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Congratulations to Helen Christian, Stephen Goodwin, Jan Schnupp, Vivien Shaw, Pawel Swietach and Robert Wilkins.
Pawel Swietach - Cardiovascular, Cell physiology Metabolism & "Urine-on-a-Strip: Point-of-Care Detection of Intravascular Haemolysis"
**Fully funded project** Clinical feasibility study and refinement of a rapid, point-of-care urinary test for detecting intravascular haemolysis
Mehran Ahmadlou - Neuroscience Neural Circuits Underlying Approach-Avoidance Strategies in a Territorial Context'
Survival in territorial environments demands adaptive behaviour, as animals must balance access to resources with the risks of competition and predation. In the wild, animals must recognize when and where resources can be obtained, while simultaneously avoiding predators and navigating social hierarchies. Failures in these underlying circuits can manifest as anxiety-associated disorders such as post-traumatic stress disorder, impulsivity, anhedonia, depression, or pathological aggression. Understanding how animals adapt—or fail to adapt—in resource-limited, semi-natural contexts can therefore provide critical insight into the neural basis of mental health disorders. In this project, the Neurobehavior Lab, run by Mehran Ahmadlou, will investigate how neural circuits governing approach, avoidance, and defensive aggression support survival in complex environments. Freely moving mice will forage for nutritional resources in a territorial arena, competing with conspecifics for access while adapting to predatory threats. Using a combination of optogenetics, chemogenetics, Neuropixels recording, and miniaturized two-photon imaging, we will dissect how the brain integrates internal states with external challenges to guide adaptive strategy. Particular focus will be given to networks spanning the prefrontal cortex, hypothalamus, and midbrain survival circuits (periaqueductal gray, superior colliculus, and ventral tegmental area). To bridge the neural activity and behaviour, we will employ computational modeling approaches to capture how animals adjust their strategies and how circuit-level perturbations alter these computations. By resolving neural dynamics at the population and single-cell level, and linking them to quantitative models of decision-making, we will uncover how distributed circuits generate flexible territorial behaviours. By mapping the neural basis of behavioural flexibility in territoriality, this work will illuminate how adaptive survival strategies are generated—and how their breakdown drives neuropsychiatric conditions.
Mehran Ahmadlou - Neuroscience - 'The Neuromodulatory Control of Perception'
The Neurobehavior Lab run by Mehran Ahmadlou will, in collaboration with the Bruno lab, investigate how subcortical hubs orchestrate the balance between multiple neuromodulatory systems to shape sensory perception and behavioural responses. Neuromodulators such as acetylcholine, noradrenaline, serotonin, and dopamine exert widespread influence on cortical circuits, dynamically shifting cortical neurodynamics to regulate attention, arousal, and decision-making. However, how different neuromodulatory systems are coordinated by subcortical structures to tune cortical computations during perception remains poorly understood. Using Neuropixels recording, miniaturized two-photon imaging, optogenetics, and chemogenetics in head-fixed and freely moving mice, we will dissect how subcortical neuromodulatory hubs interact with cell-type-specific cortical microcircuits to guide perception under varying sensory and behavioural demands. Computational modelling of cortical dynamics will further link neuromodulatory activity to changes in network states and perceptual outcomes. This work will provide a mechanistic understanding of how neuromodulatory systems collectively sculpt perception and behaviour, and how their dysfunction may contribute to neuropsychiatric conditions such as attention-deficit / hyperactivity disorder and schizophrenia.
Lisa Heather: Cardiac Sciences/Metabolism & Endocrinology – 'Targeting Metabolism to Protect the Heart in Diabetes'
Diabetes affects 10% of the adult population worldwide, and cardiovascular disease is the leading cause of mortality in people with diabetes. However, we currently don’t understand why diabetes is so detrimental for the heart, and have limited treatment options to treat the heart in diabetes. We need to understand the cellular mechanisms by which diabetes affects cardiomyocyte function, as this will allow us to identify novel therapeutic targets for the treatment of this disease. Type 2 diabetes is primarily a metabolic disease, characterised by increased blood glucose and fatty acids. Cardiac metabolism changes early on in the development of diabetes, and this has been shown to contribute to the development of diabetic heart disease. However, we currently don’t fully understand the mechanisms that link metabolic dysfunction to cellular dysfunction in the heart, and studies are needed to unpick the signalling pathways directly regulated by abnormal metabolism. In addition, the metabolic origin of the diabetes complications makes metabolic therapy an attractive target to improve function in the diabetic heart. Work in the Heather group focuses on understanding the role of metabolism in the development of cardiovascular disease in diabetes, and investigating the potential for reversing this therapeutically. In this project the candidate will use pre-clinical and cell models of type 2 diabetes, along with metabolic tracers, mitochondrial respirometry, molecular biology and bioinformatics techniques to investigate the critical role for metabolism in diabetes.
Molly Stevens - Bionanoscience 'Development of biocompatible micro and nanoparticles for the delivery of vaccines'
The Pandemic Sciences Institute, University of Oxford, is committed to finding solutions to counteract future pandemic threats through science, innovation and building systems of global preparedness. This DPhil project is a collaboration between two PSI research groups led by Professor Dame Molly Stevens and Professor Dame Sarah Gilbert working towards novel delivery mechanisms for vaccines. Professor Molly Stevens’ team is interested in applying innovative bioengineering approaches and designer biomaterials to address some of the major healthcare challenges across diagnostics, advanced therapeutics and regenerative medicine. Professor Sarah Gilbert leads a research team generating vaccines against emerging pathogens, developing technology for the rapid transfer of vaccines into GMP manufacturing and assessing novel vaccine delivery mechanisms. This DPhil project represents an exciting opportunity to build on the current and innovative research programmes from these two research groups with the aim of developing new biomaterials and micro and nanoparticles for the delivery of vaccines through various routes of administration. The successful candidate will have full access to state-of-the-art laboratories in the Kavli Institute of Nanoscience Discovery within Prof. Molly Stevens’ laboratory.
Molly Stevens - Bionanoscience 'Engineered Organoid Co-Cultures to Advance Vaccine Delivery'
Despite significant advances in vaccine development, only a handful of vaccines have been approved for respiratory delivery. Although the mucosal barrier poses significant delivery challenges, it is hypothesised that intranasal or aerosolised vaccines could lead to better local protection and superior long-term protection compared with other delivery methods. While novel formulations can be tested in animal models and in vitro models, we still struggle to understand mechanistically the factors which make a respiratory mucosal vaccine successful. Work within the Stevens group has focussed on novel formulations for synthetic vaccines (LNP or polyplexes), as well as controlled drug delivery platforms such as pulsatile microparticles, capable of releasing therapeutics (i.e. small molecule, protein, nanoparticles) at pre-determined time points and polymer formulations which allow for long term, sustained drug release over 180 days. The Provine group has shown that lymphoid organoids derived from human tonsils can be used as an in vitro system to study vaccine responses, demonstrating the ability to model vaccine responses to adenoviral vector vaccines. In complementary systems, the Pollock group has demonstrated that human lymph node samples are technologically advanced models for the assessment of adaptive immune responses post vaccination. Meanwhile, the Lambe group has developed mucosal organoid systems which act as ideal models to assess the efficiency of vaccines delivered to respiratory sites like the nose and lung. These organoid systems are designed to mimic the complex physiological interactions between the lung, the primary site of infection for respiratory pathogens, and the lymphatic system, where the immune responses is initiated, however, in their current usage do so in isolation. In this project, we aim to develop and understand the interactions between lymphoid organoids and mucosal organoids as a semi-reductionist model of infection and immune response for vaccine development. We aim to use these models to assess how pulsatile or long-term exposure to a vaccine formulation influences the humoral response in lymphoid organoids, and how these two delivery mechanisms change uptake and or response in mucosal organoids.
Mehran Ahmadlou - Neuroscience 'Neural Mechanisms of Behavioural Strategies under Expected and Unexpected Uncertainty'
Adaptive behaviour relies on the brain’s ability to navigate uncertainty. Not all uncertainty is the same: it can be expected or unexpected. Expected uncertainty arises from known variability in outcomes within a stable environment. This variability can relate to timing, effort, value, or probability of outcomes. For example, rolling a die always produces a number between 1 and 6, or a vending machine may dispense snacks according to a fixed probability. Here, uncertainty stems from the range of possible outcomes, but the underlying rules remain consistent. In contrast, unexpected uncertainty emerges from sudden, unpredictable changes that violate previously learned rules—so-called structural knowledge of the environment. Examples include a traffic pattern shifting when a road closes without notice, a restaurant unexpectedly changing its menu, or a software update that radically alters a familiar interface. Unlike expected uncertainty, unexpected uncertainty reflects a change in the environment itself, invalidating prior expectations and requiring rapid behavioural adaptation. Differentiating these two types of uncertainty is critical for understanding learning, decision-making, and behavioural flexibility. By studying how the brain responds to expected versus unexpected uncertainty, we can uncover the neural mechanisms that support adaptive strategies in dynamic environments. The Neurobehavior Lab has developed a task in which freely moving mice and humans build structural knowledge of their environment while also experiencing unexpected uncertainty. This framework allows us to model and explain behavioural variability in how strategies are chosen under each form of uncertainty. To uncover the underlying neural mechanisms, we will combine advanced methods in freely moving mice—including miniaturized two-photon microscopy, Neuropixels recordings, fibre photometry, and targeted manipulations with optogenetics and chemogenetics. In collaboration with other groups, the project may also expand to explore the corresponding neural mechanisms in humans.
Mehran Ahmadlou - Neuroscience 'From Body Signals to Choice: Neural Mechanisms of Reward-based, State-dependent Decision-making'
Every day, we make choices—what to eat, whether to wait for something better, or how much risk to take. These decisions might feel rational, but they are powerfully influenced by what is happening inside our bodies. Hunger or stress, for example, can make us more impulsive, more risk-seeking, or less sensitive to the actual value of a reward. These shifts are not only part of everyday life but also play a role in mental health conditions such as addiction, depression, obsessive-compulsive disorder, and eating disorders. The brain systems that shape these processes connect deep hypothalamic regions, which monitor internal states like hunger and stress, with higher-order areas in the prefrontal cortex, which are crucial for evaluating options and making decisions. When these systems interact, the “equations” of decision-making, how strongly we care about reward size, how patiently we wait for delayed rewards, or how we respond to uncertain outcomes, can change dramatically. In this project, the Neurobehavior Lab will study how hypothalamic signals of hunger and stress alter decision-making in a multi-choice task and will investigate the neural basis. Using advanced methods in freely moving mice—including miniaturized two-photon microscopy, Neuropixels recordings, fibre photometry, and targeted manipulations with optogenetics and chemogenetics—we aim to uncover how these internal signals reshape neural representations of reward amount, delay, and uncertainty, and how these changes ultimately affect choice behaviour. This research will shed light on how body states influence behaviour and help explain why decision-making often goes awry in some of the most prevalent neuropathological conditions.
Jacinta Kalisch-Smith - Cardiac Sciences / Development & Cell Biology 'Characterising placental vascular defects in mouse and human models'
Poor placental vascular formation is a major but unappreciated cause of fetal and neonatal cardiovascular disorders including congenital heart defects, fetal growth restriction and stillbirth. A major problem in this field is that these diseases are investigated primarily at term, when the baby is born. This is despite the placental vessels forming from very early in pregnancy. This project will investigate early placental development using mouse and human models to investigate how they form, their progenitor populations, the gene programmes they use to grow and what pregnancy disorders affect them. In this project, you will use high throughput imaging and analysis techniques to create 3D models of the placental vasculature. Training in wet lab work will be provided including genotyping of mouse genetic knockouts, gene expression assays to assess RNA and protein levels, and in vivo cell culture; gene knockdowns of key transcription factors and growth factors. These assays are well established in the Kalisch-Smith laboratory and will build on recent exciting findings.
Tom Keeley – Cell Biology 'Exploring cell autonomous oxygen homeostasis'
Oxygen homeostasis is a crucial and ubiquitous function of all eukaryotic cells, operating across a wide range of time scales and oxygen levels. Whilst specialised central and peripheral mechanisms control systemic arterial oxygen levels, this cannot provide localised or regional oxygen homeostasis. Transcriptional adaptations to hypoxia orchestrated largely by the hypoxia-inducible factors does occur ubiquitously, yet cannot provide rapid homeostatic control. This project will explore the role of a more recently described oxygen sensing pathway in mediating rapid and ubiquitous oxygen homeostasis. Coordinated by 2-aminoethanethiol dioxygenase (ADO) and the Cys branch of the N-degron pathway, this pathway controls the stability of regulators of G-protein signalling 4 and 5. State-of-the art molecular biological techniques will be employed to study how these proteins interact with the subcellular environment to affect cell autonomous oxygen homeostasis, focusing on control of mitochondrial function. Analysis of protein expression and location will be paired with functional readouts of cell physiology, including measurements of intracellular oxygen levels and second messenger signalling.
Outreach: How Science Week's 2025 theme made me reflect on how I talk about science (by Dr Katherine Brimblecombe)
Science week 2025 theme: Change and adapt
Body Donation
In order to continue to provide world-class education and training for our medical students, we rely on generous and public-spirited people who would like their bodies to be of use after their death. Bodies donated to Oxford are a vital resource for teaching students about the structure and function of the human body, for training healthcare professionals and for developing innovative medical and surgical techniques.
Molly Stevens - Next-Generation mRNA Vaccines: Safer Delivery with Biodegradable Polymers
This project focuses on advancing mRNA vaccine delivery by exploring biodegradable polymers as an alternative to traditional lipid nanoparticles (LNPs). While LNPs, used in vaccines like Pfizer/BioNTech and Moderna, are effective for delivering mRNA into cells, their full immune impact is not yet well understood, potentially leading to adverse effects. Biodegradable polymers, on the other hand, offer greater safety and efficiency due to their ability to be easily cleared from the body and their customizable properties for improved delivery. The project aims to develop lipid-like polymeric nanoparticles (lipidoids) that combine the benefits of both polymer and lipid systems. By synthesizing and testing a wide range of nanoparticle formulations, the goal is to identify new polylipidoid particles that outperform current LNP technology in delivering mRNA to the immune cells in the skin. Success in this research could lead to the development of more effective and safer vaccines, offering better immune responses with fewer side effects. The findings will be important for combating infectious diseases and enhancing the future of vaccine technology.
Molly Stevens - Developing next-generation biosensing technologies
Point-of-care (PoC) testing is vital for managing disease outbreaks and improving healthcare access, especially in low- to middle-income countries (LMICs) where disease prevalence is high and resources are scarce. Traditional molecular diagnostics, such as PCR, require specialized equipment and skilled personnel, making them impractical for PoC settings in resource-limited areas. This project aims to advance PoC diagnostics by integrating platinum nanocatalysts (Pt@Au) into paper-based lateral flow assays (LFAs). These enhanced LFAs offer superior detection limits compared to conventional tests and provide colorimetric results that minimize user error. Additionally, they can incorporate a barcode-style system for multiplexed detection, enabling differential diagnosis across multiple diseases. The project focuses on developing next-generation multiplexed LFAs that can detect both nucleic acids and proteins simultaneously with high sensitivity. By enabling the simultaneous detection of multiple biomarkers in a single test, this project seeks to improve disease management and public health outcomes in LMICs, offering a practical and effective tool for comprehensive diagnostics in challenging settings.
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.