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Results

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

Open Access Awards 2017/18 30 Sep 2018

Not available

Amount: £21,050
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

How curiosity enhances hippocampus-dependent memory 06 Jun 2018

In today’s world, it is most desirable to optimize cognitive capacities, such as learning, across the lifespan. One fundamental, yet poorly understood, method is via a person’s intrinsic curiosity. Despite the ubiquity and importance of curiosity in everyday life, we have a very limited appreciation of the exact neural mechanisms of curiosity-enhanced learning. Because initial curiosity studies have relied on the passive encoding of material, one fundamental aspect of curiosity – active exploration to acquire further knowledge – remains to be investigated. I, therefore, propose a new virtual reality paradigm to characterize the neural mechanisms of how active curiosity enhances memory. Across three principal approaches, I will ask how separate stages of memory (orientation vs. initial learning vs. different modes of consolidation) contribute to curiosity-related memory enhancements and why curiosity-based learning might vary between healthy individuals. I will uncover whole-brain mechanisms and ‘zoom in’ on specific curiosity- and memory-related brain structures using complementary state-of-the-art measures and analyses. Combining such approaches is vital if we are to understand how curiosity enhances memory, but may also aid crucial translation of laboratory-based findings on learning and memory to real-world issues (e.g., influence on educational policies and implications for cognitive resilience in the elderly).

Amount: £959,155
Funder: The Wellcome Trust
Recipient: Cardiff University

Identifying the pathogenic triggers of CD8 T-cells in multiple sclerosis . 13 Nov 2014

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), affecting 2.5 million individuals worldwide. Treatments are available, but are complicated by side effects and variable response profiles. There is an urgent need to define the pathogenesis of MS and design novel therapeutics. There is evidence that CD8 T-cells play a major role in the pathogenesis of MS. Studies also suggest a role for herpes viruses in MS, however, it remains unclear what triggers di sease. My preliminary data demonstrates that CSF resident T-cells have an antigen-driven phenotype. T-cell receptor (TCR) usage in the CSF resident CD8 T-cell repertoire is highly skewed with a restricted number of dominant TCRs. I hypothesize that a viral infection, such as EBV, triggers CD8 T-cells, which subsequently target and damage host cells. Here, I intend to identify the pathogenic triggers of dominant CSF-resident T-cells, thereby elucidating the aetiology of this debilitating disease. Specific aims: 1. To perform an in-depth phenotypic analysis of T-cell populations in the CSF of MS patients. 2. To identify dominant CSF resident TCRs in MS patients. 3. To define the pathogenic triggers of dominant CSF-resident TCRs.

Amount: £173,892
Funder: The Wellcome Trust
Recipient: Cardiff University

Landscapes of Health: The Black Sea in the Socialist World. 25 Nov 2014

Landscapes of Health: The Black Sea in the Socialist World is a workshop with two main objectives. First, it seeks to develop our understanding of the role of Black Sea health resorts in socialist medical theory, practice, and culture. It highlights the importance of the sea, rest, environmental health, and natural healing to socialist ideas and practices of health. The workshop develops the idea of the Black Sea coastline of socialist Bulgaria, Romania and the Soviet Union as a shared zone of h ealth in the geography of the socialist world. Second, the workshop develops the idea of health resorts as international meeting places. The workshop marks the 70th anniversary of the Yalta conference (February 4-11, 1945), and brings to light the role of medicine and socialist ideas of health in Cold War diplomacy. Health resorts were showcases of the socialist world, in a Cold War contest fought publicly over welfare and standards of living. This workshop brings together for the first time scholars studying the health resorts of the Black Sea, with contributions from specialists in the history of medicine, history, film, architecture and urban planning, and scholars of both the Soviet Union and the Eastern Bloc.

Amount: £4,900
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

The role of innate immune regulation in viral pathogenesis and the development of anti-viral T cell memory 11 Jul 2017

Immune mechanisms that regulate antiviral immune responses determine whether the host can control pathogen replication and virus-induced immunopathology. The pathogenic human cytomegalovirus (HCMV) establishes chronicity and induces inflammation-associated pathologies. Cytomegalovirus (CMV) also induces the largest known expansion of T cells, and thus represents an important tool for identifying mechanisms inducing robust T cell immunity. CMV may also be exploited as an attenuated vaccine vector. Using a CMV model of viral pathogenesis, I identified that immune regulation during initial infection determines the extent of virus-induced inflammation and development of long-lived virus-specific immunity. The key goals of this proposal are: Identify innate immune components that mediate viral pathogenesis and understand how they are controlled Test whether innate immune pathways can be a) safely targeted therapeutically to treat viral disease and/or b) used to predict genetic risk of CMV pathogenesis Identify the early immunological events that promote CMV-specific T cell memory development, and elucidate whether regulatory pathways controlling these factors can be harnessed to enhance virus-driven memory T cell formation induced by attenuated viral vectors This research will determine whether innate immune activation can be exploited to: 1) safely treat viral pathogenesis and/or 2) enhance virus-induced T cell memory responses.

Amount: £1,942,612
Funder: The Wellcome Trust
Recipient: Cardiff University

Establishing objective measures for identifying children with Autism Spectrum Disorders using eye-tracking technology in the UK and India 09 Nov 2016

Autism Spectrum Disorders (ASD) contribute significantly to total years lived with disability globally. Most people with ASD in low-income countries are belatedly or never diagnosed, mainly due to the paucity of mental health specialists - hence critical years for treatment are missed. Objective measures for ASD detection are needed. Multiple cognitive markers of ASD have been identified using eye-tracking technology; testing these markers in combination holds promise for effective identification of children with ASD. This proposal aims to establish objective measures for identifying children with ASD using eye-tracking technology in high and low-income settings. Stage 1 will analyse existing eye-tracking data from the British Autism Study of Infant Siblings, to establish a combination of eye-tracking tasks that has the highest probability of identifying children with an ASD diagnosis. Stage 2 will be a case control pilot study to determine whether the same combination of markers identifies children with an ASD diagnosis in India. The feasibility and acceptability of these eye-tracking tasks will also be assessed in an Indian context. Establishing effective, acceptable and feasible methods for objectively identifying children with ASD will improve detection in these settings and translate into a greater number of children benefiting from early interventions worldwide.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Integrative Neuroscience. 14 Jul 2014

Not available

Amount: £149,985
Funder: The Wellcome Trust
Recipient: Cardiff University

Medicine and the Bishop in Medieval England, c.1100-c.1400. 04 Dec 2013

This project investigates the role of medicine in the life of the late medieval bishop, through an examination of three key themes. The bishop as a beneficiary of medical knowledge and treatment considers both medical provision within the episcopal household, and the role of preventative medicine (especially the six non-naturals) in protecting the bishop's health. The bishop's medical knowledge examines the medical knowledge of the late medieval episcopate: what medical knowledge did the bishop did, where did he obtain it from, and how did he use it? Understanding the bishop's body explores the role of medical knowledge in the formation of episcopal reputations, suggesting that medical interpretations of the episcopal body could be crucial in the formation of a reputation for sanctity or failure. Overall, the project aims to combine medical and ecclesiastical history in order to provide a detailed case study of the impact of medicine on a particular social group, and thus to improve ou r understanding of the links and potential tensions between spiritual and medical understandings of health and well-being as they existed in late medieval England.

Amount: £150,282
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Control of homeostasis and inflammation by the macrophage metabolome. 07 Apr 2014

Macrophages are a heterogeneous population of immune sentinels who shape the physiology of most tissues; this fundamental role often contributes to the pathogenesis of inflammatory disorders such as rheumatoid arthritis and cancer. Recently, marked heterogeneity in tissue-resident macrophage origins has been observed, with many having prenatal rather than adult bone marrow origins. Little is currently known about how the functions of these distinct macrophage populations are controlled. However, I have observed that the phenotype of tissue-resident macrophages can be directed through tissue-specific transcription factors, which control modulators of macrophage function including metabolic regulators. I have identified extensive regulation of metabolic enzymes during an inflammatory response with a clear disparity between bone marrow-derived and tissue-resident macrophages. These enzymes have the potential to direct distinct macrophage functions through both control of the metabolome an d direct interactions with key transcription factors. I hypothesise that precise regulation of metabolic enzymes is critical for specific macrophage function. The objectives are: i) characterise the metabolomes of distinct macrophage subsets during inflammation; ii) determine functional consequences of metabolic modulation; and iii) investigate specific functions of select metabolic regulators in inflammation in-vivo. Understanding how metabolic regulation controls cell function could lead to no vel therapeutic approaches to inflammatory diseases.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: Cardiff University

Biomedical Vacation Scholarship 23 Jun 2014

Not available

Amount: £4,000
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

The immunopathogenesis of Epstein-Barr virus-associated malignancies. 26 Nov 2012

Epstein-Barr virus (EBV) infects >90% of the human population and is associated with a broad spectrum of diseases, including an array of distinct malignancies. Indeed, EBV was first isolated from a Burkitt lymphoma tumour specimen almost 50 years ago and represents the prototype human oncogenic virus. The global burden of EBV-associated malignancies is startling, with approximately 200,000 new cases reported annually. At present, however, there are no commercially available vaccines, no effectiv e antiviral drugs and no virus-targeted therapeutics to prevent or treat these devastating malignancies. The research questions in this proposal reflect the pressing need for rational intervention in the EBV-associated oncogenic process, collectively aiming to identify pathways to prevention and cure. Novel immunotechnological approaches will be developed to profile EBV-specific T-cell immunity and reveal the immunological lesions that underlie the failure of immune surveillance in otherwise imm unocompetent individuals. These tools will also be used to monitor a poxvirus-vectored vaccine that aims to generate EBV-derived latent antigen-specific T-cell responses to correct the immune deficit and effectively target transformed B-cells. Further, novel bispecific high affinity T-cell receptor-based reagents will be developed to redirect T-cell immunity against established EBV-associated malignancies. Successful delivery and application of these cutting edge immunotechnologies and immunothe rapeutic strategies will have direct translational implications for human health.

Amount: £2,065,190
Funder: The Wellcome Trust
Recipient: Cardiff University

Open access award 2013/14. 16 Sep 2013

Not available

Amount: £30,000
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Excitatory-inhibitory balance in adolescents at high genetic risk of mental disorder: a study of cortical gamma oscillations and GABA concentrations in 22q11.2 deletion syndrome. 26 Jun 2013

Neurodevelopmental disorders such as schizophrenia, autism and ADHD share clinical features, environmental risk factors and show familial co-aggregation. Recent genetic findings suggest that both common and rare genetic variants confer susceptibility across this spectrum of disorders, suggesting common pathogenic mechanisms. Cortical excitatory-inhibitory imbalance is proposed as one potential mechanism for the increased risk of mental disorder across traditional diagnostic boundaries. Marker s of disturbance in this balance include gamma oscillations (measured by magnetoencephalography, MEG) and GABA concentrations (measured by MRS). These markers have been shown to be abnormal in idiopathic schizophrenia, autism and ADHD. The 22q11.2 deletion is one of the strongest known genetic risk factors for mental disorder. I propose to use MEG and MRS to investigate cortical gamma oscillations and GABA concentrations in a sample of adolescents with 22q11.2 deletion syndrome and a sample o f unaffected siblings. I will conduct between-group analyses to determine whether the 22q11.2 deletion is associated with abnormal gamma oscillatory activity and GABA concentrations in the cortex. I will also investigate the relationship between gamma oscillations, GABA concentrations and psychopathology in 22q11.2DS. To my knowledge, this will be the first study of gamma oscillations and GABA concentrations in this high-risk group.

Amount: £307,019
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

Institutional Strategic Support Fund 2011/12. 20 Dec 2011

The Trust’s major directions for use of this Fund are as follows: 1. To assist the Institution in developing its research strategy across College’s and Schools 2. To encourage new inter-departmental synergies, cross-disciplinary collaborations, and inter-institutional initiatives 3. To add value to existing Wellcome Trust investments in the Institution. Strengthening Biomedical and Clinical SciencesCardiff University will build on successes of the first ISSF Award, widening the portfolio to encompass all the priority research areas in the College of Biomedical and Life Sciences (CBLS). We will build new links with relevant research in computing, physical sciences, humanities and social sciences and consolidate ties with partner Universities in the South West. CBLS, which includes all the Health-related Schools in the University, has recently completed a comprehensive review of its research portfolio and identified five Themes around which investment will be focused: Immunology, Infection & Inflammation; Mind, Brain & Neuroscience; Cancer; Public Health & Integrative Biosystems. The ISSF Award will impact in all these areas. Previous ISSF success 2013The Award, with matched funding, supported new academic appointments, seven project grants, thirty-one seedcorn grants and eight mobility awards. Infrastructure was supported through substantial spend on new equipment. Public engagement was supported through contributions to high profile local events and stand-alone meetings.

Amount: £750,000
Funder: The Wellcome Trust
Recipient: Cardiff University

Tractometry. 04 Oct 2011

Not available

Amount: £1,788,305
Funder: The Wellcome Trust
Recipient: Cardiff University

Using machine learning algorithms to analyse complex genetic data in sub-phenotypes of psychiatric disorders. 25 Jun 2012

The main objective for my PhD will be to apply machine learning methods and algorithms to complex genetic data in an attempt to identify features that characterise different sub­ phenotypes in psychiatric disorders. This will not only look for the contribution of individual genes, but also at possible biological gene-gene interactions and functional pathways. The use of non-parametric machine learning techniques will allow us to go beyond classical statistical (parametric) methods and search for more complex underlying patterns in the data.

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

Modulating hippocampal neurogenesis to restore learning and memory in mesial temporal lobe epilepsy. 25 Jun 2012

Learning and memory dysfunction is the commonest neuropsychological effect of mesial temporal lobe epilepsy (mTLE). Because the underlying neurobiology is poorly understood, there are no pharmacological strategies to restore learningand memory function. Neurogenesis in the adult dentate gyrus is important for allocentric hippocampal learning, is impaired in chronic mTLE due to chronic neuroinflammation, and we have recently shown thatrestoring neurogenesis in animal models returns allocentric learning to normal. Using 30 cultures of sclerotic hippocampus from epilepsy surgery patients we also show that this antineurogenic effect is Q£!1!y mediated via IL-1beta release. Cytokines released into the stem cell microenvironment from astrocytes, neurons and microglia are key modulators of neurogenesis under normal and neuroinflammatory states and are also primed by the complement system. Status epilepticus induced epigenetic modification of hippocampal neural stem cells also appears to play a role bothin normal and in chronically altered neurogenesis in mTLE. Our objectives are to examine the role of cytokines, the complement system andepigenetic modification in generating and maintaining the anti-neurogenic niche in animal models and human mTLE, and whether these affect hippocampal learning, in order to identify drug targets for treating cognitive impairment in human mTLE.

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