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Cardiff University
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Results

Amount: £2,768
Funder: The Wellcome Trust
Recipient: Cardiff University

Feasibility of a large-scale, international, clinical-genetic study of postpartum psychosis 11 Apr 2019

<p>Postpartum psychosis&nbsp;represents a unique opportunity to study the effects of reproductive factors&nbsp;on the human brain.<br> One of the most severe and dramatic psychiatric illnesses, it affects ~1 in 1000 women soon after childbirth, in many cases unexpectedly.Genetic factors may be involved, but its causes remain poorly understood.</p> <p style="margin-left: 0cm; margin-right: 0cm">The lack of official recognition and definition have hindered research and negatively impacted sufferers.&nbsp;</p> <p>For the first time this project will harness pre-existing international collaborations and datasets to establish cross-culturally valid definitions and standards of assessment of postpartum psychosis and create a pipeline for data acquisition, quality control and harmonization. Genome-wide analyses will provide metrics and preliminary evidence for a larger study. New collaborations and additional datasets will be sought.</p> <p style="margin-left: 0cm; margin-right: 0cm">This study will lay the&nbsp;foundation&nbsp;for a postpartum psychosis international consortium.&nbsp;It will provide data beyond the lifetime of the funding and a robust, systematic approach to uncover the biology of psychosis triggered by childbirth. It will potentially give clues into new, fast-track targets for translational and pharmacological research and improve risk prediction.</p> <p>Moreover, it will contribute to the de-stigmatization of mental disorders related to female reproduction by providing evidence-based, accessible information to the public.</p>

Amount: £89,126
Funder: The Wellcome Trust
Recipient: Cardiff University

Profiling superantigen-induced immunosuppression of unconventional T cells during sepsis 11 Apr 2019

<p style="margin-left: 0in; margin-right: 0in">Sepsis is a life-threatening illness that is triggered by an exaggerated immune response to severe infection. Despite improving survival rates, patients are often left immunosuppressed. This defining feature is considered to be the main driving force behind morbidity and mortality in sepsis. <em>Staphylococcus aureus</em> is a leading cause of sepsis and, like other bacteria, secretes potent exotoxins (superantigens)<em> </em>which suppress, or even deplete, circulating T cell populations, including antimicrobial T cells (MAIT cells, &gamma;&delta; T cells). These &ldquo;unconventional&rdquo; T cells are known to be depleted in the blood of sepsis patients yet our knowledge on a link between the action of superantigens and unconventional T cell depletion in sepsis is incomplete.</p> <p style="margin-left: 0in; margin-right: 0in">&nbsp;</p> <p style="margin-left: 0in; margin-right: 0in">This proposal will use advanced polychromatic flow cytometry and RNA sequencing to profile the immunosuppressive actions of a panel of bacterial superantigens (cellular exhaustion, excessive cytokine production) on antimicrobial human T cells. Using cohort of patients with acute bacterial sepsis, correlations between patterns of superantigen-induced immunosuppression and depleted MAIT and &gamma;&delta; T cells in sepsis will be examined. This approach will aim to determine whether superantigens promote the depletion of certain MAIT and &gamma;&delta; T cell clonotypes during sepsis, providing novel insight into the pathogenic mechanisms driving sepsis-mediated immunosuppression.</p>

Amount: £99,292
Funder: The Wellcome Trust
Recipient: Cardiff University

Making advanced characterisation of tissue microstructure clinically practical: a data-driven approach to efficient microstructural MRI 24 Apr 2019

<p style="margin-left: 0in; margin-right: 0in"><strong>Diffusion MRI</strong> (dMRI) is the preferred tool for quantifying tissue microstructure, but current technology prohibits comprehensive assessment. Even in the extensively-studied brain white matter (WM), state-of-the-art measurements invalidate commonly-applied <strong>biophysical model</strong> constraints, and parameter estimates are unreliable. Moreover, models disregard myelin, a key WM-component typically considered &lsquo;off-limits&rsquo; with dMRI.</p> <p style="margin-left: 0in; margin-right: 0in">We have <strong>reached a hiatus</strong> in advancing tissue characterisation by dMRI alone, motivating multi-contrast MRI including myelin-sensitive contrasts. <u>Simultaneously</u> varying multiple experimental variables is now possible through <strong>ultra-strong gradients</strong>. However, as the <strong>dimensionality </strong>of the accessible MRI acquisition space increases, efficient data acquisition and representation become challenging, hampering the clinical translation of microstructural MRI.</p> <p style="margin-left: 0in; margin-right: 0in">I will develop methods to optimise the execution and data representation of multi-contrast MRI experiments, with the goal of comprehensive tissue-characterisation in a clinically-applicable time. I will employ 1) a top-down approach that considers that the tissue properties most important to characterise are <u>known</u>, and assumes that <strong>analytical models</strong> exist that can be optimised to maximise precision per unit acquisition time; 2) a bottom-up approach that considers that the dimensionality of the analysis-space is <u>unknown</u>. Starting with rich multi-contrast data, I will develop <strong>data-driven approaches</strong> to characterise the measurement information-content and to select the most relevant measurements.</p>

Amount: £300,000
Funder: The Wellcome Trust
Recipient: Cardiff University

SP3: Scalable Software for Pathogen Reads to Clinical Results using Next Generation Sequencing 28 Feb 2019

<p>Scalable Pathogen Pipeline for turning Next Generation Sequencing Pathogen data into<br> Clinical Results<br> Recently, technology has developed which allows us to read the DNA blueprint of microbes<br> rapidly. This technology is now being widely used on bacteria, both to decide optimal<br> treatments, and to track the transmission of infection. A key requirement is the need for<br> integrated software to turn DNA sequence data into a microbial identification and a prediction<br> of resistance, and into a usable depiction of microbial transmission.<br> Existing software solutions work and improve on conventional laboratory methods, but are<br> difficult to deploy and validate outside the University settings where they were<br> created. However, there is global demand for similar, readily deployed, high quality services.<br> The Scalable Pathogen Pipeline (SP3) project will address this demand. Building on a range<br> of proven existing tools, it will provide a sustainable, open source, software framework,<br> together with validation data, to clinical and research settings. It will be deployable without the<br> need for extensive software or genomics expertise.</p>

Amount: £1,029,833
Funder: The Wellcome Trust
Recipient: Cardiff University

Building and Interrogating Relationships between the Medical Humanities and Humanities Approaches to the Sciences 06 Oct 2018

<p>&ldquo;Building and Interrogating Relationships between the Medical Humanities and Humanities Approaches to the Sciences&rdquo; offers a programme of events led by Cardiff University&rsquo;s ScienceHumanities Initiative, in collaboration with international partners, Duke University. Running over three years, we offer multiple events where humanities approaches to medicine and health are placed in sustained and productive dialogue with humanities approaches to other sciences and technologies. Humanities scholars working on medicine and health all too rarely consider other sciences and technologies, despite their proximity and comparative practices. It is time we were more ambitious in looking across this larger context. Our programme meets this challenge, igniting new methods for understanding the relations between medicine and the humanities. The programme focuses on three key themes: Populations, Energies, and Healthy Futures. Our vision is to generate further research that transforms our methodologies and enables us to meet future challenges to our understanding of medicine and health. Through annual workshops, colloquia, and summer schools, each theme will be interrogated in local, regional, and international contexts and by different forms of expert knowledge. Our project&nbsp;is an opportunity to uncover a new perspective on medical humanities that places itself in a wider ecosystem of sciences and technologies.</p>

Amount: £30,560
Funder: The Wellcome Trust
Recipient: Cardiff University

Institutional Strategic Support Fund 30 Sep 2019

Not available

Amount: £1,400,000
Funder: The Wellcome Trust
Recipient: Cardiff University

Design and development of AMPA receptor modulators with a much improved safety profile as novel drugs for treating the cognitive dysfunction associated with schizophrenia and other CNS disorders 30 Sep 2019

Around 1% of the population will suffer from schizophrenia at some point in their life. Symptoms such as paranoia and/or hearing voices can be reasonably well treated by existing medications. However, these drugs have little effect on the other symptoms (lack of motivation and impaired social function) and impaired cognition, including difficulties with attention, memory and problem-solving that result in a “brain fog”. These largely untreated symptoms remain a huge barrier to the resumption of a fully functional, “normal” life for these individuals and are associated with an annual estimated cost in the UK alone of around £12 billion. Professor Simon Ward from the University of Sussex has received a Seeding Drug Discovery Award to identify and develop drug which is a selective modulator of the AMPA receptor which has the potential to provide an innovative new treatment for patients with schizophrenia. If successful the team expect to have a compound ready for clinical evaluation in just over three years time. Nerve cells (neurons) communicate with each other by releasing chemicals known as neurotransmitters that interact with proteins called receptors on adjacent neurons. Levels of the neurotransmitter glutamate, which is crucial for normal cognitive function, are altered in schizophrenia. A specific subtype of glutamate receptor, the AMPA receptor, is thought to be associated with cognition and therefore increasing AMPA receptor function should improve cognitive performance in schizophrenia and thereby addressing an unmet need and revolutionizing the functional outcome of this patient population.

Amount: £1,026,950
Funder: The Wellcome Trust
Recipient: Cardiff University

INSTITUTIONAL TRANSLATION PARTNERSHIP AWARD (iTPA): CARDIFF UNIVERSITY 30 Sep 2018

The Cardiff institutional Translational Partnership Award (iTPA) aims to embed a more translational culture within the university's academic staff. It will combine the educational and community-building activities needed to assist researchers with industrial engagement and help them align their research outcomes with industrial needs. The iTPA will also provide fund projects during the so-called Translation-of-Concept phase for projects where proof-ofconcept has already been established. These activities will all be coordinated by a Translational Research Lead whose role will be to identify clear bottlenecks, gaps and barriers to translation of Cardiff science and identify the key external partners needed to provide an external, market-informed viewpoint in collaboration with the University's Commercial Development Team.

Amount: £600,000
Funder: The Wellcome Trust
Recipient: Cardiff University
Amount: £5,500
Funder: The Wellcome Trust
Recipient: Cardiff University

The mammillary bodies and memory: from encoding to consolidation 17 Jul 2018

<p>The mammillary bodies (MBs) are critical for memory but their specific functions have remained largely elusive. Historically, the MBs were associated with memory encoding, however, our recent findings suggest an as yet unexplored role in memory consolidation, both at the cellular and at the systems level. The proposed research will use multi-level, comparative approaches to investigate the contribution of the MBs to post-encoding processing, during wakefulness and sleep. The combined rodent/human methodologies will take advantage of the unique benefits provided by each line of research. The application of convergent techniques with rodents (inactivation, calcium-imaging, electrophysiology, behaviour) will interrogate the contributions of the MBs to different stages of memory processing, both in an intact system and when the system is disrupted. Complementary research with humans will address similar questions. fMRI will help to assess diencephalic contributions in the intact system. The impact of damage to the MB system on aspects of sleep-related consolidation will also be assessed. Together, this research will provide a comprehensive analysis of post-encoding memory processes and support the development of wide-reaching models of MB function.</p>

Amount: £1,563,892
Funder: The Wellcome Trust
Recipient: Cardiff University

How curiosity enhances hippocampus-dependent memory 06 Jun 2018

<p>In today&rsquo;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&rsquo;s intrinsic <em>curiosity</em>. 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 &ndash; <em> active exploration to acquire further knowledge</em> &ndash; 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 &lsquo;zoom in&rsquo; 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).</p>

Amount: £959,155
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

Value in people award. 21 Oct 2008

Not available

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

4th International Workshop on Genetics, Medicine and History "Early history of human molecular genetics" to be held in Gothenburg between 11-12 June 2010 30 Jan 2009

To bring together those working on and interested in the history of human and medical genetics, whether clinicians, laboratory or social scientists, or historians. This international workshop is one of a series of workshops organized by the Genetics and Medicine Historical Network as satellite meetings of the annual conference of the European Society of Human Genetics. The first three workshops (Birmingham 2003, Brno 2005, Barcelona 2008) were very successful judging from attendance and the discussions and collaborations they stimulated. The theme "Early History of Human Molecular Genetics" emphasizes the importance and urgency of recording the personal experiences of the protagonists of this essentially recent scientific era that has transformed modern medicine. It is hoped that this theme will bring together geneticists, historians and philosophers of science from other continents as well as Europe in a true international spirit.

Amount: £3,000
Funder: The Wellcome Trust
Recipient: Cardiff University

Characterisation of phospholipid-esterified eicosanoids generated by lipoxygenases. 11 Feb 2009

The proposed studies will address the hypothesis that PE-H(p)ETEs are transducers of LOX bioactivity in immune cells, through characterising the biology and fate of these lipids in platelets and monocytes/macrophages. Aim 1. Determine kinetics and mechanism of formation of PE-HETEs by purified recombinant LOX isoforms in vitro. The factors that regulate oxidation of PE versus arachidonate in intact cells are unknown. This aim will characterise PE oxidation mechanisms and kinetics using reco mbinant 12- and 15-LOXs in vitro. Aim 2. Characterise changes in the biological behaviour of PE by LOX oxidation. Introduction of a polar (O(O)H) group will change PE conformation, altering membrane physicochemical properties, including membrane thickness/phase. The ability of PE-H(p)ETEs to modulate membrane behaviour will be characterised by X-ray diffraction, using isolated cell membrane and purified lipid. Also, LOX regulation of PE dynamics in live cells will be determined using mass spectrometry and live cell imaging. Aim 3. Characterise PE-H(p)ETE metabolism and reactions of oxidised PE with cellular proteins via formation of covalent adducts or non-covalent interactions. Oxidized PE may interact with membrane proteins through a number of mechanisms. In this aim, decomposition of the hydroperoxy group of esterified HpETE including formation of protein adducts will be characterised.

Amount: £234,374
Funder: The Wellcome Trust
Recipient: Cardiff University

Identification of mechanisms underpinning regulatory T cell involvement in disease. 02 Feb 2009

Studies of T cell mediated tolerance indicate that a subpopulation of T cells, named regulatory T cells (Tregs) serve as a major negative influence on the immune system. These cells, characterised by expression of CD4 and the transcription factor, Foxp3, keep both innate and adaptive immune responses in check and suppress responses to both self- and non-self antigens. A clear objective of Treg research is to determine how they can be manipulated therapeutically to treat a wide range of immune-ba sed diseases. In my laboratory we have found, using mouse models and studies of patients with cancer, that tumours represent a defined location of Treg enrichment. This finding highlights the utility of studying tumours for the purpose of identifying conditions and mechanisms that facilitate Treg involvement in disease. The key goal of this project is to use tumours to identify mechanisms that promote or inhibit the involvement of Tregs in a given immune response. This informat ion will subsequently be utilised in the design of strategies to block or enhance the activity of the cells for immunotherapeutic purposes.

Amount: £829,539
Funder: The Wellcome Trust
Recipient: Cardiff University

Functional analysis of nuclear proteins in the Drosophila male germ-line. 25 Feb 2009

Understanding cell type specific regulation of gene expression is critical for understanding differentiation in multi-cellular organisms. The male germ-line is a unipotent cell type, committed only to making sperm. During spermatogenesis dramatic changes in gene expression occur, to facilitate the differentiation of highly specialised cells. We have previously identified a group of testis specific transcriptional regulators important for this spermatogenesis specific gene expression in Drosop hila. We will test the TEV protease system for cleavage of target proteins in the Drosophila male germ-line with known factors, and develop a P-element replacement exon tagging approach to allow specific ablation of potentially many target proteins in a controlled manner. We will test this approach by initiating the analysis of testis-specific functions of conserved potential transcriptional regulators that act in both the male germ-line and in other cell types, concentrating on a small set of proteins for which we already have localisation data and functional predictions.

Amount: £90,898
Funder: The Wellcome Trust
Recipient: Cardiff University

Characterization and optimization of T cell/antigen interactions 02 Oct 2008

T-cells recognise 'foreign' peptides bound to self-major histocompatibility complex (pMHC) molecules with their specific T-cell receptors (TCRs) and are critical for the elimination of pathogen-infected and tumour cells. Our preliminary data indicates that while natural T-cell receptors (TCRs) may be the best available solution for recognition of a particular antigen they are far from the best possible solution. We have produced T-cells that the HIV virus cannot escape from and manufactured TCRs that are 100 times better than the best natural TCRs at recognizing human cancer antigens when transduced into primary human T-cells. Our objectives are to: (1) Produce TCRs to a range of pathogen- and cancer-specific peptide antigens (2) Build optimized vehicles for expression of TCRs in T-cells without TCR chain mispairing (3) Determine the optimal TCR binding affinity, kinetics and glycosylation status for antigen recognition (4) Produce and characterize optimal epitopes for a range of natural T-cells (5) Optimize interactions between the MHC and T-cell coreceptors We are working with groups from around the globe that wish to apply this knowledge to new therapeutic approaches to cancer and infection by the adoptive transfer of patient-autologous T-cells, or 'immortalized' human killer T-cell lines, expressing optimized antigen-specific TCRs.

Amount: £805,574
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