- Total grants
- Total funders
- Total recipients
- Earliest award date
- 22 Nov 2005
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Proteomic characterisation of secreted antiviral factors in cell-mediated immunity to human cytomegalovirus 30 Sep 2018
Human cytomegalovirus (HCMV) is a widespread human pathogen, infecting 60-80% of the population. Infection is asymptomatic in immunocompetent individuals but causes disease in immunocompromised patients, such as transplant recipients. Current therapeutic tools are limited, with no available vaccine and a limited array of antivirals. HCMV triggers a broad and robust immune response involving both the innate and adaptive immune systems. Antiviral immunity is mediated in part by proteins secreted by immune cells and infected cells. In order to counteract this immunity, HCMV encodes numerous evasion factors that modulate the function of immune cells and the array of proteins they secrete (‘secretomes’). In this project, I will apply mass-spectrometry to generate comprehensive profiles of the secretomes produced by different immune cells when exposed to HCMV-infected cells. Using this technique, it will be possible to identify important and potentially novel secreted antiviral factors that can subsequently be validated and investigated to determine their mechanism of action. This will contribute to a better understanding of HCMV immunity and may facilitate the design of novel effective vaccine candidates and therapies.
Investigating the role of the RNA binding protein HuR in spinal tissues using a mouse transgenic model 31 May 2018
Understanding the biological mechanisms underpinning chronic back pain is essential for future development of treatments for this debilitating condition. The roles of post-transcriptional gene control in the regulation of spinal structures such as the intervertebral disc (IVD) are poorly understood. Using a conditional knockout mouse model of the post-transcriptional regulatory protein HuR, we have demonstrated that it can perform an important role in the development of the embryonic spine. Building on these findings, this vacation scholarship project will test the hypothesis that tissue-specific knockdown of the RNA binding protein HuR in the IVD of adult mice results in acute degeneration of the tissue. To do this the project has three major aims: Archived lumber spines from control and knockout mice will be processed for routine histological analysis Sections will be blindly scored for IVD degeneration. Immunohistochemistry will be used to assess the levels of HuR in IVD tissue from control and knockout mice to confirm the extent of the knockout and the specific tissues affected. This project involves a program of work that is realistic in scope for a summer scholar, provides practical and analytical research training whilst also directly complementing ongoing research in the supervisor's laboratory.
Recent reports have implicated statins in the risk of developing Type 2 Diabetes Mellitus (T2DM). Statins are very successful in the management of cardiovascular disease but can also alter the immune response. The immune altering abilities of statins are thought largely dependent on statin type and dose. The NLRP3 inflammasome appears to be a key regulator of statin-mediated alterations of immune function. Hyperglycaemia can activate NLRP3 and in macrophages leads to the production of IL-1beta, which exerts detrimental paracrine effects on pancreatic beta cells leading to apoptosis. The mechanism of action of statins in inducing the NLRP3 inflammasome and resultant beta cell death is yet to be fully elucidated. Furthermore, it is not known whether statin-induced NLRP3 activation is exacerbated under hyperglycaemic conditions. Statins have also been associated with poor response to sulphonylureas, a front line therapy for T2DM. Sulphonylureas act by blocking potassium efflux (leading eventually to insulin exocytosis from the beta cell), which is a major mechanism for NLRP3 activation. In this study, pancreatic beta cell lines and macrophages will be used to investigate the mechanisms of statin induced NLRP3 activation in vitro, and to determine if specific statins compete with sulphonylureas resulting in altered insulin secretion.
Trypanosomiasis is a disease caused by single-celled parasites of the genus Trypanosoma. T. brucei is responsible for Human African Trypanosomiasis (HAT; also called ‘sleeping sickness’) in sub-Saharan Africa. Improvements in surveillance and control have led the WHO to include the elimination of HAT as part of its Roadmap for Elimination of Neglected Tropical Diseases (WHO, 2011). However, pathogenic trypanosome species, notably T. congolense and T. vivax, also infect livestock, often causing devastating economic and social hardship for individuals who rely on such animals for their livelihood. T. congolense, which is particularly virulent in cattle, causes a wasting disease that results in anaemia, weight-loss, abortion and decreases in milk-production. Whilst the majority of our current understanding of trypanosomiasis stems from experiments conducted with T. brucei, the animal trypanosomiases, caused primarily by T. congolense and T. vivax, remain comparably understudied, particularly with respect to their metabolism. There is gathering evidence that these species differ fundamentally in their underlying energy metabolism, with consequent implications for differing drug targets and resistance mechanisms. This PhD project aims to use cutting edge molecular and cellular methods to identify central differences in the metabolism and energy generation between T. congolense and T. brucei.
Thrombosis is defined by the abnormal formation of a clot within a blood vessel. Deep vein thrombosis (DVT), a subset of venous thromboembolism (VTE), commonly occurs within the deep veins of the legs. A variety of genetic and acquired risk factors have increased the prevalence of DVT during the past decade. Due to its somewhat asymptomatic nature, DVT can lead to complications in untreated individuals. While some research has been done on DVT, the direct causes of the disease are still relatively unknown. The purpose of this project is to identify the factors causally associated with DVT which may not have been identified through observational epidemiology. I will use an advanced causal analysis technique in genetic epidemiology called Mendelian randomization (MR) to determine what causes DVT. My first aim is to investigate what causes DVT using a hypothesis-free MR analysis. To do this I will use MR-Base - a database containing compiled GWAS summary data. I will then focus in more detail on a known cause of DVT (high BMI) and investigate what might mediate this causal effect. It is anticipated that the findings made during this project be a starting point for a prophylaxis against the outlined disease.
This project involves development of a novel dissolving microneedle array device, incorporating a nano suspension of haloperidol decanoate to provide transdermal delivery of a formulation that will dissolve in skin and act as a depot. Dissolving microneedle arrays are minimally invasive devices, consisting of an array of micro projections arranged on a baseplate in a defined configuration. These microneedles, up to 600 µm in length, are hard in the dry state and when applied to the skin using manual thumb pressure, painlessly penetrate the outermost layer of the skin, the stratum corneum. The needle tips dissolve in interstitial fluid releasing the nano suspension formulation into the viable skin tissue. Haloperidol can then be slowly and constantly be release over long periods of time to maintain constant plasma levels. A number of key parameters need to be assessed: 1. Nanosuspension formulation using a nano precipitate/ultra sonification method 2. Nanosuspension physicochemical characterisation for particle size and zeta potential 3. Formulation of microneedle arrays using aqueous blends of biocompatible polymers 4. In skin dissolution of the microneedle formulations
Our risk of dying from infectious disease is determined partly by our genes. We have identified a gene that is associated with risk of severe disease due to influenza in previously healthy adults. Mice lacking this gene also have more severe clinical signs after influenza infection, providing further support for its importance. The protein encoded by the gene is present at high levels on immune cells, but we do not yet fully understand its function. In this study, we will use a range of experimental approaches, integrating data from a genetically modified mouse model and computer-based analysis of next generation sequencing data, to elucidate how this gene functions during influenza to protect against severe disease. We will further study how variations in the gene render some people more susceptible to critical illness, using blood cells from donors carrying different versions of the gene, and by making small artificial changes in the gene in cultured cells. By determining the immune events and molecular pathways involved, the long-term goal is to identify possible new therapeutic targets to improve medical treatment of critically ill patients.
Epigenetic transgenerational inheritance of metabolic, reproductive, and endocrine phenotypes through the male germline: effects of developmental bisphenol A and dexamethasone exposure 30 Sep 2018
The majority of heredity is accounted for by transmission of genetic material from one generation to another. However, in recent years evidence has accrued that some environmental factors can cause variations in phenotype that are inherited through the germline without changes in DNA sequence – so-called environmental epigenetic transgenerational inheritance. We are interested in how metabolic/reproductive/endocrine effects of developmental exposure to two exogenous endocrine insults – bisphenol A, an endocrine disrupting chemical that leaches from plastics and thermal paper, and dexamethasone, a synthetic glucocorticoid administered to pregnant women at risk of preterm delivery – may be transmitted inter/transgenerationally through the male germline. We will expose mice to human-equivalent doses of these chemicals and breed for three generations to obtain both phenotypic data and spermatozoa for epigenetic analyses (using RNA-seq, RRBS, and ATAC-seq). We will investigate the functional significance of any spermatozoal epigenetic changes detected; for example, using zygote pronuclear microinjection to determine the role of spermatozoal non-coding RNAs. The ubiquity of human exposure to these chemicals means that even small inter/transgenerational epigenetic effects would have significant implications at the level of public health; we therefore expect this work to be of interest to the wider scientific and medical community.
Lung cancer remains the leading cancer-related cause of death in the UK. Early detection and treatment are critical to improving outcomes. Our lab has collected a unique set of lung tissue samples from patients with pre-cancerous disease, some of whom have gone on to develop cancer. By studying the genetic and molecular profiles of these samples we aim to elucidate the mechanisms of progression from pre-cancerous disease to invasive cancer. By doing so we can identify future methods of treatment and prevention. My work focuses on analysis of vast quantities of data produced by this program. We have recently studied the genetics of these samples, including which genes are expressed, which are mutated, and how they are regulated. From these complex networks we identify key signals of instability in the genome, which we believe are driving progression to cancer. These data provide a snapshot of early cancer. The first aim of this project is to investigate the dynamics of this process using longitudinally collected samples, and new techniques which can probe these samples on a single-cell level. The second aim is to study the immunological mechanisms by which some pre-invasive lesions regress and do not become invasive cancer.
Streptococcus pneumoniae (the pneumococcus) is a major disease causing pathogen and can cause sepsis, meningitis and pneumonia especially in at risk populations such as young children and the elderly. Understanding genetic factors in disease virulence, transmissibility, and drug resistance informs the management and treatment of infectious disease. By using deep sequenced patient samples of S. pneumoniae it is possible to build a clearer picture of its within host diversity. I aim to develop statistical and computational methods for the analysis of deep sequenced pathogen data that are also able to deal with large datasets, of the order of thousands of samples. I aim to apply these methods to the analysis of deep sequencing data derived from nearly 4000 S. pneumoniae samples taken from patients in the Maela refugee camp, Thailand. The methods I develop will help to identify significant genetic factors for disease dynamics and antimicrobial resistance. The project will contribute to the understanding of S. pneumoniae and will also provide tools of more general applicability to the investigation of deep sequenced pathogen data.
Apoptosis is a highly conserved and controlled process, with the Bcl-2 family of proteins playing an important role as key regulators. The family consists of both pro- and anti-apoptotic proteins and there is a careful balance within a cell controlling its fate. High levels of the anti-apoptotic proteins are often observed in cancer and not only contribute to the development of the tumour but also confer resistance to current therapies including chemotherapy and radiation treatment. In particular over-expression of myeloid cell leukemia-1 (Mcl-1) is one of the most common forms of genetic abnormality in cancer. In addition Mcl-1 has been shown to be essential for some tumours survival, resulting in a genetic vulnerability of the cancer cells which can be exploited by the design of Mcl-1 specific inhibitors. As a single agent, an inhibitor would target tumours that rely on Mcl-1 for survival and in combination with other therapies it is expected to overcome Mcl-1 mediated resistance. We have recently identified a small molecule capable of modulating the interaction between Mcl-1/Noxa. In this proposal we now seek to improve the binding affinity and selectivity of the compound through synthesising a small library of analogues.
Genomic instability triggers catastrophic events that restructure parts of the genome and provide a proliferative advantage to the cancer cell (e.g. through oncogene amplification) in up to 30% of cancers. There is recent evidence that suggests these types of events may also impact immune responses, by affecting genes that are involved in the interaction between cancer cells and their microenvironment. This project aims to study the impact of two well defined catastrophic events, chromothripsis (massive chromosome-wide rearrangements) and kataegis (hypermutated regions), on genes involved in immune-related pathways in oesophageal adenocarcinoma. The student will work with whole-genome sequencing data from 120 samples of oesophageal tumours available from the International Cancer Genome Consortium and will employ bioinformatics approaches to address the following key goals: (1) identify chromothripsis and kataegis events using computational protocols previously established in the group; (2) identify the genes affected by these events via genomic overlap methods; (3) summarise the proportion of the genes affected that are involved in immune signalling pathways (as recorded in relevant pathway databases). This will enable us to assess the likely impact of such catastrophic events on immune system processes and further clarify their implication in immune evasion during cancer development.
Influence of experience and circadian rhythms on Infra slow oscillations (ISOs) in the rodent brain 31 May 2018
Infra-slow oscillations (ISOs) of
Neural circuits in the brain underlie sensory perception and motor control, functions that are often impaired during neurological disorders. However, many aspects of circuit function remain unclear. These include how sensory and motor information is represented and transformed as it flows through neural circuits. In this project, I will study the properties of Golgi cells, a particular type of inhibitory neuron in the cerebellar cortex, a brain area that helps coordinate movements and predict thier sensory consequences. To do this I will use a new high speed 3-dimensional microscope technology that can measure signals as they rapidly flow through complex neural circuits deep within the brain of mice expressing fluorescence reporters of neural activity. By examining how the activity of populations of inhibitory neurons change during different behavioral tasks and during learning, I will determine how these neurons contribute to information processing in the cerebellum. By combining this imaging method with methods for manipulating neuronal activity and network models of circuit function I will identify the underlying mechanisms. This research will lead to fundamental new insights into cerebellar function and will provide a framework for understanding what goes wrong during neurological disorders.
Cells are surrounded by a lipid membrane, which isolates the cell content from the extracellular solution. The hydrophobic core of the membrane is impermeable to many hydrophilic substances including amino acids. To circumvent this problem, cells use transporters that can translocate amino acids across the membrane. This translocation process can sometimes be proton-coupled, but in some cases, certain transporters appear to function without the need for proton coupling. The reasons why some transporters are proton-coupled while others are not and how the proton coupling works, remain elusive. Humans contain two closely related types of amino acid transporter, the cationic amino acid transporters (CATs), which are proton independent and the proton-coupled amino acid transporters (PATs), which use protons for transport. Recent work in the Newstead laboratory has characterized a bacterial homolog of CATs that is proton-dependent, which was surprising. My DPhil project is trying to understand the mechanism of proton coupling in these transporters using a comparative approach between these two example proteins. Comparison of residues at key locations provides a working hypothesis of which residues may give rise to proton dependence. We will investigate this via the use of biochemical and cell-based transport assays, X-ray crystallography and molecular dynamics simulations.
Evidence suggests that electrical muscle stimulation (EMS) can evoke sensory feedback to the central neural system and create adequate functional muscle activation and force perception by notational motor commands generated within the CNS. Despite being widely explored, the mechanisms of force perception and generation remain subject of controversy, which hinders EMS application for recovery of everyday life functions in post-stroke survivors. This study aims to identify the feasibility of using EMS to evoke adequate judgments of force and heaviness during weight holding. Ten healthy adults will perform a 2-stage trial. First, the activation patterns of 8 major upper-limb muscles and the elbow and wrist joint angles during holding for 30s randomly presented 5 objects of similar size and shape but different weight will be recorded using surface electromyography and 2D electrogoniometry, respectively. Time-amplitude and cross-correlation analyses will establish weight- and joint-angle dependencies of muscle activation and inform the EMS program design. Then, the task will be completed without visual feedback by holding the object or replacing it with the respective EMS. Perceived comfort and similarity between the tasks will be tested following an adapted protocol for determining the running speed preference. Data reliability will be evaluated by repeating the trial.
The role of the Trem2 R47H mutation in the development of Alzheimer disease phenotypes in APP knock-in mice 31 May 2018
The field of research into Alzheimer’s disease is lacking a transgenic mouse model which shows progressive degeneration like in humans. Recently, there has been increased interest in the involvement of the immune system of the central nervous system, particularly microglia, which co-localise with amyloid-beta plaques, potentially limiting toxicity. TREM2 is a protein expressed by microglia and the R47H mutation is an identified risk-factor for Alzheimer’s disease. We propose that combining this microglial risk-factor with raising amyloid beta in APP knock-in mice may exacerbate the Alzheimer's phenotype, potentially leading to tau pathology. Initially I will be taught to perform whole-cell voltage-clamp in brain slices. I will then use a novel TREM2(R47H) knock-in mouse and examine variables previously reported as altered in transgenic APP/PSEN1 mice (and confirmed in APP knock-in mice, unpublished). In particular I will record spontaneous and miniature excitatory postsynaptic currents, the frequency of which is dependent on the probability of glutamate release and number of synapses; the amplitude dependant on the number of postsynaptic receptors. These experiments will help to elucidate the effects of microglia in early synaptic changes involved in AD and will provide initial characterisation of the TREM2 mice that will be crossed with APP knock-in mice.
Investigating components implicated in Alzheimer’s disease and other tauopathy pathogenesis 30 Sep 2018
Tauopathies including Alzheimer’s are widespread neurodegenerative diseases which cause progressive decline in cognition and yet the mechanisms driving the pathogenesis remain obscure. Central to these diseases is the protein Tau. In normal conditions, Tau locates to axons, cable like cellular structures that wire the brain. However, during tauopathies the behaviour of Tau is altered, Tau detaches from axons, instead it occupies other parts of the neuron and forms aggregates. During this process, Tau becomes unconnected from its normal protein partners and instead it associates and sequesters other factors. The nature of these toxic interactions is unknown. Here we will investigate how the network of proteins surrounding Tau changes during disease by using a new technique referred to as BioID2. For this, we will engineer Tau (by attaching BirA) so that it adds a tag (biotin) to proteins in close proximity to facilitate their isolation and identification. BioID2 will be performed in already well stablished models of tauopathies in Drosophila, because it’s genes and proteins can be manipulated with ease and are similar to that of humans. The outcome will be a comprehensive understanding of how Tau interactions changes in pathogenic conditions, giving insight into Tau toxicity and novel therapeutic targets.
The surface of all cells are coated with hundreds of different proteins that allow individual cells to signal to each other, attach to each other and sense the environment. These surface proteins are regularly internalised as part of normal cellular processes. For cells to remain healthy they must efficiently recycle some of these proteins back to the cell surface. To do this there are a number of multi-protein complexes that recognise the internalised proteins and select them for transport back to the cell surface. One such pathway is mediated by the recently identified retriever and CCC complexes. The aim of my PhD is to understand how these complexes interact with one another and how they recognise specific proteins to regulate their recycling. I will combine biochemical and molecular techniques with gene editing in cell culture to define the function of these multiprotein complexes. This is important because the recycling of cell surface proteins needs to be tightly regulated to ensure the correct levels are present. Failure to maintain the correct balance between degradation and recycling contributes to the pathogenesis of many neurodegenerative conditions including Parkinson's disease.
Effects of unilateral lower limb eccentric training on neuromuscular and musculoskeletal characteristics associated with fall risk in older people 31 May 2018
Age-related musculoskeletal functional decline is multifaceted with comorbidities including sarcopenia, osteoporosis, compromised strength and balance, limiting the capacity to perform daily activities and increasing fall risk. Therapeutic activities to alleviate this decline often have poor adherence, and therefore efficacy, in elderly populations as a low aerobic capacity and fear of falling limits exercise tolerance. A previous project confirmed the efficacy of chair-based eccentric exercise targeting the hip and knee muscle groups to improve muscle strength and mass in older people, however balance remained unchanged. The current project has been designed with these findings and the requirements of older people in mind. The project will examine the impact of unilateral eccentric contractions that simulate loaded downhill walking using newly developed equipment (BTE Eccentron). However, the exercise will be modified to ensure the ankle muscle group is targeted specifically to improve the likelihood of influencing balance in addition to muscle mass and strength. Cognitive attentional demands (visual feedback) will require subjects to match the predetermined intensity during every ‘step’, also improving engagement throughout the entire activity. Key goals include: 1. Identify adaptations and size of effect 2. Disseminate findings rapidly in high-impact international journals 3. Provide evidence-base for larger funding applications