- 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
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.
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.
Biological markers for the development of autism related phenotypes in genetic mouse models 30 Sep 2016
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.
Multiple Sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system that causes demyelination and axonal loss and leads to chronic disability in young adults. Brain plasticity, that is the ability to adapt to damage, can limit the clinical impact of MS. Plasticity is influenced by brain reserve and cognitive reserve. Reserve mechanisms represent the brain’s resilience to damage, conferred by the brain’s pre-morbid functional and structural characteristics. Due to brain plasticity and reserve, in MS there is a discrepancy between the degree of damage and the clinical manifestations of the disease. In this PhD project, I propose to investigate (a) the relationship between brain plasticity and reserve in healthy volunteers; (b) its alteration with MS inflammation; (c) the role of reserve as a predictor of recovery mechanisms in MS patients. I will conduct longitudinal experiments, involving both healthy volunteers and MS patients using a strong behavioural paradigm to induce plasticity. Advanced functional and structural MRI will be used to quantify the amount of reserve, to identify mechanisms of plasticity occurring with behavioural training and to understand changes in energy usage with plasticity.
Gene validation of mesothelioma NanoString study 31 May 2018
Mesothelioma immunotherapy is in an experimental phase, and the main question is how to identify patients who are most likely to benefit from this treatment. To apply individualised treatment plans successfully, we need a better understanding of the tumour microenvironment. There is relatively little known about the immune signature and T cell homing in mesothelioma. The hypothesis is that patients, with higher frequencies of activated T cells in the tumour tissue respond better to a cancer vaccine. Preclinical studies show that L-selectin and its ligands on high endothelial venules (HEV) promote homing to the tumour tissue and improve immunotherapy. Analysis of Nanostring data from 24 patient samples for over 770 genes, will determine if L-selectin and HEV can be used to stratify mesothelioma patients for immunotherapy and will also enable us to search for other novel biomarkers. The experimental design will also inform us whether the biomarkers we identify are only predictive in immunotherapy or also applicable to patients receiving chemotherapy alone. The overall aim is to genes that are highly expressed in a current mesothelioma NanoString study using molecular biology tools. This study will identify potential pathways and ultimately a marker that is predictive of immunotherapy outcomes.
Translational neuroimaging in Huntington’s Disease: a time-course analysis of HD-related effects on myelination 30 Sep 2018
Huntington’s disease (HD) is a genetic, progressive, neurodegenerative disorder leading to cognitive deficits such as difficulties in information processing, attention and executive functions. Currently, this devastating disorder cannot be cured, hence the importance of gaining an insight into its pathogenesis and of looking for biomarkers of treatments’ efficacy. Evidence shows that HD is associated with white matter (WM) degeneration. Further, myelin break-down has been implicated in WM deterioration in HD. This emphasizes the potential of quantitative MRI metrics assessing white matter microstructure and myelination, to inform about disease pathogenesis. However, demyelination remains relatively unexplored in HD as compared to other neurodegenerative diseases. The purpose of the present research project is to carry out a time-course analysis of HD-related effects on myelination, by employing novel quantitative MRI techniques to uniquely combine whole-brain myelin mapping with assessment of axonal morphology.
Dihydrofolate reductase interactome: an unrecognised network that can control DNA synthesis and cell replication 08 Apr 2016
We aim to characterise and map the interactome of dihydrofolate reductase (DHFR), a well-validated anticancer drug target. DHFR is an enzyme that catalyses a key reaction in the biosynthesis of DNA building blocks. Although therapeutics targeting DHFR are available for cancer treatment, resistance against them is frequently found. To combat against this issue, it is essential to fully characterise DHFR, from its catalytic behaviours to regulatory network, as this information will find uses for future drug development. DHFR binds to a wide variety of biomolecules other its substrates, including its parental mRNA and enzymes responsible for post-translational modifications (PTMs). We believe that it is crucial to investigate these non-substrate interactions, as their functional roles have not identified. We hypothesise that DHFR is embedded in a molecular network of interactions that are responsible for controlling the activity of DHFR. Based on the applicant’s expert enzymology knowledge of DHFR catalysis, we set 3 objectives to study the DHFR interactome: Characterising the effect of PTMs on DHFR catalysis; Isolating the effect of mRNA binding; and Mapping the interactome of DHFR. This work will advance our knowledge of DHFR. Lastly, publications and data generated here will also form a strong basis for grant applications.
I would like to apply for one of the Wellcome Trust Humanities and Social Science Small Grants in order to organize a two-day workshop on "Promoting Health through Food Policy in Diverse Societies" at Cardiff University. The aim of the workshop will be to explore the ethics of healthy eating policies and weight-loss interventions in light of diverse views of health, diverse views of the role of health in well-being, and diverse views about how eating practices contribute to well-being. The guiding question of the workshop will concern how health-related food policies can be designed in a way that is respectful of that diversity. The key goals of the workshop will be to provide the foundations for a future large collaborative grant application (e.g. Wellcome Trust Collaborative Awards in Humanities and Social Science); to publish a special issue in a prestigious journal (e.g. the Journal of Agricultural and Environmental Ethics), which I will be editing; and to have an impact on society by providing policymakers and practitioners with a policy brief after the event.
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.
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.
It is widely assumed that control processes help to extract task-relevant information from episodic memory. Preparatory control processes are thought to facilitate this by influencing the way in which retrieval cues are processed. Neural correlates of preparatory control processes will be obtained by contrasting brain activity elicited by cues directing participants to prepare to retrieve different types of episodic information. Neural correlates of retrieval cue processing will be obtained by c ontrasting brain activity elicited by unstudied items across different episodic memory tasks. The overarching aim of the proposed research is to investigate the extent to which retrieval control processes directly impact upon successful episodic retrieval, thus extending the study of retrieval control from the correlational to the causal. Key goals will include: i) separating EEG correlates of preparatory control processes according to the accuracy of the subsequent memory judgment, then asking whether this neural activity predicts retrieval accuracy, ii) observing whether a resource depletion manipulation decreases both EEG correlates of retrieval control processes and episodic retrieval accuracy, and iii) employing EEG source localisation to identify possible neural generators of retrieval control processes, then targeting these cortical regions with transcranial magnetic stimulation (TMS) and observing the effects on episodic retrieval accuracy.
Over the past couple of years new genomic technologies, such as DNA microarrays and high throughout genomic sequencing, have begun to enter clinical practice in a range of conditions. While the promise of such approaches - as heralded by the NHSs 100,000 genomes project - is considerable, the challenges raised by integrating these technologies into the clinic are no less great. To a considerable extent, these challenges centre on professional decision making: these technologies produce large amounts of data, some of which is clinically relevant, some of which is not, but large amounts of which - for example so called VUSs, variants of unknown significance - are uncertain. It is this uncertainty - whether or not a specific stretch of DNA is clinically relevant - and the decision making processes that surround it, that this project will examine. The method used will be ethnographic observation and interviews with laboratory staff, clinical geneticists and other members of the mu ltidisciplinary teams that create, review and interpret this genomic data. While some similar work is taking place in the US, and some UK studies are exploring the impact of this kind of data, particularly around informing patients, there are no current studies focusing on the way professionals generate and interpret this kind of data.
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.