- Total grants
- Total funders
- Total recipients
- Earliest award date
- 20 Oct 2005
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Non-Invasive Blood Glucose Meters 30 Sep 2015
Diabetes is affecting hundreds of millions of people worldwide who have to monitor their condition using invasive methods (e.g. pricking of finger or insertion of needle into hip region). It is clear that non-invasive, continuous monitoring has the potential to help and encourage patients to monitor their diabetes more closely due to the associated improved quality of life. This incentive will lead to a reduction of hyper/hypoglycaemic episodes and the subsequent reduction of long-term risks, such as morbidity and shorter life expectancy, when this condition is poorly monitored and managed. The Trust has awarded a team, led by Professor Adrian Porch from University of Cardiff, £892k to develop a non-invasive blood glucose monitor (NIBGM). Their device will improve the quality of life of people with diabetes and, with better management of their condition encouraged by the device, improve their life expectancy. It is fundamentally different from all other glucose monitoring systems on the market in that it does not require blood to be extracted from the patient, or for the sensing element to be inserted into the patient’s body. It is merely attached to the person’s hip with adhesive, does not require blood extraction, and provides an instant readout of the blood glucose level on a unit that can be carried in the person’s pocket. The underlying technology for the device is based on microwaves and how they interact with the person’s blood. However, there is no heating (the microwave field strength is much smaller than that generated by a mobile phone) and the only sensation is that of touch. It is envisaged that final device will be around the size of a £2 coin and will be ready for mass-manufacture.
Our experiments are directed at enhancing the potency of adoptive T cell immunotherapy (ACT). To date, all three applicants have made a series of independent observations on different aspects of T cell biology following genetic manipulation of mouse T cells. Each of these genetic changes has had the effect of significantly promoting anti-tumour immune responses. A natural progression of these findings, to be pursued in this grant, is to explore in the context of adoptive T cell immunotherapy, the potential overlapping, additive or synergistic effects of combining these genetic manipulations of T cells. Specifically, in this proposal we will: Determine whether adoptive transfer of CD8 T cells with maintained L-selectin and/or deficiency in SHP-1 induces regression of vascularised tumours in mouse Determine whether the removal of Tregs from the tumour bearing hosts has an additional or synergistic effect on CD8 mediated tumour regression in mice Determine whether human CD8+ T cell reactivity to tumour antigens can be similarly modified by maintained L-selectin and/or SHP-1 deficiency and whether sensitivity to Tregs is altered
Generation of standards for structural and quantitative assays of novel lipids generated by innate immune cells in humans 11 Aug 2014
This grant will focus on extending our understanding of the biological actions and potential therapeutic applications of recently-described hydroxyeicosatetraenoic acid-phospholipids (HETE-PLs), generated by platelets, neutrophils and monocytes/macrophages. A multidisciplinary approach combining biophysics, chemistry, genetics, cell biology and in vivo techniques will be utilized. Basic biochemical studies will be complemented by in vivo murine studies, and clinical studies in a human disorder with known elevated risk of thrombosis and plasma lipid peroxidation. A series of integrated aims is proposed: 1. Determine their role in regulating membrane biophysical behaviour (lysosome formation, phagolysosome fusing, microvesicle formation, etc). 2. Determine their role in regulating function of membrane proteins that require lipid microdomains, e.g. TLRs and their accessory proteins. 3. Determine how they regulate activity of coagulation enzymes at the cell surface. 4. Determine th eir function as ligands for innate immune receptors. 5. Determine how the regulate complement binding to activated immune cells. 6. Determine their role in the pathogenesis of antiphospholipid syndrome in human patients.
Institutional Strategic Support Fund FY2013/14 14 Oct 2013
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.
Our work over the past 5 years has revealed that multiple members of the TNFSFare selective positive or negative regulators of axon growth throughout the developing mousenervous system. Two very recent key discoveries arising from this work underpin the proposed programme and take our research in exciting new directions that will significantly advance our understanding of how the nervous system gets wired up in development. First, we discovered that TNFR1 expressed in sympathetic target tissues activates reverse signalingvia membrane integrated TNFalpha expressed by sympathetic axons as they ramify within thesetissues, promoting axon growth and tissue innervation (Kisiswa et al., Nature Neuroscience, 2013, 16:865-873). This discovery raises a host of interesting and important questions about the cell biology and mechanism of action of TNFalpha reverse signalling and why this has evolved to regulate axon growth in the developing nervous system. It also raises the question of how extensively reverse signaling operates within the TNFSF in the nervous system and what is the balance between forward and reverse signaling in the regulation of neural process growth. Second, we discovered that certain TNFSF signaling loops that either promote or inhibit axon growth are very sensitive to the ambient neurotrophin concentration. This reveals the existence of unsuspected feedback loops that selectively modulate the response of neurons to the neurite growth-promoting effects of neurotrophins. This raises questions about how, where and when these feedback loops operate and what it their significance for establishing patterns of innervation in vivo.
The cognitive thalamus: more than a relay. 01 Apr 2014
How do brain circuits support different but complementary aspects of event memory? The answer lies in distributed networks across the medial temporal lobe, prefrontal cortex and parietal cortex. Via their widespread connectivity, nuclei within the rostral thalamus support these memory networks. Indeed, one group (the anterior thalamic nuclei) forms the backbone of the extended hippocampal system, thought to be vital for episodic memory. We know remarkably little, however, about the nature of rostral thalamic information and how it impacts upon memory. We have recently discovered neurons in the rostral thalamus of freely-moving rats with hitherto unsuspected spatial properties. These cells are unlike any previously described in the region as they closely resemble place cells, boundary vector cells, and grid-cells (Fig.1A-F) found in hippocampal and parahippocampal regions. This discovery is set to transform our understanding of the region.
The role of microglia in Alzheimer’s disease pathogenesis is still controversial. Activated microglia are found to be associated with amyloid plaques in brains of AD patients and in mouse models. They may play a neuroprotective role by secreting proteolytic enzymes that degrade Abeta and expressing receptors involved in its clearance and phagocytosis. However, microglia might also contribute to disease progression through production of inflammatory mediators. Despite the recognised importance for research into the role of microglia in AD, there is currently an unmet need for human cell models that enable in-depth mechanistic studies. One route to the development of highly informative cell models is the differentiation of human patient-derived iPS cells, which intrinsically incorporate human genetics and bridge the gap between clinical AD and animal models. This project will develop AD microglial models by building on work that has established a standardised protocol for the derivation of microglia from human iPSCs. The project will be structured to firstly gain an in-depth characterisation of iPSC-derived microglia. Secondly, the iPSC-derived microglial model will be validated against anticipated microglial phenotypes. Finally, once established, the model will be used to investigate the role of AD risk genes in aspects of microglial biology.
The imprinted gene Grb10 is subject to epigenetic regulation leading to tissue specific differential parental-allelic expression. While the paternal allele is expressed exclusively in the CNS, the maternal allele is excluded from the CNS (and expressed in many non-CNS tissues) [1, 2]. The maternal allele is involved in aspects of development , and is thought to be key for coordinating the maternal-pup physiologies . However, other than our original observation of a role in social dominance behaviour , very little is known about the brain and behavioural function of paternal Grb10. This project will examine aspects of neural function at the molecular, cellular and behavioural level. Specifically, cellular and molecular analyses will focus on examining the neurogenic potential of Grb10KO ES cells and, separately, the phenotype of cells with CRISPR altered epigenetic regulation of Grb10. We will aim to use these neural findings, and previous studies , to guide the exploration of a number of other behaviours in Grb10KO mice, including aspects of cognition. Finally, we will explore the interaction of maternal diet whilst pregnant and subsequent Grb10 regulation and expression in offspring brain.
Biological markers for the development of autism related phenotypes in genetic mouse models 14 Jul 2014
Autism spectrum disorders (ASD) are developmental disorders manifesting in early childhood resulting in language and social deficits in adulthood. Recent studies on mouse models for ASD based on highly penetrant genetic signals in patients have started to reveal aspects of the molecular and cellular underpinnings of ASD related phenotype in adulthood but little is known about their development. One of the most common genetic variations found in ASD is a deletion on chromosome 16p11.2 which creates cognitive/social/language impairment as well as seizures and hyperactivity. Mouse models of 16p11.2 have shown anatomical and functional alterations caused by the deletion which may be relevant to ASD. We will characterise the behaviours of this mouse model over the lifetime of the model that relate to the human clinical features of the deletion. Using the mouse models means that we can look more invasively and give predictive data regarding the brain regions involved in the development of the disorder. To achieve this objective we will use histology to identify neuronal networks involved in the phenotypes of the disorder. Using genetic, behavioural and electrophysiological recording techniques we will identify biomarkers for the development of the mouse phenotypes. A second aspect of our project will address the question of the generalisation of our findings to other genetic forms of ASD. To achieve this goal we will use another unrelated genetic mouse model for ASD, mice lacking the synaptic protein Neuroligin-3. Using the same approach to identify biological markers in the two mouse models we will be able to compare their developmental trajectories identify their markers that can be used for a large population of ASD mouse models.
Huntington’s disease (HD) is a neurodegenerative disorder characterised by focal loss of medium spiny striatal neurons (MSNs), positioning it as an attractive model for developing cell replacement therapies (CRTs). Induced human pluripotent stem cells (hiPSc) are potential donor cells, for CRT in HD, but a key requirement for fully functional grafts is differentiation into "authentic" MSNs. Previous work in the host lab indicated that hiPSc lines derived from developing striatum (whole ganglionic eminence: WGE) demonstrate an increased propensity to differentiate back into MSNs, compared to non-striatal or nonneural derived hiPSc lines. This may be due to retained epigenetic profiles, thus I will establish (i) whether WGE-derived hiPSc lines retain epigenetic characteristics of the source tissue, and (ii) the effect of this on directed differentiation and functional recovery in a HD animal model. New hiPSc lines will be derived from the developing striatum, cortex, cerebellum, and skin of the same fetus and directed towards a MSN fate. In vitro immunocytochemical and electrophysiological analysis will be followed by grafting of optimised lines with subsequent behavioural and histological analysis. The global gene expression profiles will be determined at key stages using the HumanHT-12 v4 Expression BeadChip to characterise epigenetic differences.
Generation and characterisation of cortical interneurons from human pluripotent stem cells 10 Feb 2014
Inhibitory interneuron dysfunction is believed to lead to runaway excitation implicated in seizure­ based diseases, such as epilepsy. However, due to a lack of defined aetiology and causal mechanisms of the pathogenesis, there is currently no effective treatment for these conditions. The generation of neurons from pluripotent stem cells, either derived from patients carrying defined genetic variants, or engineered in culture with disease relevant genetic modifications, offer a unique path to investigate the underlying disease mechanisms. Moreover, exciting experimental cell therapy has shown that foetal-derived interneuron precursors can reverse seizure severity and reduce mortality in adult epileptic rodents. These proof-of-principle studies raise hope for potential interneuron-based transplantation therapies for treating epilepsy. Therefore, this PhD project aims to generate defined functional cortical interneurons from human pluripotent stem cells. The specific objectives are: 1, To establish an interneuron reporter cell line by genome editing in human ESCs; 2, To optimise interneuron production strategy and to perform phenotypic and functional characterisation of the derived human neurons; 3, To investigate the differentiation potential and functionality of hPSC-derived interneurons in vivo by transplantation. The anticipated outcome of this work will be the establishment of an improved inhibitory neuron differentiation regime and parameters for interneuron transplantation.
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.
The functions of postsynaptic density implicated in psychiatric disorders in associative memory formation. 10 Feb 2014
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.
Modulating hippocampal neurogenesis to restore learning and memory in mesial temporal lobe epilepsy. 10 Feb 2014
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 and epigenetic 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.
ADHD is a common, impairing neurodevelopmental disorder associated with poor outcomes. It is frequently comorbid with depression, which develops after the onset of ADHD. Identifying children with ADHD at risk of later depression provides opportunity for early intervention. Children with ADHD and chronic irritability are a potential at risk group. In population studies irritability has been shown to predict depression, and a genetic relationship between irritability and depression has been found. Although irritability is a common feature of ADHD, its contribution to depression is yet to be fully explored within an ADHD population. The key aims of this proposal are to test whether children with ADHD and chronic irritability represent a subgroup at increased risk of later depression, and whether presence of chronic irritability in ADHD indexes higher genetic loading for depression. These aims will be addressed using a large clinical ADHD sample. Comparisons will be made between children with and without chronic irritability in terms of later depression, family history of depression and molecular genetic loading for depression. Findings will be expanded upon using a longitudinal population sample, to establish whether irritability cuts across diagnostic boundaries increasing risk of depression in a broad group of child neurodevelopmental disorders.
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.