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Funders:
The Wellcome Trust

Results

Do abnormal blood vessels impact bone loss in osteoporosis? 27 Apr 2017

Vascular endothelial growth factor (VEGF) has important roles in the blood vessels of adult tissues and in disease. Dr Clarkins laboratory have found that deletion of VEGF by bone forming osteoblast (osteocalcin; Ocn expressing) cells results in severe bone porosity similar to osteoporosis. To investigate how vascular endothelial cell- factors contribute to this porous phenotype, further experiments from Dr Clarkins lab collected conditioned media (CM) from osteoblasts (OBs) of mice with VEGF removed and added to vascular endothelial cells. In the absence of VEGF, endothelial cells were found to upregulate inhibitors of mineralisation including sclerostin which may contribute to osteoporotic bones of VEGF KO mice. The goal of my studentship project is to investigate how endothelial cells produce sclerostin, which is important as sclerostin has previously been reported to be secreted only by bone cells. I will investigate this by immunolabelling of sections of VEGF KO and WT long bones for sclerostin and a blood vessel marker CD31. I will also treat endothelial cells with CM from VEGF WT and KO cells and undertake Western blotting for sclerostin. Inhibiting blood vessel anti-mineralisation factors could provide a new a means to treat degenerative bone disease such as osteoporosis.

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

Developing efficient xeno-free mechanoculture of stem cells for tissue engineering 27 Apr 2017

The aim of this project is to develop a completely xeno-free culture system for human mesenchymal stem cells (hMSCs), cultured on synthetic peptide hydrogels (PeptieGel Design, Ltd.) and ‘mechano-cultured’ in a simple wave tank bioreactor with dynamic hydrostatic pressure acting as a dominant stimulus to control cell growth and differentiation into active osteoblasts and chondrocytes. Our hypothesis is that the changing pressure (which replicates the loading experienced during anabolic exercise) will stimulate mechanotransduction pathways in the cell that promote the growth, asymmetric division and subsequent differentiation of hMSCs by enhancing the signal transduction of autocrine and paracrine growth and transcription factors. Our project goals therefore are to: Combine a simple wave tank bioreactor with our hydrostatic pressurisation system. Culture hMSCs in synthetic peptide hydrogels as encapsulated 3D microcarrier beads. Compare growth of conventionally cultured (T-flasks) hMSCs to the bioreactor cultured hMSCs Switch to differentiation media (chondrogenic and osteogenic) to determine how hMSCs differentiate during the end stages of mechanoculture. A summary of these goals is attached in the supporting document (fig. 1.)

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

In vitro characterisation of neurons and glia derived from mouse ES cells having Y chromosome gene deficiencies 27 Apr 2017

The brain is a sexually dimorphic organ, which can explain why many psychiatric disorders are gender-biased. While it has been thought that fetal sex hormones play a crutial role in brain sexual differentiation, emerging evidence indicates that genetic and/or epigenetic factors encoded by sex chromosome genes are also involved. Here, we focus on several Y-linked genes expressed in the male brain, which may act in a dominant manner. Sry, Uty and Smcy genes, whose products can participate in histone modification, are of particular interest. However, their functions in the brain remain unknown mainly because of difficulties in conventional gene-targeting of Y loci in embryonic stem cells (ESCs). In this project, we will take advantage of Crispr/Cas genome-editing technology that allows us to modify Y-linked genes. Mutant alleles of these three genes in ESCs were created and then differentiation will be induced of neurons and glia from the mutant ES cells. Differential gene expression between wild-type and mutant cells will be analysed by RT-RCR and bisulfite PCR, and subsequently epigenetic status of these differential genes will be elucidated. The project will reveal influences of Y-linked genes on sex-specific epigenetic modification and lead to better understanding of gender-biased psychiatric disorders.

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

Mechanical testing of tendons and ligaments 27 Apr 2017

The mechanism for collagenous connective tissue damage is little understood. The micromechanics of collagenous tissues is important to understand as it may contribute to injury prevention and be useful in designing treatments for pre existing tissue damage. Bontempi et al in 2009 theorised a relationship between the the probability density function of the stretch value of individual fibrils and the 2nd derivative of stress with stretch. This relationship gained experimental backing in 2016. Recent research suggests that fibrils fail in the order they are first recruited. Combining this model with Bontempi's work suggests fibrillar level damage can be found by performing a stress - stretch test in vivo. However the relationship between order of recruitement and failure is yet to be experimentally proven. A collagen fibril is considered recruited once it is straight enough to bear load and be treated as a Hookean material. During my research I will be tracking fibrils from point of first recruitment to failure. A tensile loading rig will be used with a microscope to image the tendons at different stretch levels.

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

Identification of genes important for susceptibility to taxol-induced apoptosis 27 Apr 2017

CRISPR-based genetic screens have emerged as cutting-edge tools to identify genes important for many processes. Microtubule-disrupting agents, such as paclitaxel (Taxol) and docetaxel (Taxotere), are widely used chemotherapeutic agents that kill highly replicating tumor cells. However, such agents also trigger NFkappaB-dependent responses that can negatively influence tumor clearance by promoting tumor survival and metastasis. Moreover, how transformed cells develop resistance to taxol and related compounds is poorly understood. Here, we wish to use CRISPR-based genome-wide screening methods to screen for genes that, upon inactivation, confer resistance to taxol and related compounds. Identification of genes required for taxol-induced cell death will generate new insights on how taxol initiates apoptosis in tumors as well as potential resistance mechanisms.

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

Developing a behavioural task for measuring the ability of listeners to perform auditory scene analysis. 27 Apr 2017

The auditory brain separates simultaneous sounds arriving at the ear into identifiable and localisable sources by a process known as Auditory Scene Analysis (ASA). The two steps that are involved in ASA are i) segregation of the simultaneous auditory information and ii) the integration of the sounds from the same source into one stream. To understand how these two steps are connected and how different auditory cues interact to shape the scene, this project will develop a behavioural task and analyse the performance of human listeners. A target vowel will be presented alongside with a distractor vowel, and human listeners will identify what the target is. Listeners will only be able to identify the target if they can separate the two sounds: changing the location and pitch of target and distractor will help this. In order find out whether the separation of competing sounds is facilitated by the formation of perceptual streams, the vowels will also be presented as part of a sound sequence. Our hypothesis is that the ability to identify a target vowel will be improved by the formation of two perceptual streams. The long-term goal is to develop a behavioural paradigm suitable for humans and animals.

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

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

Investigating the association between genetic and epigenetic variability in immune genes and depression in young adults. 27 Apr 2017

Depression is one of the most commonly occurring mental health disorder in student populations, and the general population. However, despite its prevalence the environmental and biological factors that cause depression, and the underlying pathophysiology of the disorder remain poorly understood. The current diagnosis of depression is largely subjective, and there are no clinically validated biomarkers that can be used to assist in diagnosis and treatment selection. Variability in genes encoding inflammatory cytokines has been linked to the aetiology of depression. The aim of this project is to identify candidate inflammatory biomarkers which could potentially be useful for diagnosis and treatment selection in depression. The main objectives will be to determine whether polymorphisms and DNA methylation patterns in the interleukin 1 beta (IL-1B) and Tumour Necrosis Factor alpha genes are associated with depression in the student population in Northern Ireland.

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

Characterising in vitro airway responses to inhaled particulates 27 Apr 2017

Few new inhaled medicines have reached the market in the past thirty years despite considerable investment into developing new drugs for the treatment of airway diseases. One of the main reasons for the attrition of candidate inhaled therapies during drug discovery is the induction of inflammatory responses observed in rat airways during in vivo studies. Currently, in vitro cell based assays are poorly predictive of in vivo airway responses, largely due to the different methods of drug exposure adopted in in vivo and in vitro studies. The majority of current in vitro cell based toxicity assays introduce the drug in suspension or solution whereas in during in vivo studies the exposure is performed as an aerosolised powder. This impacts the physico-chemical properties of the particles and how they interact with the airway epithelial cells and resident alveolar macrophages. The aim of this project is to compare the morphology, cell viability and inflammatory markers associated with airway cell exposure to inhaled medicines dosed in solution, suspension and as aerosolised particles. This will enable a better understanding of the physico-chemical properties of drug particles that influence airway toxicity, facilitating more predictive in vitro assessment of the safety of new inhaled medicines.

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

Pathways of nanopore assembly by bacterial toxins and immune effectors 27 Apr 2017

To attack cells in our body, bacteria make use of toxins that drill holes in the cell membranes. Following a similar strategy, our immune system makes use of such pore forming proteins to target cancerous, virus-infected and bacterial cells. In the course of their action, pore forming proteins are first secreted as monomers, bind to the membrane, and next self-assemble into oligomeric pores. Some of the various open questions are how these pore assembly processes take place on more complicated, composite membranes such as bacterial envelopes. This project will aim to contribute to answering these questions, while providing the student research expertise in nanoscale microscopy methods applied to process that is essential for bacterial attack and immune defence. More precisely, the student will image live bacteria (E. coli) as they are attacked by the membrane attack complex. This is part of on-going atomic force microscopy experiments in the supervisors lab, which offer the possibility to visualise bacterial cell wall degradation in real time. Time permitting, the student will also be exposed to computational approaches to analyse such new data as well as past data on assembly and membrane insertion of immune effector perforin.

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

Prevelance of zoonotic bacterial pathogens in dog faeces collected from recreational areas in Cambridge 27 Apr 2017

In this study we will be investigating the prevalence of zoonotic bacteria in dog faeces collected from public recreational parks in Cambridge. More specifically, we will be looking for  E. coli, Salmonella, Campylobacter and Yersinia sp. which are known to cause gastrointestinal disease in humans. We will be using microbiological, biochemical and molecular techniques to identify the bacteria. We will then investigate the antibiotic resistance profiles of isolated bacteria in order to determine the risk of spread of antibiotic resistance and the impact this could have on  public health.

Amount: £0
Funder: The Wellcome Trust
Recipient: Anglia Ruskin University

Contextual effects on symmetry perception 27 Apr 2017

The human visual system is tasked with extracting and recognising objects and surfaces from the feature-rich backgrounds in which they are embedded. Most objects in natural scenes appear symmetric. Symmetry plays an important role in perceptual organisation, particularly in figure-ground segregation (symmetry is a property of the ‘figure’ rather than the ‘ground’). If this is the case then the visual system should be able to easily segment symmetry from background noise. Thus, this project will investigate the mechanisms responsible for contextual modulation of symmetry by examining spatial and temporal properties of centre-surround interactions in symmetry processing. We will examine how texture-surrounds influence the perception of a symmetrical central-target, as well as how symmetrical surrounds change the appearance of a noise central-target. We predict that symmetry detection will be impaired by a noise surround, and a symmetrical surround will make a noise centre appear more symmetric. By studying contextual effects on symmetry perception, we can gain insight into the role of symmetry in figure-ground segregation and the spatial and temporal limitations of these mechanisms in normal vision. Furthermore, it allows to predict how these mechanisms will be affected in an aging visual system and in abnormal processing of context (schizophrenia, autism).

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

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

Drug-eluting implants made of "green" materials for long lasting therapies 27 Apr 2017

Controlled release implants offer many potential advantages over traditional, periodic systemic injections including reduction or elimination of unwanted side-effects, enhanced efficacy and increased patient convenience and compliance. Implantable drug delivery devices also offer several advantages over conventional oral or parenteral dosage forms. Firstly, implantable devices allow site specific drug administration where the drug is needed most. For this application, biodegradable materials are particularly attractive as they require no surgical retrieval. Naturally-derived biodegradable materials generally offer superior biocompatibility and milder processing compared with synthetic degradable materials. The main aim of this project is to develop drug eluting implants based on natural biopolymers providing long lasting drug release. The devices will be formulated using two natural ocurring polymers zein and lignin. These two biopolymers can be obtained from renewable sources and consequently are a more environmental-friendly option and will reduce significantly the cost of the implants.Model molecules will be used to evaluate drug release: nile red as a model of hydrophobic drugs and methylene blue as a model for hydrophilic drugs. This will be achieved by: Formulation and characterization of zein/lignin implants containing hydrophobic and hydrophilic molecules. Evaluating biocompatibility of the developed systems. Evaluating drug release from the developed systems.

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

Disease-specific quality of life in children with suppurative otitis media, including children with Down Syndrome and Autistic Spectrum Disorder 27 Apr 2017

Acute otitis media (AOM) is a bacterial or viral infection of the middle ear which may accompany an upper respiratory tract infection. AOM can occur at any age, however, it is most common between 3 months and 3 years old. At this age, the Eustachian tube is structurally and functionally immature. Diagnosis of AOM is made by clinical and physical examination with an otoscope. Otoscopic examination can show a bulging, erythematous tympanic membrane with indistinct landmarks and displacement of the light reflex. The treatment for AOM are analgesics such as paracetamol or ibuprofen and many cases resolve spontaneously. Antibiotics are frequently given. Antibiotics relieve symptoms quicker and may reduce the chance of residual hearing loss and labyrinthine or intracranial sequelae. With the emergence of antibiotic resistant organisms, it is recommended that a round of antibiotics be administered only for children at highest risk or for those with recurrent acute otitis media(RAOM). RAOM is defined as four or more episodes of AOM in a 6 month period. The aim of this project is to investigate the impact on the quality of life of children that present with recurrent acute otitis media(RAOM).

Haemocompatibility and biocompatibility of a polyurethane-based polymer for use in prosthetic heart valves 27 Apr 2017

Developing valves with efficient function and long-term durability without the need for anticoagulation therapy, coupled with the ability to be accommodated in many different types of patient, are the principal requirements of replacement heart valves. The current treatment options available do not fit well with these critieria. The overall aim of the project is to develop a biomimetic polymer alternative to pericardium heart valve leaflets with a more repeatable, consistent and predictable production process. Main research objective: To investigate the haemocompatability of the polymer valve. That is, to measure the blood's response to contact with the valve by measuring parameters such as thrombogenicity, activation of coagulation, blood cell countsand platelet activation. Secondary research objective: To carry out a comprehensive collaborative literature review with my supervisor to deisign an experiment that helps us to understand the blood's response to the polymer in a dynamic environment i.e. simulating the in vivo scenario of blood being pumped across the valve and therefore coming in contact with the valve while under stress. Time allowing, we will then carry out this experiment. We hypothesize that the polyurethane-based material will have equivalent haemocompatibility to that of a commercially available aortic heart valve replacement.

Defining the molecular mechanism targeting CENP-E to centrosomes 27 Apr 2017

Accurate distribution of the genetic material to the daughter cells is essential to ensure correct progression through cell division. There is an ATP-dependent mechanism in place to ensure the alignment of all chromosomes. CENP-E is a motor protein that mediates chromosome capture and bi-orientation during mitosis. CENP-E is also found at centrosomes, where it is thought to be loaded, to then walk to microtubule ends bound to kinetochores. Its function at centrosomes is unclear. However in yeast, it has been suggested that kinesins bring the spindle checkpoint proteins to kinetochores from centrosomes. CENP-E may therefore in human cells bring the checkpoint proteins to unattached kinetochores. Here, we will crystallize the centrosome-targeting domain of CENP-E and define its sequence requirements using site-directed mutagenesis of conserved residues to test its recruitment to centrosome to gain insights into the role of motor proteins at centrosomes.

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

Automated single-cell microscopy of insulin-to-insulin regulation in C. elegans 27 Apr 2017

Insulin-like peptides (ILPs) play evolutionarily conserved roles in many physiological processes, including development, ageing, and neural function. Humans and other species possess multiple ILPs, and cross-regulation between ILPs is important for biological function. Here we exploit the stereotyped anatomy of C. elegans to dissect the regulation between two ILPs: ins-3 and ins-6. ins-3 negatively regulates ins-6 expression during the control of larval development. ins-3 is expressed in three identified neurons, while ins-6 is expressed in two identified neurons. Our key goal is to map out the regulatory connections from ins-3 neurons to ins-6 neurons. We will determine in which neurons is ins-6 affected in an ins-3 knock-out mutant using an ins-6::mCherry transcriptional reporter. We will next determine from which neurons ins-3 acts from, by examining ins-6 expression in a set of ins-3 mutant strains where wild-type ins-3 is selectively restored to each of its three neurons. All of the above strains have been made and will be analysed with an automated system for fluorescence microscopy to measure ins-6 reporter expression. This work will provide insights into cross-regulation between ILPs at single-cell level, and show how ILPs mediate communication in the nervous system.

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

The experiences of participants in care home research 27 Apr 2017

In the UK, it is estimated that 416,000 older adults (age 65+) live in care homes, a figure predicted to increase due to our increasingly aging population. Despite this, care home research is sparse in comparison to other areas of gerontology. The key goal of my project is to explore participants’ experiences of participating in care home research. First, I will conduct a systematic search of the literature to produce a narrative review of research in care homes, identifying the extent of involvement of staff, residents and relatives. Second, I will conduct six semi-structured interviews with individuals who have already participated in a research project. The questions will address the participant’s role in the home, their previous experience in research, their views on research, perceived challenges and enablers to conducting research in care homes and recommendations for future research. Data will be thematically analysed and the findings presented in a report highlighting the challenges and benefits of conducting research in care homes, and making recommendations for improving methodologies. My work will inform the ENRiCH (Enabling Research in Care Homes) Network, and my findings will be further disseminated to stakeholders at a learned society conference and through a peer-reviewed journal article.

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