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Funders:
The Wellcome Trust

Results

Optimisation of carrier materials for the delivery of olfactory ensheathing cells in spinal cord injury 27 Apr 2017

Transplant-mediated repair is a promising method in spinal cord injury (SCI) treatment. This involves transplanting therapeutic cells that promote nerve regeneration at the site of injury. For SCI, one promising therapeutic cell type is olfactory ensheathing cells (OECs). These have been shown to remyelinate demyelinated axons and promote new synapses following injury. They are also easily accessible clinically via trans-nasal endoscopic biopsy, and compelling pre-clinical evidence means that they are now close to being formally tested as part of a first-in-man clinical trial. However, currently these cells are delivered as a simple cell suspension, and this is unlikely to be optimal for creating a permissive and optimised repair environment. Thus, the objective of this project will be to develop and engineer optimised biomaterial scaffolds for OEC delivery. In doing so, it is hoped that a permissive 3D extracellular environment can be created, and the phenotype and behaviour of OECs optimised for spinal cord repair. Promising prospective biomaterials include fibrin, collagen and collagen-fibrin blends. To this end, we will investigate the effect of these promising carrier materials on OEC survival and phenotype, particularly with a focus on changes they may cause on 3D cell morphology.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Understanding the contribution of antibodies, against meningococcal serogroup B pili, to the bactericidal activity of sera from individuals vaccinated with Bexsero. 27 Apr 2017

The Bexsero vaccine provides protective immunity against many strains of Nm B and is composed of an outer membrane vesicle (OMV) backbone which contains the PorA serosubtype P1.4 and three other Nesserial proteins. These include; neisserial adhesion A(NAdA), neisserial heparin binding antigen(NHBA) and factor H binding protein (fHbp). However, the contribution of antibodies against key antigens within the OMV to Nm killing is unknown. Therefore, we will attempt to elucidate if antibodies generated against pili contribute to Nm killing in individuals vaccinated with Bexsero by using their sera in bactericidal assays. We will initially characterize pili expression in 10 meningococcal isolates for which the Bexsero vaccine isn’t predicted to protect against. SM1 and immune dot blotting will ascertain if pili are expressed at the bacterial surface. The presence of antibodies against pili in sera from 3 individuals who have been vaccinated with Bexsero will be confirmed using Western blotting and Tricine SDS-PAGE. The production of three pili negative strains will then be done using the MAG-1 knockout construct and natural transformation assays will be carried out on HBHI agar. Bactericidal assays using 10% sera from individuals vaccinated with Bexsero will be done for three pili expressing and knockout pairs.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Bristol

Up and down regulation of MafB gene in the developing chick hindbrain. 27 Apr 2017

The project's aim is to up and down regulate MafB gene, that is expressed in the Nucleus Laminaris (NL) and Nucleus Angularis (NA), in the developing chick hindbrain and ask questions about: 1) formation of nucleus Laminaris and nucleus Angularis in the dorsal hindbrain; 2) other effects on hindbrain development e.g interfering with fgf8 molecule expression, which in turn would affect the development of the cranial motor nerves VI, VII and nVIa. Such experimental techniques as in ovo electroporation, immunofluorescence and in situ hybridization will be used to look at the genes expressed in the auditory brainstem. The in ovo electroporation constructs used will overexpress MafB and also express a dominant negative version of MafB and immunofluoresce analysis will be carried out to test whether the electroporation was successful. The in situ hybridization analysis will be performed to establish the effect of MafB on the expression of such genes like FGF8, Pou6F2, N-cadherin, gamma catenin, cadherin-13 and cadherin-22 in the hindbrain. These techniques would also allow the analysis of the formation of the nucleus Laminaris in the developing hindbrain.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

MOLECULAR DIAGNOSIS OF BACTERIAL INFECTION IN THE LUNG 27 Apr 2017

Patients with chronic respiratory diseases such as bronchiectasis and COPD suffer from frequent exacerbations (chest infections) that are typically treated with antibiotics +/- corticosteroids. The goal of treatment with preventative measures is to reduce the frequency of chest infections and this is the major end-point in most randomized trials of new drugs in these diseases. Previous dogma held that the airways were sterile and that exacerbations were caused by exogenous acquisition of bacteria from the environment. More recent work suggests that the bacteria isolated during exacerbations are often found in the lungs when patients are well and that they may represent an overgrowth or alteration in the natural microbial flora of the lungs (the microbiome). We hypothesise that if this is true, the presence of pathogenic bacteria at low levels in the lung when patients are well will predict future bacterial chest infections. 1. To test the hypothesis that the presence of bacteria known to be associated with exacerbations(particularly Haemophilus influenzae and Pseudomonas aeruginosa) in the sputum microbiome is associated with the future risk of exacerbations of bronchiectasis over 1 year follow-up 2. To test whether the bacterial load of these pathogens is associated with an increased risk of exacerbations.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Dundee

Micro-Metagenomics: Exploring the Application of Microfluidics to Viral Diagnostics 27 Apr 2017

The ultimate goal of the research is to develop a microfluidic system, usable in labratory and field situations, for the detection and quantification of the viral diversity in a sample. The initial stage will focus on analysing viral properties in order to differentiate the viruses into their different families. This data, which focuses on the size, shape and deformability of the viruses, will be used to inform mathematical modelling which will lead to the selection of nano scale filters to be used for testing. Analysis will then be performed on microfluidic experiments to validate models and test the effectiveness and efficiency of the filters when used for viral separation. For this research we will use easy to handle and non pathogenic viruses, as well as control substances with known proportions of these different viruses to allow us to effectively evaluate our initial systems. This will also be complemented by modelling of the particles as they interact with the filters to further investigate the dynamics and properties of separation. A key aim of this research is to generate a wealth of data which will have applications in the viral detection at low concentrations in bodily fluids and unbiased characterisation of viruses.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Dundee

Investigating the Mechanisms Underlying Drug-Induced Retinotoxicity 27 Apr 2017

Summary: Quinoline-based compounds have been reported to cause forms of retinal dystrophy across a range of species (e.g. chloroquine-induced Bull’s Eye Maculopathy in humans, fluoroquinolone-induced retinal degeneration in cats, quinine-induced retinotoxicity in zebrafish). The precise mechanism underlying this form of retinal degeneration/toxicity is unknown. Here we will use a zebrafish drug-treated model to examine the precise effect of quinoline toxicity on retinal histology and retinal pathways. For this study we will examine quinine, fluoroquine, chloroquine and a novel quinoline compound. Aim: To use an induced zebrafish model to facilitate understanding of the cellular and molecular basis underpinning quinoline-induced retinotoxicity Goal 1. Determine drug dose which induces retinotoxicity Drug treat larval zebrafish and examine visual function using two visual behaviour assays: optokinetic response and semi-automated optomotor response (equipment available in the Zebrafish Facility). Goal 2. Investigate whether retinotoxicity affects retinal histology Drug-treat larval zebrafish and compare retinal histology to vehicle treated controls using fluorescent microscopy. Goal 3. Investigate whether retinotoxicity affects the expression of genes involved in visual function Compare the expression of genes involved in visual function in drug and vehicle treated zebrafish. This project will assist understanding of the cellular and molecular basis underpinning quinoline-induced retinotoxicity

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

How asthma and depression impact upon cardiovascular disease: a study of co-morbidities. 27 Apr 2017

The supervising group has modelled the impact of the innate immune response on the cholesterol biosynthesis pathway in previous publications. Using microarray measurements as a crude estimate of protein concentrations, from a time course study of CMV infected macrophages, we incorporated time course enzyme concentrations into an ordinary differential equation (ODE) model of the pathway and used numerical integration to simulate the impact of enzyme concentration changes that result from infection on pathway activity. The group also has a novel model of atherosclerosis and has previously combined this with microarray data to investigate the impact of infection on plaque formation in atherosclerosis. Here, the student will extract measurements of transcriptional activity of the genes coding for proteins associated with atherosclerosis pathways from published studies of CD4+ T-cells from patient cohorts with asthma, depression, asthma with depression and a control cohort. These measurements will be used to estimate protein abundance and will be incorporated into our ODE model of atherosclerosis disease progression. The resulting model will be numerically integrated to simulate the inflammatory impact of asthma, depression and asthma with depression on atherosclerosis plaque formation in order to explore their role as comorbidities of cardiovascular disease.

Amount: £0
Funder: The Wellcome Trust
Recipient: Ulster University

The response of the gut microbiota to a range of anti-diabetic medications and its impact on glucose control 27 Apr 2017

The key goal of this project is investigating the effect dietary intake and gut microbiota have on glucose regulation in established diabetic patients prescribed a range of anti-diabetic medications. Evidence from the literature suggests an altered microbiota is associated with changes in multiple heath parameters, including glucose regulation (Cani et al. 2014). Previous studies have illustrated that dietary intake impacts the gut microbiota profile and can enhance its diversity, an independent marker of improved functionality in vivo (Cotillard et al. 2013). This project involves microbial DNA extraction to study the effect of various anti-diabetic medications on the gut microbiota profile (from time of prescribing to 8 week follow up). Dietary intake will be assessed to determine the role of diet on the baseline microbiota in diabetic candidates. Dr. O’Connor’s team have extensive expertise in analysing gut microbiota profiles and determining the role of diet in shaping microbiota in specific populations (Power et al. 2015, O’Connor et al. 2014, Power et al. 2014, O’Connor et al. 2013), especially during aging and aging-related health loss (Claesson et al. 2012). Dr.O'Connors group have numerous ongoing dietary intervention trials to determine the role of specific food ingredients on gut microbiota in specific population groups.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Limerick

Lignin-based hydrogels as an innovative solution to combat the global healthcare challenge of medical device-associated infections 27 Apr 2017

The proposed research involves investigation of the antimicrobial properties of zinc-loaded, lignin-based hydrogels as candidate infection-resistant medical device coatings to combat the escalating burden of device-associated infections. Lignin is the second most abundant naturally-occurring polymer globally and is also a major waste product of industrial processes, for example paper and bio-refinery industries. The rationale of this project is based on the ability of lignin-based hydrogels to absorb metallic cations, which are widely recognized for their broad-spectrum bacteriostatic and bactericidal activities, and consequently enhance the inherent, and recently reported, antimicrobial activity of lignin itself. Prevention of bacterial colonisation on implanted medical devices with the use of lignin-based hydrogel coatings is anticipated to have transformational impacts on patient health and would, additionally, represent an important mechanism of re-using this major industrial waste product. Key goals are to: Determine resistance of the novel materials to adherence of Proteus mirabilis and Staphylococcus aureus, representative Gram-negative and –positive nosocomial pathogens respectively. Characterise efficacy of eluted metallic cations, including zinc, in inhibiting growth of nosocomial pathogens. These findings will ultimately inform further development of these innovative, low-cost and environmentally-friendly materials as medical device coatings to combat the global healthcare challenge of device-associated infections.

Amount: £0
Funder: The Wellcome Trust
Recipient: Queen's University Belfast

The effects of a novel GluK2 receptor antagonist UBP2002 on epileptogenesis 27 Apr 2017

Glutamate is the major excitatory transmitter in the mammalian CNS and is involved in key physiological functions and in a variety of neurological conditions, including stroke, chronic pain, anxiety and epilepsy. The actions of glutamate are mediated via four classes of receptors: AMPA, Kainate, NMDA and Metabotropic. Kainate receptors (KARs) are composed of five subunits (GluK1-5). KARs are involved in many physiological functions, however they have also been implicated in the pathophysiology of epilepsy. Little is known about the physiological roles of KARs in neurological disorders, compared with the other glutamate receptor classes, mainly due to the lack of selective drugs. Recently this setting started to change with the development of selective GluK1 antagonists. This project aims to test the ability of a novel GluK2 antagonist UBP2002 (produced at the University of Bristol) to prevent the development of and to reverse epileptic activity induced by electrical stimulation on Hippocampal slices. Current antiepileptic drugs (AEDs), although effective in controlling epileptic seizures in the majority of patients, have limited efficacy against drug resistant epilepsies. Therefore, there is a need for new drugs acting on different targets than those of currently available AEDs and for the development of new therapies for epilepsy.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Bristol

Thermogelling materials for the improved vaginal retention of bioactives 27 Apr 2017

The transmission of HIV via the vaginal route can be hindered by the intravaginal administration of microbicides, as demonstrated by the CAPRISSA004 trial. Whilst there are promising ongoing investigations of this pre-exposure prophylaxis using intravaginal rings, there is a need for single-use products, such as vaginal gels, which limits the exposure to drug. Gels are poorly retained in the vagina, which reduces patient compliance and has led to the failure of a clinical trial (FACTS001). One method to improve retention is the use of "thermogelling" materials, which drastically increase in viscosity upon warming in the vagina. There are, however, a limited number of commercially available thermogelling polymers, and many materials show toxicity and low mechanical strength. Thus, it is desirable to develop novel thermogelling materials from biocompatible polymers, which would offer new platforms for the intravaginal delivery of drugs. This project aims to produce novel thermogelling materials using a hitherto poorly-explored temperature-responsive polymer, poly(N-vinylcaprolactam) (PNVCL). The student will aim to synthesise poly(ethylene glycol) (PEG) macroinitiators, from which PNVCL may be grown to yield PNVCL - PEG - PNVCL block copolymers, which are expected to posses thermogelling behaviour. This behaviour will then be explored using rheometry.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Hertfordshire

Human Skeletal Muscle Wound Repair: An Association between Genetic Variation and Stem Cell Migration? 27 Apr 2017

Insufficient recovery following exercise-induced muscle damage (EIMD) can lead to muscle injury, with natural genetic variation perhaps influencing the extent of both. Skeletal muscle regeneration is a complex process that is mediated by muscle stem cells (called satellite cells). However, little is known about whether specific genetic variations (polygenic profile) influence dynamics of satellite cells and their impact on skeletal muscle regeneration. For that reason, we aim to conduct an in vitro muscle cell damaging study on primary skeletal muscle stem cells (previously derived from participants with specific polygenic profiles) to provide potential mechanisms regarding the individual response to injury in vitro. We hypothesise that activated satellite cells from individuals with a specific genetic profile will display better rates of recovery, following mechanical injury, compared with cells from participants without this profile. Our objective is to utilise stem cell-based research to provide oversight of the in-depth genetic mechanisms underlying the adaptations of muscle cells to injury repair. Our ultimate aim is to use current technology to prevent injury and promote recovery initially in the sporting world, but ultimately in the wider population as exercise becomes more widely accepted as a health intervention.

Investigating the effects of phosphatases on Trk signalling and cell fate in neuroblastoma 27 Apr 2017

Neuroblastoma is highly variable in outcome; it might be aggressive and fatal, but might also spontaneously regress. Expression of TrkA is strongly associated with patient survival (due to differentiation or apoptosis of the cancer cells), whereas TrkB is associated with unfavorable, metastatic cancer. My supervisor's group generated cell lines that over-express the different Trk-receptors. These cell lines mimic the characteristics of the human tumours; i.e., TrkA cells differentiate upon NGF stimulation, and TrkB cells proliferate upon ligand (BDNF) binding. My supervisor's group found that NGF and BDNF activate the same major pathways but with different dynamics (i.e., different signal duration). Therefore, we hypothesise that the different downstream dynamics of TrkA and TrkB signalling is responsible for the diffent cell fates, differentiation and proliferation, respectively. Since phosphatases are important regulators of signal duration; my aim is to investigate the activity of five phosphatases in TrkA and TrkB cells by Western blotting. Moreover, we wold like to test if we can modify cell fate by altering phosphatase activity in TrkB over-expressing neuroblastoma cells (i.e., induce differentiation of cells instead of proliferation).

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

Effects of the highly potent and specific NLRP3 inhibitor MCC950 on synaptic transmission and plasticity in the rat hippocampus 27 Apr 2017

Activation of the NLRP3 inflammasome results in the activation of caspase-1, which cleaves pro-IL-1beta into its active form, IL-beta. Excess IL-1beta has been shown to be involved in neurodegenerative diseases in the brain including Alzheimer’s and Parkinson’s disease. IL-1beta has also been shown to inhibit synaptic plasticity such as long-term potentiation (LTP) in the hippocampus. Recently a novel inhibitor of the NLRP3 inflammasome has been discovered namely, MCC950. To date little is know of its action in the central nervous system. We hypothesize that this novel inhibitor may be able to rescue the impairment of LTP caused by excess IL-1beta. Hippocampal slices will be perfused with LPS and hypoxia, activating the inflammasome and thus inhibiting LTP. Slices will be perfused with MCC950 to investigate if it can modulate this inhibitory effect of LPS and hypoxia on LTP. This study may show for the first time an important role for inflammasomes in synaptic plasticity. MCC950 could thus prove to be protective against cognitive decline in neurodegenerative diseases.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

Does pharmacological intervention attenuate hallmarks of ocular cancer or blindness in a zebrafish model of Von Hippel-Lindau Disease? 27 Apr 2017

Von Hippel-Lindau (VHL) disease is an autosomal dominant condition affecting 1 in 36000 people. VHL is characterised by the formation of multiple benign and malignant neoplasms. Retinal hemiangioblastomas (RH) are the most common manifestation of VHL disease, presenting in up to 85% of patients. Vision loss is a common clinical presentation in VHL patients as current therapies are invasive and not effective. Furthermore, removal of RH is restricted to the peripheral retina. Although zebrafish do not develop RH, they are a useful in vivo model in the vhl studies as they possess many hallmarks associated with the disease. Defects in the vhl tumour suppressor gene leads to a systemic hypoxic response and subsequent uncontrolled blood vessel development in vivo. Ectopic and vasculature leakage has previously been shown in the vhl zebrafish model. This research aims to investigate the efficacy of a commonly used anti-angiogenic compounds (quininib analogues), in reducing the angiogenic hallmarks displayed by vhl patients. Its ability to rescue or improve visual function will be measured and endpoints will employ behavioural and morphological analysis.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

Can factors secreted by MUC1-ST educated monocytes influence breast cancer stem cell growth? 27 Apr 2017

Aberrant glycosylation of glycoproteins expressed by cancers can lead to tumour:immune cell interactions that are cancer specific. One such interaction is the binding of a tumour-associated glycoform of the mucin, MUC1-ST, to the sialic binding lectin, Siglec-9, expressed by monocytes and macrophages. The engagement of Siglec-9 by MUC1-ST, leads to the secretion of factors by monocytes associated with tumour-progression. Interestingly, one such factor that has been identified is growth hormone and the growth hormone receptor has been found to be associated with normal mammary stem cells. To investigate if growth hormone or other factors secreted by MUC1-ST educated monocytes can influence breast cancer stem cells we will examine the extent to which breast cancer cells lines show cancer stem cell properties by: 1. Determining the expression of the breast stem cell markers (CD44 and CD24) using flow cytometry, in the presence or absence of media from MUC1-ST educated monocytes. 2. Looking at mammosphere growth in the same medium, where we will also take into account the production of GH by blocking the GHR using specific blocking antibodies.

Amount: £0
Funder: The Wellcome Trust
Recipient: King's College London

CRISPR/Cas9 enabled study of cis-regulatory regions of the NPY gene 27 Apr 2017

NPY is a neuropeptide, expressed in the hypothalmus, which known to be involved in appetite regulation. Although little is known about the regulation of the NPY gene preliminary studies in the MacKenzie lab have identified highly conserved enhancers around the NPY locus many of which drive reporter gene expression in mouse hypothalamus. Dr Mackenzie's lab has recently carried out CRISPR based knockouts of regions of the NPY locus in mice and wish to study the affect on mouse feeding patterns and NPY gene expression in order to further characterise the enhancers controlling NPY. This will initially involve the use of in situ hybridisation and Qrt-PCR on tissues derived from genome edited mice from which candidate NPY enhancer regions have been ablated. Understanding the regulation of this gene will bring us significantly closer to understanding the factors affecting appetite, increased food intake and obesity.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Aberdeen

Role of neuronal nitric oxide in the vasodilatory response to mental stress 27 Apr 2017

Nitric oxide (NO) is a potent regulator of vascular tone. Until relatively recently, it was assumed that the isoform of NO synthase responsible for tonic NO release was endothelial nitric oxide synthase (eNOS). However, we now know that in humans, neuronal NOS (nNOS) is the primary NOS isoform responsible for regulating vascular tone in vivo. Neuronal NOS is also activated by mental stress and contributes directly to resistance vessel vasodilatation. However, our preliminary data indicate that this response is biphasic, suggesting a second mechanism underlying the vasodilatory response to stress. We hypothesise that this additional mechanism may be mediated through agonism of beta2 adrenoceptors. This hypothesis will be tested in healthy volunteers exposed to mental stress (Stroop test), using the gold-standard technique of venous occlusion plethysmography to measure forearm blood flow, coupled with intra-arterial infusions of selective inhibitors of nNOS and beta2 adrenoceptors. The key goals of this research are (i) to better define the regulation of vascular tone in healthy humans with a view to understanding potential mechanisms underlying vascular dysfunction in disease states; and (ii) gain a broader understanding of early experimental medicine approaches in the clinical setting.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Role of hypoxia in tumour cell metabolism 27 Apr 2017

Previous research has shown upregulation of haem oxygenase 1 (HMOX1) in hypoxic cells and tissues. However, we currently do not understand what benefit this confers on hypoxic cells. HMOX1 is the first enzyme involved in the breakdown of haem, releasing carbons as bilirubin/biliverdin, free iron, and oxidising NADPH. We hypothesise that HMOX1 upregulation is required for hypoxic cell viability through permitting metabolic adaptation. The objectives of this project are to elucidate whether knock-down of HMOX1 causes loss of hypoxic cell viability. Additionally, I aim to determine how HMOX1 activity supports mitochondrial metabolic function by tracing the flux of carbons through mitochondrial metabolic pathways in the presence or absence of HMOX1 in normoxic and hypoxic conditions using stable isotope (13C)-enriched glucose or glutamine. Through these studies, I aim to improve understanding of the role of HMOX1 in hypoxic cells , and may provide some evidence to propose HMOX as a potential therapeutic target in cancer.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Birmingham

A novel nanoparticle/microneedle array patch (MAP) combination 27 Apr 2017

The overall aim is to design, prepare and evaluate novel nanoparticle/microneedle array patch (MAP) combinations for prevention of HIV infection. The key objectives are: Design, produce and characterise dissolving microneedles Combine long-acting anti-retroviral nanoparticles and microneedles in composite MAPs Study MAP performance in vitro and extrapolate to human treatment

Amount: £0
Funder: The Wellcome Trust
Recipient: Queen's University Belfast