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.
Physical Activity, Sedentary Behaviour and Brain Health
How are the epileptogenesis clocks ticking?
The epileptogenesis process is associated with large-scale changes in gene expression, which contribute to the remodelling of brain networks permanently altering excitability. About 80% of the protein coding genes are under the influence of the circadian rhythms. These are 24-hour endogenous rhythms that determine a large number of daily changes in physiology and behavior in our bodies. In the brain, the master clock regulates a large number of pathways that are important during epileptogenesis and established-epilepsy, such as neurotransmission, synaptic homeostasis, inflammation, blood-brain barrier among others. In-depth mapping of the molecular basis of circadian timing in the brain is key for a complete understanding of the cellular and molecular events connecting genes to phenotypes.
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.
Mechanisms Underlying the Persistence of Cancer-Related Fatigue
Cancer-related fatigue is a prominent and debilitating side effect of cancer and its treatment. It can develop prior to diagnosis, generally peaks during cancer treatment, and can persist long after treatment completion. Its mechanisms are multifactorial, and its expression is highly variable. Unfortunately, treatment options are limited. Our research uses syngeneic murine models of cancer and cisplatin-based chemotherapy to better understand these mechanisms. Our data indicate that both peripherally and centrally processes may contribute to the developmental of fatigue. These processes include metabolic alterations, mitochondrial dysfunction, pre-cachexia, and inflammation. However, our data has revealed that behavioral fatigue can persist even after the toxicity associated with cancer and its treatment recover. For example, running during cancer treatment attenuates kidney toxicity while also delaying recovery from fatigue-like behavior. Additionally, administration of anesthetics known to disrupt memory consolidation at the time treatment can promote recovery, and treatment-related cues can re-instate fatigue after recovery. Cancer-related fatigue can also promote habitual behavioral patterns, as observed using a devaluation task. We interpret this data to suggest that limit metabolic resources during cancer promote the utilization of habit-based behavioral strategies that serve to maintain fatigue behavior into survivorship. This line of work is exciting as it points us toward novel interventional targets for the treatment of persistent cancer-related fatigue.
Valentine’s Day for people with multiple sclerosis: promoting brain repair through remyelination
Current disease-modifying therapies in multiple sclerosis are all focused on suppressing the inflammatory phase of the disease. This has been extremely successful, and it is doubtful that significantly more efficacious anti-inflammatory treatments will be found. However, it remains the case that people with relapsing-remitting multiple sclerosis acquire disability on treatment, and enter the secondary progressive phase. I argue that we now need treatments that prevent neuronal degeneration. The most promising approach is to prevent axons degenerating by remyelination. Since the discovery that the adult brain contains stem cells which can remyelinate, the problem now is how to promote endogenous remyelination, and how to know when we have achieved this! We have successfully identified one drug which promotes remyelination but unfortunately it is too toxic for use in the clinic. So the hunt continues.
Inflammation and Pregancy
Talk(1): Fetal and maternal NLRP3 signaling is required for preterm labor and birth. (DOI: 10.1172/jci.insight.158238) Talk(2): Maternal IL-33 critically regulates tissue remodeling and type 2 immune responses in the uterus during early pregnancy in mice (DOI: 10.1073/pnas.2123267119)
Early life adversity, inflammation, and depression-onset: Results from the Teen Resilience Project
My research focuses broadly on the lifelong health disparities associated with experiences of adversity early in life. In this talk I will present the results of our recently completed Teen Resilience Project, a prospective and longitudinal study of first onset depression during adolescence. First, I will present the results on whether and how inflammatory processes may be shaped by early life adversity. Second, I will present data on the role of stress-induced inflammation in reward-related psychological processes. Finally, I will discuss the biobehavioral predictors of first-onset depression in this sample.
Pro-regenerative functions of microglia in demyelinating diseases
Our goal is to understand why myelin repair fails in multiple sclerosis and to develop regenerative medicines for the nervous system. A central obstacle for progress in this area has been the complex biology underlying the response to CNS injury. Acute CNS damage is followed by a multicellular response that encompasses different cell types and spans different scales. Currently, we do not understand which factors determines lesion recovery. Failure of inflammation to resolve is a key underlying reason of poor regeneration, and one focus is therefore on the biology of microglia during de- and remyelination, and their cross talk to other cells, in particular oligodendrocytes and the progenitor cells. In addition, we are exploring the link between lipid metabolism and inflammation, and its role in the regulation of regeneration. I will report about our recent progress in our understanding of how microglia promote regeneration in the CNS.
From Vulnerable Plaque to Vulnerable Brain: Understanding the Role of Inflammation in Vascular Health, Stroke, and Cerebrovascular Disease
Every year around 100,000 people in the UK will have a stroke. Stroke is a leading cause of adult disability, and cerebrovascular disease more broadly is a major cause of dementia. Understanding these diseases – both acute and chronic manifestations of cerebrovascular disease – requires consideration not only of the brain itself, but also the blood vessels supplying it. Atherosclerosis – the hardening of arteries as we age – may predispose to stroke by triggering the formation of blood clots that block the blood supply to the brain, but also involves inflammation that may cause chronic damage to the brain and prime both the brain and body for injury. Understanding this interaction between systemic disease and brain health may have important implications for our understanding of healthy ageing and provide novel therapeutic approaches for reducing the burden of cerebrovascular disease. This talk will consider how advances in imaging may facilitate our understanding of the processes underlying atherosclerosis and how it affects the brain in stroke, as well as work currently underway to translate this understanding into improving treatments for stroke.
Regenerative Neuroimmunology - a stem cell perspective
There are currently no approved therapies to slow down the accumulation of neurological disability that occurs independently of relapses in multiple sclerosis (MS). International agencies are engaging to expedite the development of novel strategies capable of modifying disease progression, abrogating persistent CNS inflammation, and support degenerating axons in people with progressive MS. Understanding why regeneration fails in the progressive MS brain and developing new regenerative approaches is a key priority for the Pluchino Lab. In particular, we aim to elucidate how the immune system, in particular its cells called myeloid cells, affects brain structure and function under normal healthy conditions and in disease. Our objective is to find how myeloid cells communicate with the central nervous system and affect tissue healing and functional recovery by stimulating mechanisms of brain plasticity mechanisms such as the generation of new nerve cells and the reduction of scar formation. Applying combination of state-of-the-art omic technologies, and molecular approaches to study murine and human disease models of inflammation and neurodegeneration, we aim to develop experimental molecular medicines, including those with stem cells and gene therapy vectors, which slow down the accumulation of irreversible disabilities and improve functional recovery after progressive multiple sclerosis, stroke and traumatic injuries. By understanding the mechanisms of intercellular (neuro-immune) signalling, diseases of the brain and spinal cord may be treated more effectively, and significant neuroprotection may be achieved with new tailored molecular therapeutics.
Innate immune response in brain pathologies: Lost in translation?
Inflammation is a key component of the innate immune response. Primarily designed to remove noxious agents and limit their detrimental effects, the prolonged and/or inappropriately scaled innate immune response may be detrimental to the host and lead to a chronic disease. Indeed, there is increasing evidence suggesting that a chronic deregulation of immunity may represent one of the key elements in the pathobiology of many brain disorders. Microglia are the principal immune cells of the brain. The consensus today is that once activated microglia/macrophages can acquire a wide repertoire of profiles ranging from the classical pro-inflammatory to alternative and protective phenotypes. Recently, we described a novel ribosome-based regulatory mechanism/checkpoint that controls innate immune gene translation and microglial activation involving RNA binding protein SRSF3. Here we will discuss the implications of SRSF3 and other endogenous immune regulators in deregulation of immunity observed in different models of brain pathologies. Furthermore, we will discuss whether targeting SRSF3 and mRNA translation may open novel avenues for therapeutic modulation of immune response in the brain.
Covid And Cognition
ONS figures suggest that at least 10% of individuals suffering COVID -19 Infection continue to experience several weeks after testing positive, and other studies report the proportions as even higher (e.g. Logue et al., 2021). One of the most prevalent reported symptoms among these “Long Covid” sufferers is cognitive dysfunction (Davis et al., 2020). However, to date the cognitive sequelae of COVID -19 are little understood. There are a number of reasons why COVID -19 infection might be associated with cognitive impairment and mental illness (e.g. Bougakov et al., 2020). In particular, increasing evidence indicates inflammation (e.g. Huang et al., 2020) and dysfunctional clotting (e.g. Taquet et al., 2021) as issues of major concern, both of which have been previously linked to a range of cognitive deficits (e.g. Vintimilla et al., 2019; Cumming et al., 2013). Indeed, evidence is beginning to emerge that cognitive issues may be widespread in the post-infection period, particularly among hospitalised and ventilated patients (e.g. Hampshire et al., 2020; Alemanno et al,. 2020). Here I shall present “Hot off the [SPSS]Press” results from a study on memory and cognition following COVID infection in a non-hospitalized cohort.
Phospholipid regulation in cognitive impairment and vascular dementia
An imbalance in lipid metabolism in neurodegeneration is still poorly understood. Phospholipids (PLs) have multifactorial participation in vascular dementia as Alzheimer, post-stroke dementia, CADASIL between others. Which include the hyperactivation of phospholipases, mitochondrial stress, peroxisomal dysfunction and irregular fatty acid composition triggering proinflammation in a very early stage of cognitive impairment. The reestablishment of physiological conditions of cholesterol, sphingolipids, phospholipids and others are an interesting therapeutic target to reduce the progression of AD. We propose the positive effect of BACE1 silencing produces a balance of phospholipid profile in desaturase enzymes-depending mode to reduce the inflammation response, and recover the cognitive function in an Alzheimer´s animal and brain stroke models. Pointing out there is a great need for new well-designed research focused in preventing phospholipids imbalance, and their consequent energy metabolism impairment, pro-inflammation and enzymatic over-processing, which would help to prevent unhealthy aging and AD progression.