PhD Studentship: Mitochondrial Metabolism and Novel Therapeutic Strategies for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) (Fixed Term)
Supervisors: Professor Andrew Murray, Department of Physiology, Development and Neuroscience, University of Cambridge Dr Ross Lindsay, Novo Nordisk Funding: Fully funded PhD studentship (Home/UK tuition fees and stipend) supported by Novo Nordisk Proposed Start date: 5 January 2027 Project Overview Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately one in three adults worldwide and is rapidly becoming the leading cause of chronic liver disease. Beyond its effects on the liver, MASLD substantially increases the risk of cardiovascular disease, type 2 diabetes and other metabolic complications. Despite its growing prevalence, the cellular mechanisms that drive disease progression remain incompletely understood, and there remains a pressing need for new therapeutic approaches. Mitochondria play a central role in cellular energy metabolism and are increasingly recognised as key determinants of metabolic health. Alterations in mitochondrial function contribute to hepatic lipid accumulation, oxidative stress, inflammation and disease progression in MASLD, making mitochondrial metabolism an exciting target for next-generation therapies. Recent advances in mitochondrial-targeted medicines have opened new opportunities to modify disease mechanisms rather than simply treat symptoms. This PhD project will investigate how mitochondrial metabolism is altered during MASLD and evaluate novel mitochondrial-targeted therapeutic strategies to restore metabolic function. Working at the interface of basic science and translational medicine, the student will employ state-of-the-art experimental approaches to understand how mitochondrial pathways can be manipulated to improve metabolic health and inform the development of future therapies. Research Training The successful candidate will receive comprehensive training in a wide range of cutting-edge techniques, including: In vivo physiological and metabolic phenotyping in preclinical models Ex vivo analysis of tissue metabolism and mitochondrial function Advanced mitochondrial bioenergetic analysis using high-resolution respirometry and complementary approaches Metabolic phenotyping and analysis of mitochondrial function across multiple tissues Data analysis and interpretation using contemporary approaches in metabolic physiology The project offers outstanding training in mitochondrial biology, metabolic disease and translational physiology, equipping the student with advanced experimental and analytical skills that are highly sought after in both academia and the pharmaceutical industry. The student will be encouraged to take increasing ownership of the project, contributing to experimental design, data interpretation and scientific communication. An Industry-Academia Partnership This studentship is jointly supervised by the University of Cambridge and Novo Nordisk, providing a unique opportunity to experience research in both academic and industrial environments. The student will benefit from close interaction with scientists at Novo Nordisk, gaining valuable insight into the discovery, validation and development of novel therapies for metabolic disease. Exposure to both sectors will provide an excellent foundation for a future career in academia, biotechnology or the pharmaceutical industry. Throughout the PhD, the student will become part of an internationally recognised research community in metabolism and mitochondrial biology. There will be opportunities to collaborate with leading researchers, publish findings in high-impact international journals, and present their work at national and international scientific conferences. The project will therefore provide not only exceptional scientific training but also valuable opportunities to build a professional network and develop the communication skills essential for a successful research career. This is an exceptional opportunity to contribute to research addressing one of the world's most pressing metabolic health challenges while receiving world-class training in mitochondrial physiology, translational medicine and drug discovery through a unique partnership between the University of Cambridge and Novo Nordisk. Candidate Profile We welcome applications from highly motivated graduates with a strong background in physiology, biochemistry, pharmacology, biomedical sciences or a related discipline. Applicants should have (or expect to achieve) a First or Upper Second-Class honours degree, or an equivalent qualification, and a keen interest in metabolism, mitochondrial biology and translational research. The successful candidate will be enthusiastic about developing both experimental and analytical skills within a collaborative and interdisciplinary research environment. We welcome and encourage applications from people from groups that are under-represented in postgraduate study, as well as students who may have faced an educational or socio-economic disadvantage. If you love your subject, have an aptitude for study or research, and have gained, or are on course for, a good Upper Second class degree (or overseas equivalent, see https://www.postgraduate.study.cam.ac.uk/apply/before/international-qualifications), we would very much like to hear from you. Further details about the University's commitment to widening participation in postgraduate study are available https://www.postgraduate.study.cam.ac.uk/apply/before/widening-access. Candidates wishing to discuss this opportunity further are encouraged to contact Prof. Murray (ajm267@cam.ac.uk) after 1 September 2026. Full details of the University's entrance requirements and scholarships are specified on the following link: https://www.postgraduate.study.cam.ac.uk/. Funding Full funding covering Maintenance stipend at £21,850 per annum and the University Composition Fee (at the Home rate) is provided for the studentship, with effect from 5 January 2027. The stipend is tax free and will be paid for 3.5 years, or until submission of thesis, whichever is earlier. The stipend will be reviewed annually. Application Process To apply please visit: https://www.postgraduate.study.cam.ac.uk/courses/directory/blpdpdpdn and click 'Apply Now' selecting the following course: PhD in Physiology, Development & Neuroscience (Full-time) Start Date: 5 January 2027 Project Supervisor: Professor Andrew Murray Project Title: Mitochondrial Metabolism and Novel Therapeutic Strategies for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Research Proposal: Please add the project overview information (listed above) Please visit this link for full details of what your application should include - https://www.postgraduate.study.cam.ac.uk/courses/directory/blpdpdpdn/apply Please note there is a £20 application fee attached to using the Cambridge Postgraduate Application Portal. Application Deadline Completed applications (with ALL supporting documentation and references) to be submitted via the application portal by 23:59pm (midnight) UK time on 25 September 2026 at the latest. Interviews will be scheduled in October. The University actively supports equality, diversity and inclusion and encourages applications from all sections of society. The University has a responsibility to ensure that all employees are eligible to live and work in the UK.
Neuroinflammation in Epilepsy: what have we learned from human brain tissue specimens ?
Epileptogenesis is a gradual and dynamic process leading to difficult-to-treat seizures. Several cellular, molecular, and pathophysiologic mechanisms, including the activation of inflammatory processes. The use of human brain tissue represents a crucial strategy to advance our understanding of the underlying neuropathology and the molecular and cellular basis of epilepsy and related cognitive and behavioral comorbidities, The mounting evidence obtained during the past decade has emphasized the critical role of inflammation in the pathophysiological processes implicated in a large spectrum of genetic and acquired forms of focal epilepsies. Dissecting the cellular and molecular mediators of the pathological immune responses and their convergent and divergent mechanisms, is a major requisite for delineating their role in the establishment of epileptogenic networks. The role of small regulatory molecules involved in the regulation of specific pro- and anti-inflammatory pathways and the crosstalk between neuroinflammation and oxidative stress will be addressed. The observations supporting the activation of both innate and adaptive immune responses in human focal epilepsy will be discussed and elaborated, highlighting specific inflammatory pathways as potential targets for antiepileptic, disease-modifying therapeutic strategies.
Redox and mitochondrial dysregulation in epilepsy
Epileptic seizures render the brain uniquely dependent on energy producing pathways. Studies in our laboratory have been focused on the role of redox processes and mitochondria in the context of abnormal neuronal excitability associated with epilepsy. We have shown that that status epilepticus (SE) alters mitochondrial and cellular redox status, energetics and function and conversely, that reactive oxygen species and resultant dysfunction can lead to chronic epilepsy. Oxidative stress and neuroinflammatory pathways have considerable crosstalk and targeting redox processes has recently been shown to control neuroinflammation and excitability. Understanding the role of metabolic and redox processes can enable the development of novel therapeutics to control epilepsy and/or its comorbidities.
Ebselen: a lithium-mimetic without lithium side-effects?
Development of new medications for mental health conditions is a pressing need given the high proportion of people not responding to available treatments. We hope that presenting ebselen to a wider audience will inspire further studies on this promising agent with a benign side-effects profile. Laboratory research, animal research and human studies suggest that ebselen shares many features with the mood stabilising drug lithium, creating a promise of a drug that would have a similar clinical effect but without lithium’s troublesome side-effect profile and toxicity. Both drugs have a common biological target, inositol monophosphatase, whose inhibition is thought key to lithium’s therapeutic effect. Both drugs have neuroprotective action and reduce oxidative stress. In animal studies, ebselen affected neurotransmitters involved in the development of mental health symptoms, and in particular, produced effects of serotonin function very similar to lithium. Both ebselen and lithium share behavioural effects: antidepressant-like effects in rodent models of depression and decrease in behavioural impulsivity, a property associated with lithium's anti-suicidal action. Human neuropsychological studies support an antidepressant profile for ebselen based on its positive impact on emotional processing and reward seeking. Our group currently is exploring ebselen’s effects in patients with mood disorders. A completed ‘add-on’ clinical trial in mania showed ebselen’s superiority over placebo after three weeks of treatment. Our ongoing experimental research explores ebselen’s antidepressant profile in patients with treatment resistant depression. If successful, this will lead to a clinical trial of ebselen as an antidepressant augmentation agent, similar to lithium.
Carnosine negatively modulates pro-oxidant activities of M1 peripheral macrophages and prevents neuroinflammation induced by amyloid-β in microglial cells
Carnosine is a natural dipeptide widely distributed in mammalian tissues and exists at particularly high concentrations in skeletal and cardiac muscles and brain. A growing body of evidence shows that carnosine is involved in many cellular defense mechanisms against oxidative stress, including inhibition of amyloid-β (Aβ) aggregation, modulation of nitric oxide (NO) metabolism, and scavenging both reactive nitrogen and oxygen species. Different types of cells are involved in the innate immune response, with macrophage cells representing those primarily activated, especially under different diseases characterized by oxidative stress and systemic inflammation such as depression and cardiovascular disorders. Microglia, the tissue-resident macrophages of the brain, are emerging as a central player in regulating key pathways in central nervous system inflammation; with specific regard to Alzheimer’s disease (AD) these cells exert a dual role: on one hand promoting the clearance of Aβ via phagocytosis, on the other hand increasing neuroinflammation through the secretion of inflammatory mediators and free radicals. The activity of carnosine was tested in an in vitro model of macrophage activation (M1) (RAW 264.7 cells stimulated with LPS + IFN-γ) and in a well-validated model of Aβ-induced neuroinflammation (BV-2 microglia treated with Aβ oligomers). An ample set of techniques/assays including MTT assay, trypan blue exclusion test, high performance liquid chromatography, high-throughput real-time PCR, western blot, atomic force microscopy, microchip electrophoresis coupled to laser-induced fluorescence, and ELISA aimed to evaluate the antioxidant and anti-inflammatory activities of carnosine was employed. In our experimental model of macrophage activation (M1), therapeutic concentrations of carnosine exerted the following effects: 1) an increased degradation rate of NO into its non-toxic end-products nitrite and nitrate; 2) the amelioration of the macrophage energy state, by restoring nucleoside triphosphates and counterbalancing the changes in ATP/ADP, NAD+/NADH and NADP+/NADPH ratio obtained by LPS + IFN-γ induction; 3) a reduced expression of pro-oxidant enzymes (NADPH oxidase, Cyclooxygenase-2) and of the lipid peroxidation product malondialdehyde; 4) the rescue of antioxidant enzymes expression (Glutathione peroxidase 1, Superoxide dismutase 2, Catalase); 5) an increased synthesis of transforming growth factor-β1 (TGF-β1) combined with the negative modulation of interleukines 1β and 6 (IL-1β and IL-6), and 6) the induction of nuclear factor erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO-1). In our experimental model of Aβ-induced neuroinflammation, carnosine: 1) prevented cell death in BV-2 cells challenged with Aβ oligomers; 2) lowered oxidative stress by decreasing the expression of inducible nitric oxide synthase and NADPH oxidase, and the concentrations of nitric oxide and superoxide anion; 3) decreased the secretion of pro-inflammatory cytokines such as IL-1β simultaneously rescuing IL-10 levels and increasing the expression and the release of TGF-β1; 4) prevented Aβ-induced neurodegeneration in primary mixed neuronal cultures challenged with Aβ oligomers and these neuroprotective effects was completely abolished by SB431542, a selective inhibitor of type-1 TGF-β receptor. Overall, our data suggest a novel multimodal mechanism of action of carnosine underlying its protective effects in macrophages and microglia and the therapeutic potential of this dipeptide in counteracting pro-oxidant and pro-inflammatory phenomena observed in different disorders characterized by elevated levels of oxidative stress and inflammation such as depression, cardiovascular disorders, and Alzheimer’s disease.
Fluoxetine and vortioxetine reverse depressive-like phenotype and memory deficits induced by amyloid-β (1-42) oligomers in mice: implication of transforming growth factor-β1 and oxidative stress
A long-term treatment with antidepressants reduces the risk to develop AD and different second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are currently studied for their neuroprotective properties in AD. An impairment of neurotrophic factors signaling seems to be a common pathophysiological event in depression and AD. In particular a deficit of transforming growth factor-β1 (TGF-β1) and increased oxidative stress have been found both in depression and AD. In the present work the SSRI fluoxetine and the new multimodal antidepressant vortioxetine were tested for their ability to prevent memory deficits and depressive-like phenotype in a non-transgenic mouse model of AD (i.c.v. Aβ1-42 injection) by rescue of TGF-β1 signaling. The same drugs were also tested for their ability to modulate the expression of pro-oxidant genes as well as of genes related to the antioxidant machinery.