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Cardiff University
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Results

Assessing the anticancer properties of Biocyanin SLH 31 May 2018

Haemocyanins are oxygen-carrying proteins found in the haemolymph of molluscs and gastropods. They are of interest to biotech and medical research as strongly immunogenic carrier proteins, for making antibodies to conjugated peptides and for use as cancer vaccines. In addition, direct application of haemocyanin to tumours has been shown to produce an anticancer effect, and haemocyanins from several species including keyhole limpet have shown promise in the treatment of bladder cancer, colon cancer and melanoma. Particularly striking are their lack of toxicity and adverse effects. Recently, Mikota PLC have developed protocols for the purification of a new haemocyanin, Biocyanin SLH, from the slipper limpet Crepidula fornicata. The main aim of our proposal is to test the potential of Biocyanin SLH as an anticancer agent, by incubating it with a panel of cancer cell lines and assessing its ability to induce cell death. In addition, we will investigate the signalling pathways involved in the anticancer action of Biocyanin SLH, determining whether cell death occurs via apoptosis or necrosis, and analysing cellular production of stress molecules. Finally, we will label Biocyanin SLH with a fluorescent dye to track its interaction with cells using confocal microscopy. Keywords: haemocyanin, cancer, cell death.

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

Investigating the relationship between the cerebellum and cognition in both health and disease 30 Sep 2018

The cerebellum is traditionally ascribed only a role in motor coordination. With it containing more neurones than the rest of the central nervous system combined and with connections with almost every other area of the brain concerned with cognition, this seems exceptionally unlikely. Indeed, studies utilising magnetic resonance imaging (MRI) increasingly show strong cerebellar activity associated with cognitive processes. This is still a greatly understudied area with only a few groups researching this. We, therefore, wish to investigate the role of the cerebellum in cognition using large imaging datasets, our own high-field imaging capabilities at Cardiff and various cerebellar-specific MRI processing tools which have not yet been applied to this question. This will allow us to see how well peoples’ cognitive performance in various domains correlates with cerebellar activity and structural differences. Additionally, recent evidence suggests cerebellar structural differences in schizophrenic patients. We wish, therefore, to also investigate if schizophrenia diagnosis and genetic risk for schizophrenia similarly alters cerebellar structure and, if so, at what time during development, if certain cognitive domains are particularly affected and if cerebellar metabolite levels differ in schizophrenic patients compared to non-schizophrenic controls.

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

Exploring brain reserve in healthy and diseased brain with neuroimaging 30 Sep 2018

Multiple Sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system that causes demyelination and axonal loss and leads to chronic disability in young adults. Brain plasticity, that is the ability to adapt to damage, can limit the clinical impact of MS. Plasticity is influenced by brain reserve and cognitive reserve. Reserve mechanisms represent the brain’s resilience to damage, conferred by the brain’s pre-morbid functional and structural characteristics. Due to brain plasticity and reserve, in MS there is a discrepancy between the degree of damage and the clinical manifestations of the disease. In this PhD project, I propose to investigate (a) the relationship between brain plasticity and reserve in healthy volunteers; (b) its alteration with MS inflammation; (c) the role of reserve as a predictor of recovery mechanisms in MS patients. I will conduct longitudinal experiments, involving both healthy volunteers and MS patients using a strong behavioural paradigm to induce plasticity. Advanced functional and structural MRI will be used to quantify the amount of reserve, to identify mechanisms of plasticity occurring with behavioural training and to understand changes in energy usage with plasticity.

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

Role of intralaminar thalamic nuclei in absence epilepsy 30 Sep 2018

Seizures in absence epilepsy are characterised by brief lapses in consciousness and cessation of ongoing behaviour. They occur concurrently with aberrant rhythmic electrical activity across the whole brain in the form of oscillations named Spike and Wave Discharges (SWDs). It is widely agreed that SWDs are generated in the cortico-thalamo-cortical (CTC) circuit that consists of neurons that run within and between the cortex and the thalamus. The activity of neurons in many components of the CTC circuit are already well characterised, apart from that of the intralaminar nuclei of the thalamus (ILNs), a group of neurons that respond in an abnormal, yet consistent way during seizures. The electrical activity of single neurons in the ILNs will be recorded and manipulated in order to physiologically characterise them and understand how changing their firing pattern can alter SWDs. The techniques required to achieve this are too invasive to be completed in humans, therefore, these methods will be undertaken in genetic and pharmacological rodent models of absence epilepsy. This work will provide a better understanding of the role of ILNs in the generation and spread of SWDs and in CTC circuit function, potentially leading to novel therapeutic approaches in absence epilepsy.

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

Molecular Mechanisms of Cortical Development 30 Sep 2018

EIEE9 (Early Infantile Epileptic Encephalopathy 9) is a rare genetic condition caused by mutations in the PCDH19 (Protocadherin 19) gene. The disorder affects heterozygous females and is characterized by epileptic seizures and cognitive impairment. PCDH19 is a cell-adhesion molecule that mediates cell-cell interactions during cortical development and it is thought to play an important role in neuronal migration and synapse formation. Researchers think the disease is caused by "cellular interference": PCDH19 is located on the X chromosome and - due to random X-inactivation - heterozygous females have a mixed population of PCDH19 positive and negative cells which are unable to correctly interact with each other leading to defective circuit formation and disease. We aim to create a transgenic mouse model that will enable selective labelling of PCDH19 expressing cells. This mouse model will be a valuable tool to investigate interactions between PCDH19+ and PCDH19- cells during cortical development and to study circuit formation. We will combine our transgenic mouse with recently developed techniques for synaptic tracing to characterize the neuronal circuits in which PCDH19+ neurons are involved by identifying those neurons that connect to PCDH19+ cells.

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

Investigation of epithelial differentiation in a mouse wound model 31 May 2018

Lipoxygenase (LOX) enzymes are expressed by infiltrating immune cells and are involved in innate immune and inflammatory response, all of which are fundamental processes in wound healing. The overarching aims of this larger body of work is to evaluate the role of 12/15-LOX in the cellular orchestration of wound healing using a murine model. We have induced full thickness (4mm) wounds in wildtype and 12/15-LOX knockout mice, then measured wound closure rates and harvested skin tissue at various time points post wounding and conducted histological evaluation of skin sections. Our initial data has found that in 12/15-LOX knockout skin there is enhanced fibroblast expansion, and a reduced infiltration of macrophages, both of which might be beneficial in chronic wound states where failure in fibroblast proliferation and an overt inflammatory state occur. However chronic wounds also displays deficits in wound re-epithelialisation and given that 12/15-LOX products can inhibit epidermal hyperplasia (by modulating cyclin/CDK signalling), we believe that KO mice might also display an enhanced re-epithelialisation phenotype. Therefore, to test this hypothesis we will explore the rate of re-epithelialisation and the cytokeratin profile of epithelial keratinocytes in KO and wildtype mice at various time points post wounding.

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

Gene validation of mesothelioma NanoString study 31 May 2018

Mesothelioma immunotherapy is in an experimental phase, and the main question is how to identify patients who are most likely to benefit from this treatment. To apply individualised treatment plans successfully, we need a better understanding of the tumour microenvironment. There is relatively little known about the immune signature and T cell homing in mesothelioma. The hypothesis is that patients, with higher frequencies of activated T cells in the tumour tissue respond better to a cancer vaccine. Preclinical studies show that L-selectin and its ligands on high endothelial venules (HEV) promote homing to the tumour tissue and improve immunotherapy. Analysis of Nanostring data from 24 patient samples for over 770 genes, will determine if L-selectin and HEV can be used to stratify mesothelioma patients for immunotherapy and will also enable us to search for other novel biomarkers. The experimental design will also inform us whether the biomarkers we identify are only predictive in immunotherapy or also applicable to patients receiving chemotherapy alone. The overall aim is to genes that are highly expressed in a current mesothelioma NanoString study using molecular biology tools. This study will identify potential pathways and ultimately a marker that is predictive of immunotherapy outcomes.

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

Translational neuroimaging in Huntington’s Disease: a time-course analysis of HD-related effects on myelination 30 Sep 2018

Huntington’s disease (HD) is a genetic, progressive, neurodegenerative disorder leading to cognitive deficits such as difficulties in information processing, attention and executive functions. Currently, this devastating disorder cannot be cured, hence the importance of gaining an insight into its pathogenesis and of looking for biomarkers of treatments’ efficacy. Evidence shows that HD is associated with white matter (WM) degeneration. Further, myelin break-down has been implicated in WM deterioration in HD. This emphasizes the potential of quantitative MRI metrics assessing white matter microstructure and myelination, to inform about disease pathogenesis. However, demyelination remains relatively unexplored in HD as compared to other neurodegenerative diseases. The purpose of the present research project is to carry out a time-course analysis of HD-related effects on myelination, by employing novel quantitative MRI techniques to uniquely combine whole-brain myelin mapping with assessment of axonal morphology.

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

DNA repair in Huntington’s disease and other repeat-associated disorders 31 Jan 2017

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG repeat in the huntingtin gene, HTT. The disease has characteristic motor and cognitive symptoms resulting initially from degeneration of the medium spiny neurons (MSNs) in the striatum. There are currently no disease-modifying treatments. The length of the CAG repeat is inversely correlated with age at motor onset but other factors influence onset including genetic variation elsewhere in the genome. A recent GWAS (GeM-HD) identified genetic variation in or near DNA repair genes as modifiers of age at onset. We hypothesise that DNA repair processes trigger post-mitotic CAG repeat expansion in MSNs leading to their degeneration. The work here aims to establish a cellular model of CAG repeat expansion which we can use to assess the effects of the DNA repair genes (and their variants) implicated by the GeM-HD GWAS. CRISPR technology will be used to knock-out or introduce the relevant genetic variation into HD-iPSC lines. Functional assays will then be conducted to assess cell viability. Characterising how these genetic variants affect cells harbouring the expanded CAG repeat will better define appropriate targets in the DNA repair pathway for further exploitation in therapeutic development.

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