Self funded PhD positions -
Self funded PhD positions -
Investigating immune contributions to frontotemporal dementia and motor neuron disease
Frontotemporal dementia (FTD) is the 2nd most common form of dementia affecting younger people, with a typical age of onset in the mid-late 50s. Unlike Alzheimer’s disease, memory is relatively preserved in FTD patients. However, FTD is a debilitating disease causing severe personality changes, changes in social behaviour, loss of inhibition, irrational behaviours and changes in emotional processing. Around 15% of FTD patients also develop motor neuron disease (MND, also known as ALS). MND is characterised by selective degeneration of motor neurons, leading to progressive muscle wasting, weakness and paralysis. MND is almost invariably fatal within 2-5 years of symptomatic onset. There are no effective treatments currently available for either FTD or MND. Our research aims to better understand the molecular and cellular mechanisms underlying disease processes in FTD/MND, and identify potential therapeutic targets for both diseases. We are particularly interested in how immune dysfunction contributes to FTD/MND disease pathogenesis.
Neuroinflammation is a common feature of all neurodegenerative diseases, including FTD/MND. Increased microglial activation is observed in affected brain regions, and several pro-inflammatory cytokines are known to be elevated in patient blood and cerebrospinal fluid. We know from research into other neurodegenerative diseases that excessive inflammation can damage the brain and may contribute to neuronal dysfunction and cognitive impairments. However, this has been relatively understudied in FTD/MND. This project will investigate the causes of inflammation in FTD/MND, as well as the downstream consequences of inflammation on neuronal function and neurodegeneration.
Supervised by:
Dr Sarah Ryan
Dr Dave Brough
Understanding how inflammation affects brain disease
We know that both peripheral and central inflammation influence neurological disease. This influence progresses and worsens diverse brain diseases, but the mechanisms involved are poorly understood. Inflammasomes have become recognised as important regulators of inflammation and contributors to disease and are emerging as new therapeutic targets. Here, using unique models and tools developed by our laboratories we aim to elucidate mechanisms of activation for the NLRP3 inflammasome, which is strongly implicated in non-communicable disease. We will determine consequences of NLRP3 inflammasome activation in the brain and establish how systemic illness primes inflammasome-dependent inflammation in microglia leading to greater disease severity and poorer outcome.
Supervised by:
Dr Catherine Lawrence
Dr Dave Brough
The impact of zinc deficiency on Alzheimers disease
In addition to memory problems, people with Alzheimer’s disease (AD) also experience ‘non-memory’ behavioural symptoms including depression, anxiety, and agitation. Even though these symptoms greatly reduce quality-of-life, there are currently no effective treatments and little understanding of why they happen. Zinc deficiency (low zinc) is commonly seen in people with AD and scientists think it makes AD worse. In a mouse model of AD we have shown a zinc deficient diet causes poorer memory. Zinc deficiency is also suggested to cause changes in behaviour and mood including depression and anxiety. We have identified changes in the brains of zinc deficient AD mice that could affect their behaviour. We will therefore test in these mice whether zinc deficiency makes the ‘non-memory’ behavioural symptoms of AD worse and whether zinc supplementation can improve these behavioural problems. Our initial discoveries have given us a clue as to how zinc deficiency could affect AD, possibly by increasing inflammation (the body’s response to harm). We will therefore test if increased inflammation is the reason why zinc deficiency makes the behavioural symptoms of AD worse. Overall our results could show that zinc supplements are a potential therapy for the behavioural symptoms seen in people with AD.
Supervised by:
Dr Catherine Lawrence
Dr Dave Brough
Understanding the posttranslational control of inflammatory response
The incidence of inflammatory disease in the population is rapidly increasing hence the urgent need to validate novel targets and develop efficient anti-inflammatory drugs. Macrophages are key cells regulating the immune response and initiate critical inflammatory processes such as the activation of the inflammasome, a molecular complex responsible for the release of potent proinflammatory mediators and cell death (pyroptosis). Inappropriate activation of the inflammasome contributes to deleterious inflammatory syndromes including, diabetes, atherosclerosis or cancer. However, our understanding of the intrinsic regulatory mechanisms of inflammasome activation is incomplete thus hindering development of effective interventions for these devastating conditions.
This project will explore the molecular mechanisms of inflammasome activation. It will investigate the cellular signalling mechanisms by which the ubiquitin system mediates this activation in macrophages and delineate the mechanisms that dampen the activity of this inflammatory complex during the resolution phase of inflammation.
This project is ideal for a candidate with strong interests in cell biology and the use of molecular approaches to study human disease-relevant questions. This will involve a significant amount of cell culture, both cell lines and primary cells (murine and human), molecular biology, and imaging, using standard immunostaining techniques but also live cell using confocal microscopy. The PhD student will benefit from a stimulating environment and the cutting-edge facilities at the faculty of Biology Medicine and Health and the world-leading Lydia Becker Institute of Immunology and Inflammation. As a PhD student you will be encouraged to present your research at internal meetings as well as attending international conferences. Please email us if you are interested and would like to know more about the project.
Supervised by:
Dr Gloria Lopez-Castejon
Dr Dave Brough
The effect of dementia and aging on the functional and hemodynamic response of the brain
The neuro-vascular unit and the hemodynamic response regulate how the blood supply in our brain meets the metabolic demand of neuronal activity. There is evidence that this control mechanism degenerates with age and is also impaired in dementia. However, the basic mechanisms underlying this decreased performance in neurovascular coupling are poorly understood. We have developed an in vivo multi photon imaging approach that allows us to investigate the hemodynamic response to sensory stimulation with high spatial and temporal resolution. We can analyse the spatio-temporal properties of vasodilation as well as the effect that activity has on the neuronal function of the brain tissue. In this study we propose to compare the neural activity and hemodynamic response in animal models of dementia at several stages of the disease.
We hope to identify through this research which parameters in the complex hemodynamic response have the biggest contribution to the degeneration with dementia and also old age. This might also lead to the development of imaging based biomarkers for early detection of changes in the brain before clinical symptoms of dementia are detected.
Supervised by:
Dr Ingo Schiessl
Dr Catherine Lawrence
Prof Stuart Allan
Factors determining diagnosis, antibiotic treatment and outcomes of stroke-associated pneumonia
Stroke is the leading cause of adult disability and has huge personal, societal and economic impact worldwide. Pneumonia frequently complicates stroke and has a profound impact on clinical outcomes. Stroke-associated pneumonia (SAP; defined as pneumonia complicating stroke within 1 week) is associated with increased mortality, length of stay and worse functional outcomes. 1,2,3 As strategies to prevent and treat it are limited, SAP remains a major area of unmet need in clinical practice and research.
The overall aim of this project is to evaluate factors determining diagnosis, antibiotic treatment and outcomes of SAP. The first phase of the project will involve a systematic review and meta-analysis evaluating outcomes following SAP. The second phase of the project will use the Salford Stroke-Associated Pneumonia (SAL-SAP) dataset to investigate which factors determine suspected SAP and confirmed SAP, and how these relate to subsequent outcomes. The (SAL-SAP) dataset, linked to local Sentinel Stroke National Audit Programme (SSNAP) data,4 collects baseline demographics, routine laboratory and physiological data, imaging, stroke unit care processes, prescribing data (including antibiotic treatment) and clinical outcomes from the largest stroke service in the UK. The project will provide novel insights into diagnosis and prognosis of SAP using real-world data to inform subsequent testing of diagnostic and prognostic algorithms to guide patient management and antibiotic stewardship.
Supervised by:
Prof Craig Smith
Dr Matt Gittins
Immune/inflammatory mechanisms in stroke and vascular dementia
Stroke is a major cause of death and disability worldwide. In stroke survivors one of the most prevalent complications is post-stroke cognitive decline, which occurs in up to a third of individuals within five years and impacts significantly on quality of life. With no available treatments, post-stroke cognitive decline is a critically unaddressed and important component of vascular dementia. Despite strong evidence for the important role of innate and adaptive immunity in stroke, research on inflammation as a cause of post-stroke cognitive decline is limited. Many factors will influence and be influenced by immune status early after stroke, including infection (e.g. pneumonia), a common and severe post-stroke complication. Modifiers of immune status after stroke could therefore be a key determinant of cognitive outcome and represent an attractive therapeutic target.
This project aims to further understand how immune/inflammatory mechanisms contribute to post-stroke cognitive decline, using a variety of approaches, including clinically relevant rodent models. Ultimately, we expect findings from the project to inform the future design of clinical trials to prevent/slow post-stroke cognitive decline.
Supervised by:
Prof Stuart Allan
Neuroimmunology of concussion
Concussion, or mild traumatic brain injury, affects millions world-wide each year. It is now appreciated that a history of concussion increases the risk of developing long-term emotional and neurocognitive disorders. These include anxiety and depression, as well as neurodegenerative conditions such as Alzheimer’s. Critically, we do not know the mechanisms behind long-term negative effects of concussion on brain health.
The following project will investigate the role of the immune system across different brain regions that may be differentially susceptible to injury. We hypothesise that region-specific neuroinflammation drives and concussive symptoms after head injury.
Microglia and the interfaces between the periphery and the brain are now under intense scrutiny as hubs of inflammation. Two of the key blood-brain interfaces are the meninges and the choroid plexus. The meninges are a set of protective membranes that surround the brain and the choroid plexus is a structure that produces cerebrospinal fluid and is essential for a variety of brain function. Recent data has shown that the meninges and choroid plexus contain immune cells that are proposed to play important functions in the brain. Little is known of the role of these areas and their immune cells in concussion and how they may communicate to microglia and drive neuroinflammation.
To address this, the project will investigate the role peripheral immune cells and their communication to microglia in concussive injury in a clinically relevant mouse model. We predict that a concussive-symptoms are driven by peripheral immune cells that drive microglial-mediated neuroinflammation.
Supervised by:
Dr Andy Greenhalgh
Dr Matthew Hepworth
Prof Mark Travis