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Samira Lakhal-Littleton - Cardiac Sciences - 'Iron and the heart '
Over the past decade, research by this team has shown that iron deficiency (ID) affects much more than our ability to make haemoglobin (i.e. our risk of anaemia). Iron is required for many other processes in the body, notably making the ATP necessary to power the contraction of the skeletal and cardiac muscles. Work by this team was the first to demonstrate that ID in the heart, which we have termed “myocardial iron depletion” (MID) can cause heart failure even when haemoglobin levels are normal. Our discoveries provided a long-sought explanation for why ID, even in the absence of anaemia, is associated with increased risk of incident heart failure (HF) in the general population, and with worse outcomes in patients with HF. We are now building on these discoveries to translate them into clinical practice. Keys objectives are: 1. Discovering novel non-invasive biomarkers of MID 2. Understanding if current iron supplementation approaches correct MID 3. Exploring the role of MID in other disease conditions such as dilated cardiomyopathy Our research combines clinical studies and preclinical models of heart failure. Techniques range from proteomic and metabolomic characterisation of patient samples, to advanced MR imaging of Heart function in pre-clinical models, to cell-based work. We are a diverse team of highly motivated researchers with a shared passion for translational research.
Andrew King - Neuroscience - 'Models of the encoding of sounds by the auditory system'
Neurons in auditory cortex produce patterns of spikes in response to sound. What is the computational mapping from sound to auditory cortical responses? Can we predict the moment-to-moment responses of neurons in the auditory cortex to arbitrary sounds? This computational project involves fitting various models to the mapping from natural sounds to neural responses recorded from the midbrain and auditory cortex. The project will begin with a fitting a simple model, the linear-nonlinear model, and testing its capacity to predict neural responses to a held-out dataset of sounds. The student will then go on to analyse the linear and nonlinear parts of this model to look for different types of neuron and extend this work to include more complex network models that better reflect the physiological properties of auditory neurons and the way information processing changes between the midbrain and cortex. The structure of these more complex networks will be analysed to provide insight into the functional organization of the auditory brain.
Edward Mann - Neuroscience - 'Functional connectivity of hypothalamo-cortical circuits'
Stress exacerbates many psychiatric conditions, and repeated stress contributes to the pathogenesis of disorders such as Post Traumatic Stress Disorder, Panic Disorder and Major Depressive Disorder. The orexin (hypocretin) system is highly reactive to stress, and regulates many physiological processes that are altered in stress-related mental illness, including sleep/wake patterns, appetite and cognition. Changes in orexin levels have been reported in major depression and anxiety disorders, and polymorphisms in the orexin 1 receptor are associated with anxiety spectrum disorders, particularly in women. The orexin system is therefore an attractive target for treating stress-related disorders. Orexinergic neurons have wide projection targets across the nervous system, including hypothalamus, thalamus, cortex, brain stem and spinal cord. The projections to other hypothalamic neurons and subcortical arousal centres are important for modulating arousal, appetite and activity of the Hypothalamic Pituitary Adrenal Axis. The roles of projections to cortical circuits remain less well understood, but may be involved in regulating cortical arousal and the cognitive responses to stress and could represent promising targets for drug development to treat stress-related cognitive dysfunction. The aim of this project is to resolve the mechanisms by which orexinergic neurons directly modulate cortical network activity, using optogenetic stimulation of orexinergic projections in ex vivo cortical brain slices in combination with patch-clamp recordings, multiphoton imaging and high density multielectrode arrays.
Zoltán Molnár - Neuroscience - 'Role of SNARE proteins in cortical development'
Neural communication in the adult nervous system is mediated primarily through chemical synapses, where action potentials elicit Ca2+ signals, which trigger vesicular fusion and neurotransmitter release in the presynaptic compartment. At early stages of development, the brain is shaped by communication via trophic factors and other extracellular signalling, and by contact-mediated cell–cell interactions including chemical synapses. The patterns of early neuronal impulses and spontaneous and regulated neurotransmitter release guide the precise topography of axonal projections and contribute to determining cell survival. We study of the role of specific proteins of the synaptic vesicle release machinery in the establishment, plasticity, and maintenance of neuronal connections during development. We examine mouse models where various members of the N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex have been genetically manipulated (e.g. Snap25 or Munc13). We are focusing on the role of regulated vesicular release and/or cellular excitability in synaptic assembly, development and maintenance of cortical circuits, cell survival, circuit level excitation–inhibition balance, myelination, refinement, and plasticity of key axonal projections from the cerebral cortex. These models are important for understanding various developmental and psychiatric conditions, and neurodegenerative diseases.
Andrew Peters - Neuroscience - 'Neural circuits for learning and executing behaviour'
Behaviour is not learned and driven by single brain regions, but instead arises from cooperation across multiple areas. One prominent circuit of interdependent regions consists of a loop between the cortex, basal ganglia, and thalamus. Together, these regions are critical for learning and executing behaviour, though it is largely unknown how this is accomplished at the level of neural activity. Our lab is interested in discovering fundamental principles of this circuit, and we investigate issues like how activity flows between regions, how it changes with learning, and how activity relates to behaviour. Our experiments combine large-scale imaging and electrophysiology techniques with learned behaviours and neuronal manipulation in mice. We use simple tasks, like stimulus-response associations, to investigate the relationship between activity and behaviour. Projects in the lab can be flexible along these themes, and may typically include recording and analysis from one or more brain regions across learning.
Paul Riley - Cardiac Sciences - 'Investigating the mechanisms of autoimmunity during heart failure'
Heart Failure (HF) is a rapidly growing public health issue with an estimated prevalence of >37.7 million individuals globally and is a major unmet clinical need. HF is underpinned by cardiomyocyte hypertrophy, interstitial fibrosis, pathological remodelling and ultimately death. Current interventions do not prevent disease progression and cannot restore heart function. A critical contributor to chronic decline of cardiac function in HF is the immune system, notably the adaptive immune response. Following tissue damage there is release of cardiac antigens, such as α-myosin heavy chain (α-MHC), which are captured by dendritic cells (DCs) and presented to T-cells in the draining lymph nodes, inducing an auto-reactive T-cell response. This is due, in part, to T-cells escaping central tolerance towards cardiac self-antigens during development in the thymus. Activation of T-cells, primed against cardiac antigens, is seen as a possible mechanism for prolonged cardiac injury well after the initial insult. In support of this, anti-heart autoantibodies against cardiac epitopes are a well-known clinical epiphenomenon during HF and the presence of autoreactive T-cells post-MI has previously been demonstrated. This project will focus on understanding the mechanisms behind T-cells escaping central tolerance towards cardiac self-antigens during development in the thymus, and whether restoring this tolerance improves disease progression in HF.
Filipa Simões - Cardiac Sciences / Development & Cell Biology - 'Decoding spatial heterogeneity in the regenerating heart'
Myocardial infarction (MI) causes permanent heart tissue loss in adult mammals. Following an MI, the injured heart recruits a significant number of monocyte-derived macrophages, essential immune cells that play critical roles in both scar formation and tissue regeneration. However, we still have limited understanding of the specific factors influencing distinct macrophage functions within the damaged heart. This project aims to shed light on how macrophage heterogeneity is linked to their spatial distribution across the heart and how, in turn, this distribution shapes macrophage identity and function. Despite their vital roles in cardiac repair, the intricate local environmental cues and cell-cell interactions governing the diverse roles of macrophages in this context have not been fully deciphered. By comprehending the regenerative microenvironment, where the innate immune response persists while still supporting regeneration, and by targeting macrophage-induced pro-fibrotic pathways, we may develop therapeutic strategies that harness pro-regenerative responses in the injured mammalian heart.
Filipa Simões - Cardiac Sciences / Development & Cell Biology - 'A human vascularised cardiac organoid system for modelling cell-cell interactions and target discovery in heart disease'
A major obstacle to a deeper understanding of how the human heart responds to injury is the lack of human-derived in vitro 2D and 3D cell culture models that faithfully recapitulate the complexity of an in vivo system, where multiple resident and infiltrating cell populations co-exist and interact within the cardiac niche. Our group is working towards the development and application of self-organizing multi-lineage cardiac organoid structures to account for the complex 3D cell-cell interactions occurring between multiple cardiac cell types. We aim to facilitate translational research by enabling genetic screens and pharmacological modulation of disease states by further developing a human 3D vascularised cardiac organoid model that offers a chamber-specific, scalable and highly manipulable multi-lineage human cardiac model that reduces dependence on animal models.
Nicola Smart - Development & Cell Biology - 'Developmental insights for cardiac regeneration'
We investigate mechanisms of embryonic heart formation to inform novel strategies for regenerating the adult mammalian heart, for example after myocardial infarction. We have a particular interest in how the outer layer epicardium stimulates new coronary vessel growth and myocardial maturation, both in development and disease. Following injury, there is a partial recapitulation of embryonic processes that drive coronary vessel growth, yet fundamental differences in the regulatory pathways limit the efficacy of the adult response. Comparative analyses allow us to identify key mechanisms that may be targeted in the adult mammalian heart to enhance repair. Current projects focus on mechanisms controlling the transition of the epicardium from active (embryonic) to quiescent (adult) state, as well as the signalling pathways through which the embryonic epicardium stimulates expansion of the coronary vasculature. Our research in murine models is complemented with bioinformatic analyses and in vitro human cell-based models of development and disease.
Duncan Sparrow - Cardiac Sciences / Development & Cell Biology / Metabolism & Endocrinology - 'How does maternal fever cause congenital heart disease?'
Congenital heart disease (CHD), where a baby’s heart does not form properly in the womb, is the most common birth defect, affecting 1% of all babies. Even with the advent of modern surgical correction techniques, it is the major cause of infant mortality and morbidity, requiring lifelong medical treatment. However, we do not always know why it happens. One-third of cases result from a genetic fault, but in the other two-thirds of cases the cause is less clear. Some of the latter result from the embryo being exposed to an abnormal environment in the womb in early pregnancy. This project will investigate the effects of one particular environmental factor (maternal fever in early pregnancy) on embryonic development using a mouse model system. This can cause a suite of birth defects including severe CHD. This is especially relevant today, with increasing coverage of false claims about an association between the most effective treatment for fever in pregnant women (paracetamol) and birth defects. However, little is known of how maternal fever affects embryonic heart development. We have created a mouse model that recapitulates the CHD seen in humans. This project will use a combination of morphological and molecular methods to discover how this factor causes CHD.
The Don Mason Facility of Flow Cytometry
The Facility offers access to state-of-the-art flow cytometers and provides a bespoke cell sorting service, as well as comprehensive support on panel design, flow data analysis and cell sorting.
How to apply
Visit this page for our entry criteria and what you need to make an application, alongside some further resources to support you.
How to apply
Visit this page for our entry criteria and what you need to make an application, alongside some further resources to support you.
Upcoming Public Event: Oxford Parkinson’s Disease Centre Open Day
The Oxford Parkinson’s Disease Centre (OPDC) team are inviting members of the public to the OPDC Open Day on Monday 5 June 2023, 10am – 3pm.
Past Meetings
Previous conferences and symposia attended by Professor Ana Domingos
Anti-Racism Resources March 2023: Intersectionality of Privilege
We are all marginalised or privileged by the intersection of multiple aspects of our personal characteristics and identities such as class, religion, ethnicity, etc. Learn more about how acknowledging and understanding our own privilege helps us to be considerate about how we, and society in general, treat those that are different to us.