases (AC) and phosphodiesterases (PDE) isoforms. Local phosphorylation of targets results from the balance of local PKA and phosphatase (PP) activity. All these components can potentially be manipulated to affect local signalling. Compartmentalization of signalling provides a unique opportunity to intervene therapeutically with increased precision by selectively targeting individual nanodomains to affect only the desired function. Recently, we have conducted an integrated PDE phospho-interactome ananlysis that unveiled multiple novel and non-obvious cAMP nanodomain under specific regulation of PDE isoforms (4). We are currently validating these data and characterising the function reglated by these novel nanodomans.The overall aim of our work is to build a detailed map of cAMP nanodomains in cardiac myocytes . The map will be used as a blueprint to assess alterations in pathological conditions to gain novel mechanistic understanding of pathological processes at the molecular level. This information will guide development of new strategies for targeted therapeutic interventions.The project will test novel FRET-based reporters targeted to specific subcellular sites in cardiac myocytes to establish local cAMP dynamics at key signalling nodes that participate in the regulation of cardiac myocyte function. The work will involve biochemical and genetic approaches to study cAMP signalling at these sites in animal models of HF and in human cardiac myocytes differentiated from inducible pluripotent stem cells.
Zoltán Molnár - Neuroscience - 'Earliest Thalamocortical Interactions'
Conscious perception in mammals depends on precise circuit connectivity between cerebral cortex and thalamus. During the wiring of reciprocal thalamus-cortex connections, thalamocortical axons (TCAs) first navigate forebrain regions that had undergone substantial evolutionary modifications. In mammals, transient cell populations in internal capsule and early corticofugal projections from subplate neurons closely interact with TCAs to guide pathfinding through ventral forebrain and pallial subpallial boundary (PSPB) crossing. Prior to TCA arrival, cortical areas are initially patterned by intrinsic genetic factors. TCAs then innervate cortex in a topographically organised manner to enable sensory input to refine cortical arealization. We investigate the mechanisms underlying the reciprocal influence between thalamus and cortex during development in rodent and in human. We recently demonstrated that these axons exhibited a close anatomical relationship with the existing germinal compartments in human. By 17 PCW, TCA did not only reach the transient subplate, a well-known target for thalamic axons in the mammalian brain, but also appeared to project toward the outer subventricular zone (OSVZ). We are using transcriptomic and proteomic approaches to explore the unique target compartments of the developing cortex, such as the OSVZ and suplate. We recently identified candidates that could mediate these interaction through paracrine mechanisms by secretion of neuroactive peptides.
Rui Ponte Costa - Neuroscience - 'AI-driven brain-wide credit assignment'
We are at an exciting turning point in neuroscience. New technologies now allow us to measure and control neural activity and behaviour with unprecedented detail (Landhuis et al. Nature 2017, Lauer et al. Nature Methods 2022). At the same time, new theoretical frameworks are starting to reveal how rich behaviours arise from synaptic, circuit and systems computations (Richards et al. Nature Neuroscience 2019). We are contributing directly to the latter by aiming to understand how we learn. To this end, we are developing a new generation of computational models of brain function guided by deep learning principles. We focus on understanding how a given behavioural outcome ultimately leads to credit being assigned to trillions of synapses across multiple brain areas – the credit assignment problem. To survive and adapt to dynamic and complex environments animals and humans must assign credit efficiently. Recently, we have shown that the brain can approximate deep learning algorithms (Sacramento et al. NeurIPS 2018, Blake et al. Nature Neuroscience 2019, Greedy et al. NeurIPS 2022, Boven et al. Nature Comms 2023). In this project, you will build on state-of-the-art computational models of AI-like credit assignment in the brain and contrast it with recent experimental observations at the behavioural, systems and circuit level.
Nick Talbot - Cardiac Sciences - 'Effects on iron status on cardiorespiratory responses to hypoxia'
Iron availability has the potential to influence exercise capacity through its effects on red blood cell production, particularly at altitude where the erythropoietic drive is elevated. However, there is increasing evidence that iron levels per se may also influence cardiorespiratory function through direct effects on the pulmonary vasculature, cardiac function and cellular metabolism. This project would build upon previous research in Oxford and elsewhere to characterise the relationship between iron status and cardiorespiratory function during hypoxia, which has implications not only for athletic performance at altitude, but also for patients with chronic hypoxic lung disease. The project would be based around the study of integrative physiology in human volunteers, but we work in synergy with Prof Samira Lakhal-Littleton, whose laboratory has expertise in the use of preclinical models to dissect the mechanisms by which iron influences physiology at both a cellular and a systemic level.
Nick Talbot - Cardiac Sciences - 'Modulators of the hypoxia-inducible factor (HIF) pathway and cardiorespiratory physiology'
The hypoxia-inducible factor (HIF) signalling pathway regulates the cellular response to hypoxia, but also appears to coordinate systemic responses to hypoxia, including the pulmonary vascular and ventilatory responses. In humans, the role of the HIF pathway in cardiorespiratory physiology has been characterised to date mainly by studying small groups of patients with genetic disorders, for example those with mutations in the HIF proteins themselves, or in the associated prolyl hydroxylase domain (PHD) oxygen sensing enzymes. Recently, a number of drugs have been developed that influence HIF signalling. Roxadustat, for example, is licensed for treatment of renal anaemia, and acts by upregulating the HIF pathway through PHD inhibition. However, the effects of this drug on systemic responses to hypoxia are not well understood. This project, funded in part by a Medical Research Council award to Dr Mary Slingo, will initially examine the effects of roxadustat on physiological responses to hypoxia in healthy volunteers, with a view to longer term studies in patients receiving this drug in the clinical setting.