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Results

Non-invasive investigations of the role of GABAergic inhibitory mechanisms and task induced oscillations in human visual function. 31 Aug 2011

In order to investigate the role of GABAergic inhibition in human vision and attention, we initially plan to conduct at least four experiments studying normal visual function in healthy participants. In the first series of experiments, we aim to relate participants' gamma oscillation frequency, obtained by a MEG recording during exposure to a visual grating, to behavioural performance in visual tasks such as contrast detection, contrast discrimination, orientation discrimination, and large-field motion detection. Because there is evidence that gamma oscillation frequency is controlled by the level of GABA in the cortex, if individual differences in this measure can predict behavioural performance in a visual task it would indicate that an aspect of visual processing relies on GABAergic inhibition. In the second phase of the thesis, we will aim to relate pre-stimulus modulations of alpha oscillatory activity, obtained in top-down attentional tasks, to levels of GABA in the visual cortex, measured using MR Spectroscopy. Because there is evidence that alpha modulation reflects ability to bias perception, if individual differences in GABA levels can predict alpha modulation levels, it would indicate that top-down visual attention relies on GABAerQic inhibition.

Amount: £146,543
Funder: The Wellcome Trust
Recipient: Cardiff University

The molecular rules that govern CD4+ T-helper cell recognition of peptide-MHCII. 22 Jun 2011

The molecular interactions that govern T-cell activation: T-cells recognise foreign antigens in the form of short peptides presented at the cell surface in complex with major histocompatibility complex molecules (pMHC). pMHCs are recognised by the highly variable membrane bound T-cell receptor (TCR). There are two main subsets of T-cells; CD8+ cytotoxic T lymphocytes (CTLs) that recognize pMHC class I (pMHCI) and play a key role in directly killing tumour cells and cells infected with pathogens , and CD4+ T helper cells (Th-cells) that recognize pMHC class II (pMHCII) and play a key role in orchestrating immune responses. Research Goals: 1: Use bacterially expressed soluble pMHCII molecules to investigate the structural and biophysical rules that govern CD4+ T helper cell responses. 2: Develop enhanced peptide ligands to artificially increase the affinity of the TCR/pMHCII interaction. 3: Engineer enhanced pMHCII multimers for the enumeration and isolation of CD4+ T helper cell s. 4: Establish whether modified peptide ligands, that increase the affinity of the TCR/pMHCII interaction, can be used to develop improved peptide vaccines for treating human diseases. Understanding the molecular parameters that govern CD4+ T helper cell immunity is essential for developing therapies and diagnostics for a number of important human diseases.

Amount: £771,080
Funder: The Wellcome Trust
Recipient: Cardiff University

Biomedical Vacation Scholarship. 25 Jun 2012

Not available

Amount: £8,280
Funder: The Wellcome Trust
Recipient: Cardiff University

The role of journal press releases in shaping biomedical news reporting. 15 Jul 2013

Public understanding of science and health is an important issue in society. Whether the topic is climate change, GM foods, or vaccines, each requires informed public engagement to arrive at democratic and ethically responsible solutions. Our project aims to uncover the causes of misreporting of health-related science, with implications for improving the interaction between scientists, the media, and the public. Despite years of debate about the (mis)representation of science in the media, th ere remains little hard evidence to indicate when, where and why problems arise. Our previous research has been among the first to address this issue, suggesting that university press releases (PRs) are a source of misreporting. The proposed study will investigate an even more crucial, but hitherto ignored, link between science and the media: PRs issued by major academic journals. Understanding the origin of misreporting is crucial for three reasons. First, occasional gross failure in the sc ience-media relationship, such as in the MMR scandal, causes demonstrable harm and death. Second, the cumulative effect of smaller-scale misrepresentation damages society by jeopardising public education and eroding trust in science. Finally, knowing origins of misreporting would allow for development of corrective guidelines that improve practices in PR formulation.

Amount: £4,990
Funder: The Wellcome Trust
Recipient: Cardiff University

DEFINE - Defining endophenotypes from integrated neurosciences 12 Oct 2012

Our objective is to rebuild the foundations of psychiatry by breaking away from existing diagnostic categories to define a new biology of mental disorders. Recent genomic studies have identified a number of genetic risk factors for neurodevelopmental disorders. These implicate specific synaptic processes but do not respect current diagnostic boundaries and confer susceptibility across a spectrum of clinical phenotypes including schizophrenia, autism, attention deficit hyperactivity disorder (ADH D), and intellectual disability. Thus, in order to identify novel biomarkers and mechanisms, it will be necessary to jettison existing categorical classifications and instead take a radically different approach based on the genetic underpinnings of these conditions. By focusing upon the effects of high-penetrance mutations that each confers risk across a range of disorders we will be able to establish convergent effects on processes involved in synaptic plasticity and associated effects at a cir cuit level. This bottom-up approach will enable us to work across species and levels of complexity to identify cellular, animal and human endophenotypes that are signatures of risk across diagnostic categories. This will enable us to prioritise animal and cellular phenotypes for future drug development and identify biomarkers of fundamental disease processes for patient studies.

Amount: £5,234,843
Funder: The Wellcome Trust
Recipient: Cardiff University

Open access award 2012/13. 17 Sep 2012

Not available

Amount: £75,000
Funder: The Wellcome Trust
Recipient: Cardiff University

The role of MlR137 and its targets in associative learning. 25 Jun 2012

We aim to determine the role of miR-137 and its targets in associative learning by investigating gene expression during contextual fear conditioning, a rodent model of hippocampal associative plasticity. Allelic variation in MIR137 and a sub-set of its confirmed targets has been associatedwith increased risk of schizophrenia in the latest GWAS. The aim is to focus on the regulation of calcium channel genes by miR-137, including the confirmedtarget CACNA1C, as well as other putative targets found to be associated withschizophrenia. Research would progress to explore the effects of local inhibition of calcium channels in the hippocampus as well as characterisation of a transgenic CACNA1C knock-out model. We further aim to confirm or refute predicted targets of miR-137 that may advance our understanding of this potential pathological pathway contributing to the etiology of schizophrenia.

Amount: £150,112
Funder: The Wellcome Trust
Recipient: Cardiff University

The functions of postsynaptic density implicated in psychiatric disorders in associative memory formation. 25 Jun 2012

Variants in the genes coding for postsynaptic density (PSD) proteins Homer1, DLG1 and DLG2 have been linked to psychopathology and schizophrenia. These proteins are functionally linked to postsynaptic glutamate receptors such asAMPA, NMDA and metabotropic glutamate receptors, and are thought to be key mediators of synaptic plasticity. Since associative learning is dependent on NMDA receptor-mediated synaptic plasticity and is impaired in several psychiatric disorders, we aim to determine the roles that PSD proteins including Homer1, DLG1 and DLG2 have in associative learning, with a view to shedding light on their part in psychiatric pathology To do this, we will a) use in situ hybridization to measure the expression of Homer1 transcription variants, Homer1a and Ania-3, DLG1 and DLG2 during key components of associative learning, including memory consolidation, recall andinhibitory learning, through the fear conditioning of adult rats. b) Use antisense­mediated knockdown of these PSD proteins before consolidation, recall and inhibitory learning, as well as knockout rodent models, to evaluate their function in processes required for associative learning. c) Administer mGiu and AMPA receptor-acting drugs to transgenic animals to investigate gene dependence in associative learning processes.

Amount: £150,112
Funder: The Wellcome Trust
Recipient: Cardiff University

Refinement of the Stroke Animal Model to Further Develop Therapeutic Strategies for Functional Repair and Treatment by Neural Transplants 21 May 2012

The main aim of this project is to examine the role of the imprinted cyclin dependant kinase inhibitor gene, Cdkn1c, in neural development and the resultant behaviour in adult animals when the copy number of Cdkn1c is altered. Furthermore we will assess how manipulation of maternal environment during pregnancy interacts with Cdkn1c expression in the normal animal and how this affects midbrain structure and animal behaviour.

Amount: £36,122
Funder: The Wellcome Trust
Recipient: Cardiff University

Coma, Consciousness and Serious Brain Injury: medical humanities and decision making. 28 Mar 2011

How do clinicians and families make serious medical treatment decisions on behalf of people with profound brain damage, such as those in vegetative and minimally conscious states? What treatment pathways, assumptions, laws and policies frame the options available - and how could these best be challenged, implemented, or improved to ensure science and medicine is deployed to maximize human health and well-being? What insights can be brought to bear by a medical humanities approach to this troubling area of biomedicine/health care ethics? This symposium will bring together around 20 key experts in this field - across disciplinary and professional boundaries- to examine these questions in depth and suggest ways forward. The meeting will strengthen emerging networks and establish dialogue across different perspectives - setting the ground work for future joint research bids, publications, and policy debates. In particular the symposium is designed to lead to a subsequent high-profile event in London and journal special issue devoted to these questions. In parallel to this application I am working with a theatre director and playwright to develop a public-engagement project, and also hope this topic could be a subject for a Wellcome 'Witness Seminar', My initial seeping exercise has ensured that the concerns/expertise of a wide range of medical humanities scholars, policy makers and user groups have been integrated from the outset and that key people in the field are enrolled in this exercise. The initial symposium will work with case study material to review the issue around decision-making, drawing on expertise in the Mental Capacity Act 2005 (designed to frame decision-making for those without capacity) and reflections on the practicalities of clinical dilemmas and family experience, policy making and economics as well as reflections from philosophers and experts in medical history, disability theory, bioethics, literature etc

Amount: £5,000
Funder: The Wellcome Trust
Recipient: Cardiff University

The role of the extracellular calcium sensing receptor (CaSR) in development and plasticity. 01 Jul 2009

1. Investigate a possible role for CaSR in regulating dendritic spine density & morphology in the hippocampus 2. Further characterize the published role of CaSR in regulating gross dendritic morphology in developing neurons [1] 3. Extend preliminary observations suggesting CaSR may have a role in early development of sympathetic neuroblasts and neurons (see Appendix) 4. Participate in studies to elucidate the intracellular signaling pathways by which CaSR promotes axon growth in fetal sympathetic neurons

Amount: £141,950
Funder: The Wellcome Trust
Recipient: Cardiff University

Interleaving brain systems for recognition and episodic memory. 04 Feb 2009

We will examine the neural substrates of two key forms of memory across behavioural, systems and cellular levels. In particular, we will investigate the specific contributions of different brain regions within both the perirhinal-centred system (for familiarity discrimination), and the hippocampal-medial diencephalic system (for event memory). Of especial note is the introduction of new methods including: new behavioural tests of object recognition memory and scene learning, and new manipulat ions to block the expression of synaptic plasticity long-term potentiation (LTP) and/or long-term depression (LTD). Issues to be investigated include: the importance of regions connected to the perirhinal cortex, including prefrontal cortex and the extended hippocampal system, for different forms of recognition memory the role of thalamic-prefrontal interactions in recognition memory. diencephalic involvement in recognition memory revealed through gene-imaging perirhinal h ippocampal system interactions modelled from neuronal activity measures differentiation of the role of perirhinal cortex in perception and recognition memory whether all components of the extended hippocampal system are required for a key attribute of episodic memory scene learning whether and where LTD and LTP mechanisms are required for different forms of scene learning and recognition memory

Amount: £1,569,168
Funder: The Wellcome Trust
Recipient: Cardiff University

See it, grab it: Control of automatic sensorimotor behaviour in health and disease. 08 Oct 2008

Our goal is to understand how automatic processes are involved in the flexible, volitional control of behaviour. We will integrate different lines of research concerning automatic and unconscious activation and inhibition of motor plans, which together may challenge the traditional view that volitional and automatic behaviours are mediated separately. We will investigate: The roles of medial frontal and parietal brain regions in the activation of, competition between, and inhibition of a ction plans elicited by visual stimuli in the world around us. The inability of patients to inhibit stimulus-driven responses following focal damage to these regions, or in corticobasal degeneration. The relationship between the activation, conflict and inhibition mechanisms engaged by different sensorimotor paradigms (masked priming; flankers; object affordance). A key strength of our proposal is the principled combination of experimental domains. Careful behavioural studies will deter mine performance correlates of activation, conflict and inhibition mechanisms and how they interact. A selected population of lesion patients will allow us to test hypotheses concerning the cortical substrates of these mechanisms, and the outcomes of interfering with them. Imaging will reveal the spatial distribution of implicated areas, and also the dynamics of activation within these cortical networks.

Amount: £426,191
Funder: The Wellcome Trust
Recipient: Cardiff University

Investigation of lithium-induced macro-autophagy in Dictyostelium. 10 Jul 2008

We will investigate the molecular mechanism by which lithium (Li+) induces macro-autophagy and promotes clearance of protein aggregates. Our investigation will use a combination of genetics and cellular pharmacology to study induction of macro-autophagy and protein clearance in the social amoeba Dictyostelium. These studies will draw on our previous work on the cell biological effects of Li+ and the genetics of lithium sensitivity. We will monitor induction of macro-autophagy by use of ATG8- GFP, a fluorescent marker for autophagosome formation in living cells, and follow clearance of protein aggregates, using expression of fragments of human Huntingtin. We will examine the dose-response to Li+, and specific derivatives of VPA, and investigate their behaviour in combination with rapamycin, a mTOR inhibitor. The major component of this project will use Dictyostelium genetics to examine: i) which inostiol phosphate (IP3 or PIP3) is the immediate lithium target; ii) where in the pathway lithium interacts with autophagy regulatory (atg) genes; iii) our collection of mutants with altered lithium sensitivity to identify new components of the pathway that connects inositol phosphate signalling to regulation of autophagy. These results should inform the design and implementation of a general pharmacological therapeutic approach for the treatment of protein aggregation diseases.

Amount: £161,345
Funder: The Wellcome Trust
Recipient: Cardiff University

Imaging NMDA Spike/plateaus in Thin Dendrites in Brain Slices Using Genetically-encoded Calcium Indicators. 10 Oct 2007

Goal: to identify transgenic mice which can be used for imaging NMDA spikes in vivo. Various promising strains, starting with CERTN-L15 (Griesbeck lab, Germany), will be bred and genotyped. Somatosensory cortical brain slices will be cut from individuals with this fluorescent calcium sensing protein. Targetted whole-cell recordings will be made from individual pyramidal neurons expressing the protein, under visual control, using a two-photon microscope (Ultima, Prairie Technologies), already in the lab. Brief, focal pulses of glutamate will be uncaged or iontophoresed onto individual basal, apical oblique and apical tuft dendrites, and NMDA spike/plateaus will be evoked. Glutamate and voltage will be varied to establish thresholds and to quantify variations in fluorescence (calcium) transients with spike/plateau duration, which increases with both glutamate and depolarisation. Fluorescence transients will be mapped along the length of the input dendrite and in neighbouring dendrites , using a number of excitation wavelengths. The input site will be moved up and down single dendrites, and to different dendrites. To mimic in vivo activity, we will test different patterns of glutamate uncaging distributed along the length of input dendrites. Various strains of mouse will be tested, to identify most promising candidates for in vivo imaging.

Amount: £19,969
Funder: The Wellcome Trust
Recipient: Cardiff University

Ethics in practice: An ethnographic study of decision-making and their implications in dementia care. 18 Mar 2010

This study aims to inform how clinicians make ethical decisions over the disclosure of test results and diagnoses to adults with memory problems, particularly in the context of new medical advancements in relation to predisposition to and the early detection and diagnosis of dementia. This ethnographic study will combine an interrogation of the philosophical foundations of moral and ethical principles in particular the respect for autonomy- with the situated ethics of clinical practice, r ecognising the institutional structures, social organisations and larger social worlds in which ethical issues emerge and are acted upon. The project will view clinical assessments and diagnoses in the context of older people and their families experiences of memory problems to inform what ought to be considered in making decisions when communicating with patients and their families: what information should be communicated, when should this be communicated and how should it be communicated ? The results of this study will be disseminated to academics, policy makers, practitioners and patients and carers who are affected by memory problems and dementia.

Amount: £148,055
Funder: The Wellcome Trust
Recipient: Cardiff University

Generation of lipid standards for biological studies: oxidized phospholipids generated by activated immune cells. 07 May 2009

This proposal will establish a resource for generating and supplying oxidized phospholipid standards for biological/biochemical studies to the international research community. The study of these lipids is an emerging field, of relevance to basic mechanisms of physiology and to human disease. Detailed structural characterization, quantitation and biological studies require purified synthetic lipids. We have generated two of these compounds already, but the others (<26) require a total synthesis approach that is more time consuming/costly. Once this methodology is established, it can be applied to numerous other related structures, as detailed in our application. We request funding for an organic chemist based in the laboratories of Drs O'Donnell & Bagley. He/she would travel to Dr Porter's lab for up to 3 months to learn advanced organic synthetic chemistry required for this project, then would establish routine synthesis in Cardiff. Related approaches for other lipids are already set- up in Nashville and we do not anticipate any problems. The lipids would be available free of charge to research collaborators (currently 8) but intellectual property will be protected so that they may be commercialized at a later date. A preliminary application for this grant was approved in early 2008.

Amount: £192,231
Funder: The Wellcome Trust
Recipient: Cardiff University

Open access award. 22 Sep 2009

Not available

Amount: £45,000
Funder: The Wellcome Trust
Recipient: Cardiff University

Centre for the Development and Evaluation of Complex Interventions for Public Health Improvement (DECIPHer). 16 Sep 2008

To develop effective interventions to improve population health requires a much greater understanding of what works, why, for whom and in what circumstances. This will necessitate the development of epidemiologically and social scientifically Informed complex and multi-factorial interventions that are effective across settings and behaviours; the rigorous evaluation of complex interventions, often using pragmatic controlled trial designs with nested process evaluation and including natural experiments of new policy programmes and the use of routine data to develop and target interventions and to provide sources of data on contexts and long term outcomes for intervention studies. The centre for the Development and Evaluation of Complex Interventions for Public Health Improvement (DECIPHer) brings together team of world class researchers with expertise in a wide variety of quantitative and qualitative evaluation methods and intervention technologies to address these issues. Building on a strong track record, along with partners from public health policy and practice, and the public we will develop, test, evaluate and then implement interventions that are effective in improving the health of the population across settings and behaviours and which address health inequalities, with a particular focus on children and young people. We will also provide high quality training programmes to develop skills of public health researchers

Amount: £1,949,756
Funder: The Wellcome Trust
Recipient: Cardiff University

Biomedical vacation scholarship. 29 May 2009

Not available

Amount: £10,080
Funder: The Wellcome Trust
Recipient: Cardiff University