- Total grants
- Total funders
- Total recipients
- Earliest award date
- 10 Apr 2001
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Grant awarded to Community Service Volunteers (Training and Enterprise NE) (Tyne & Wear) 10 Mar 2009
To provide support and mentoring to people with mental health problems to help them volunteer in Newcastle.
Grant awarded to Community Service Volunteers (Training and Enterprise NE) (Tyne & Wear) 13 Jul 2004
To provide daycare services to older people living in high rise flats in Newcastle.
Positive Futures London 18 Nov 2015
This project, based on a established youth-led volunteering model is expanding as a result of self-referrals and is being delivered in Hackney, Haringey and Tower Hamlets. It will support young people aged 13 to 25 to deliver volunteering and social action projects which they have identified to be of benefit to the local community. The aim of project is that all of the young people who are participating in it will develop key skills and have positive experiences that will shape their personal development.
Serio Seed Grant 06 Sep 2018
Amyotrophic Lateral Sclerosis (ALS) is an incurable fatal disease that affects principally Motor Neurones (MNs). Interestingly, spinal MNs have extremely long axons, which makes them particularly reliant on efficient decentralized protein translation and axonal transport. We have evidence that ALS presents characteristics of distal axonopathies, with defects in axonal transport, protein homeostasis and changes in local axonal translation reported. Moreover, most ALS-mutations often directly affect RNA processing. Against this background, understanding the links between axonal length and RNA compartmentalisation could highlight new potential therapeutic avenues. Induced pluripotent stem cells (iPSCs) have proven extremely useful in studying ALS; however, the question of how axonal length affects RNA compartmentalisation in MNs cannot be systematically addressed with current in vitro paradigms, as they do not provide efficient ways to control axonal length. I will develop a platform to study how axonal length in iPSC MNs influences local mRNA translation and RNA compartmentalisation, combiningimaging and transcriptomic analysis with bioengineered alignment substrates that allow to obtain ordered arrays of very long axons in vitro.With this platform I will conduct a pilot study on axonal compartment -specific transcriptomics in MNs and analyse the effect of ALS-mutations on local translation in long motor axons
Functions of YAP/TAZ in pituitary tumours 31 May 2018
This proposal will explore how activation and accumulation of YAP and TAZ, effectors of the Hippo pathway, influence the fate and behaviour of pituitary tumour cells in vitro. Our data indicate that YAP/TAZ accumulation represses the activity of the growth hormone and prolactin promoters in mammosomatotropinoma GH3 cells, a rat pituitary tumour-derived cell line. By carrying out siRNA-mediated knockdown of Lats1, which normally inactivates YAP/TAZ, we will assess if, concomitant with a repression of differentiation, there is an increase of pituitary progenitor/stem cell markers. This will reveal if YAP/TAZ act to promote the uncommitted progenitor/stem state. In addition, we will determine if accumulation of YAP/TAZ leads to changes in cell cycle length, the number of proliferating cells and in migration behaviour. These findings will be relevant to our understanding of the function of YAP/TAZ in pituitary tumours as well as normal pituitary development and homeostasis, and will complement our in vivo research in mouse models and human pituitary tumours.
Genetic mutations cause the majority of severe childhood epilepsies. Many 'epilepsy-genes' play a direct role in synaptic transmission, such as SCN1A (coding for voltage-gated sodium channels) and GRIN2A (coding for NMDA-receptor subunits). Some mutations also induce seizures in zebrafish larvae, a novel vertebral model of genetic epilepsies. Furthermore, long-term functional neuronal recordings of large neuronal networks using light sheet microscopy are now possible in these larvae, allowing unique insights into the pathophysiological of the epileptic brain. My proposal will utilise computational network modelling to identify mechanisms leading from synaptic dysfunction to whole-brain epileptic dynamics. I will (1) analyse patients' EEG recordings and light-sheet imaging in zebrafish with corresponding genetic mutations to evaluate whether there are shared abnormal network dynamics, (2) use Bayesian inversion of generative neuronal models to understand how microcircuit dysfunction leads to these abnormal dynamics, and (3) test the predictive validity of the generative models against empirical measurements of anti-epileptic drug effects. This work will provide insights into multi-scale mechanisms underlying devastating childhood epilepsies. The computational analyses will provide novel strategies to translate observations between animal models and patients, and thus in the future will increase the potential of these models to help the development of novel therapies.
Focal adhesions under force 24 Apr 2018
Cellular development and function is influenced by the mechanical rigidity of the surrounding environment. A complex of proteins, known as focal adhesions (FAs), form a physical connection between the cytoskeleton and the extracellular matrix, transmitting and transducing mechanical stimuli. Focal adhesion kinase (FAK) is a unique player in this complex that functions as both a scaffolding and signalling protein. Furthermore, FAK can also detach from the FA and shuttle into the nucleus to modulate gene expression. Despite FAK’s physiological importance, the mechanisms that regulate its function remain poorly understood. Here I will investigate how mechanical force alters the function and localization of FAK using a combination of single-molecule and single-cell approaches. I will first test, at the single-molecule level, whether mechanical force perturbs the structure of FAK, switching it into an active conformation (Obj.1). I will then perform cellular experiments to determine whether cellular tension modulates the conformation of FAK, and if this is instrumental in converting forces into biochemical signals. I will then use a combination of single-molecule and single-cell approaches to study whether mechanical unfolding of FAK exposes key residues that can become chemically modified, leading to the translocation of FAK from the cytoplasm into the nucleus (Obj.2).
Cellular and sub-cellular sampling using laser capture microdissection to understand disease mechanisms 05 Jul 2018
We propose a laser microdissection microscope (LMD) system that due to its high precision and contact-free laser technology allows the quickest and safest method of microdissection to extract precisely defined samples comprising intact biomolecules. The sample preparation method allows users to define exactly where to extract tissue from within a tissue section, cultured live cells or embryonic fish larvae. After selection, the specimen is separated from the tissue or cell culture by the laser and subsequently transported into the collection device with a targeted laser pulse. The ability of LMD to select specific cells or sub-cellular structures is enhanced by using infrared laser-based optical trap and tweezers. These tools permit manipulation of cells or particles for extraction, in addition to moving cells, beads or particles in live tissues, without damage, for measuring of tissue stiffness or flow. Extracted samples are processed for downstream quantification using genomics, transcriptomics, microarrays, next generation sequencing, biochips, or proteomics. This will allow users to precisely correlate ‘upstream’ measurements such as imaging of cells or physiological readouts with molecular characterisation, something that is not available to the research community at King’s and presents a key barrier to our research goals.
The TwinsUK cohort is a major genomic epidemiology resource with longitudinal deep genomic and phenomic data from over 13,500 adult twins who are highly engaged and recallable. We are seeking longer term funding to support operations and management, to continue enhancement of a highly successful programme of international science. The vision is to continue to be the most deeply characterised adult twin cohort in the world, providing a rich platform for scientists to research health and ageing longitudinally. More than 800 data access collaborations and 150,000 samples have been shared with external researchers, resulting in ~600 publications since 2012. In the next 5-year phase of TwinsUK we will integrate electronic health records into an enhanced deep tissue ‘omics resource and introduce dynamic phenotypic testing into clinical visits. The majority of funds requested are to support core staff and to add new enhancements in health records linkage and sociological and environmental data. These developments will not only augment the unique scientific value of the resource but enable co-analysis of these datasets with other world renowned cohorts. The result will be a unique global resource of longitudinal omics and twin research across the life-course, with immense potential for future scientific exploitation.
Diabetes is characterized by the body's inability to regulate blood glucose. Pancreatic beta-cells regulate glucose through insulin release. Monogenic Diabetes is a rare type of diabetes caused by single gene germline mutations that make beta-cells dysfunctional. Diagnosis with Monogenic diabetes is done through genetic testing. However, similar mutations can have different phenotypes and penetrance in families, underlying the need to address the pathophysiology of the mutations ex vivo. During my PhD project, I will analyse the data available for induced Pluripotent Stem Cells (iPSCs) derived from patients with Monogenic Diabetes banked through the Human Induced Pluripotent Stem Cells Initiative (HipSci). Mutant and healthy iPSCs lines will be differentiated towards pancreatic progenitors and beta-like cells, to determine their effect on pancreas development and beta-cell function. CRISPR-Cas9 will be employed to correct the mutations. The mechanism of action of the mutants will be investigated in vitro. The function of the corrected and mutant iPSCs differentiated towards beta-like cells will be addressed in vivo. This study should contribute towards understanding the heterogeneity of Monogenic Diabetes phenotypes. In the long-term, it could help towards a more accurate detection of Monogenic Diabetes and personalized treatment.
Do antipsychotics affect white matter? 31 May 2018
Converging evidence from post-mortem studies of human brain tissue and in vivo neuroimaging suggest that white matter integrity is negatively affected across several psychiatric disorders, including schizophrenia. Antipsychotics are the first-line treatment for but a key gap in our knowledge is the precise impact of these drugs on white matter integrity and pathology. Recent evidence suggests that antipsychotic drugs may be pro-myelinating. We aim to address this question using a rodent model of Maternal Immune Activation (MIA), an established epidemiological risk factor for several psychiatric disorders. Our goal is to determine the effect of chronic exposure to the antipsychotic haloperidol on white matter integrity in the MIA model. Existing tissue samples from animals treated in four experimental conditions (Saline – vehicle, Saline –Haloperidol, MIA-vehicle, MIA- Haloperidol) will be stained for myelin basic protein and neurofilament to assess the effects of MIA, haloperidol and their interaction, on white matter. We expect that the MIA model will exhibit a loss of white matter integrity and hypothesize that haloperidol will rescue this. This research may increase understanding of the development and treatment of psychopathology, both of which are poorly understood and affect millions of people around the world.
This research examines commercial brokerage of access to healthcare. Healthcare brokerage is performed by actors spanning a range of formality and organisation. There are individuals who facilitate care for others in their communities in return for financial or social rewards, and companies that broker personalised healthcare packages for wealthy domestic and international healthcare users. Brokers are influential mediators in the process of accessing healthcare, with important implications for the forms of care that users seek and receive, yet their activities and evolution are poorly theorised. The research focuses on the companies providing healthcare brokerage services in two settings: Delhi and London. These settings offer a range of specialised healthcare services and are established destinations for domestic and international healthcare users seeking care otherwise unavailable in their home locality. The requested funds will be used to conduct preliminary research, aiming to examine the trajectories and practices of companies in these settings using interviews with representatives in the industry. The work will inform design of a Wellcome Trust fellowship application and will enable further elaboration of a conceptual framework to be written up and submitted to a peer-reviewed journal.
We are requesting funds to purchase a light sheet microscope that will be used as multi-user equipment by the applicants. The equipment is based on a technology that has two main advantages over other methods of fluorescence microscopy currently available to us. These advantages will enhance our research in a wide variety of different applications. First, light sheet microscopy can acquire optical images at very high speeds, and thus data collection of large samples becomes rapid and efficient. This will allow us to rapidly image very thick samples including small whole organisms (zebrafish and drosophila larvae, for example) and intact mouse brains. Second, light sheet microscopy substantially reduces photodamage to living samples compared to other imaging approaches because it only illuminates a small plane of the sample during image acquisition. This will allow us to image living samples for longer periods or increase our temporal resolution while imaging for shorter periods. The ten applicant groups, seven of which are currently funded by the Wellcome Trust, will be the primary users of this equipment. This number of researchers will maximise use of the equipment while guaranteeing sufficient hours for each group.
Funding is requested to purchase a Becton Dickinson FACSMelody Benchtop Cell Sorter System that will be dedicated to analysing and/or purifying living cells either obtained from HIV-1 infected patients, or purposefully infected with HIV-1 in culture. The sorter will be located in the KCL containment level 3 (CL3) laboratories at Guy’s Hospital. Flow cytometry is a recognised strength at KCL, but none of our facilities offer CL3 capability, thus prohibiting any flow cytometry-based analysis or purification of living cells infected with HIV-1, or experimental workflow that requires downstream steps involving living cells. The acquisition of the FACSMelody will be transformative for our HIV/AIDS research community, and for our collaborators, by enabling the pursuit of new projects as well as the application of additional technologies such as single cell cloning and analytics to existing projects. Our work will address key areas relevant to understanding HIV-1 immunopathogenesis, including: HIV-1’s ability to manipulate normal cell function, the role(s) of cell-encoded factors in productive HIV-1 replication, anti-viral innate immunity and mechanisms of viral evasion, the molecular basis for HIV-1 persistence/ latency and its reversal, adaptive T and B cell immune responses in infants and adults, and mechanisms of HIV-1 induced immune cell dysfunction.
Translatable EEG biomarkers of Intellectual Disability in Pre-Clinical Mouse Models of Fragile X syndrome and Tuberous Sclerosis Complex 12 May 2017
This project will introduce new electroencephalogram biomarkers of known neuronal events, including synaptic plasticity, activity of two different GABAergic inhibitory neuronal subclasses and burst firing, which can be experimentally constrained in primary visual cortex by habituation to simple visual stimuli and presentation of novelty. The immediate primary goal of the project is to show that cortical dysfunction is severe enough to be evident in these biomarkers in pre-clinical mouse models of two highly penetrant, single gene causes of neurodevelopmental psychiatric disorders, Fragile X Syndrome and Tuberous Sclerosis Complex, both of which have known synaptic plasticity and excitatory/inhibitory balance phenotypes. In each case, efficacious drug treatments exist, although neither is considered an ideal candidate for human use, motivating a secondary goal to demonstrate that altered biomarkers can be remedied. The overall goal of this application is to provide a seed for three complementary future projects: First, to take advantage of genetic and invasive experimental tools in mice to deeply understand processes of learning (habituation) and memory (novelty detection). Second, to understand their dysfunction in genetically defined neurodevelopmental psychiatric disorders and, third, to translate the use of these biomarkers into human subjects for patient stratification and assessment of response to treatment.
Collective cell migration refers to the movement of a cell population that acquires directionality through cell-cell interactions. All cells of the group may be capable of reading directional cues, or they may divide their labour with front cells, ‘leaders’, indicating the path to rest of the group. The precise molecular signals that control cell identities and behaviour in the context of collective cell migration remain unclear. We have studied this process in Neural Crest (NC) cells, a highly migratory population that arise early during embryogenesis. Our recent work has demonstrated that zebrafish trunk NC (TNC) migrate collectively and present non-exchangeable leader and follower identities. The firm allocation of TNC identities strongly suggests these are transcriptionally regulated. In this project, we will generate new NC zebrafish reporter lines that will allow the specific labelling of TNC populations by photo-conversion (leader, follower or premigratory). Labelled cells will be then isolated and processed for RNA-Seq. These data sets will allow us to characterize leader, follower and premigratory cells transcriptomic signatures. This is an essential step towards the elucidation of the genetic networks controlling TNC identities and behaviour.
Focal cortical dysplasias are common causes of treatment-resistant epilepsy in childhood, but are persistently difficult to detect on clinical magnetic resonance imaging (MRI) scans by routine visual inspection. This is especially true in children, where pathology may be masked by the dynamically changing background of the developing brain. My fellowship will investigate focal epilepsy in the context of the developing human brain. I will build analytical tools from clinical MRI data to better detect subtle MRI lesions and, using quantitative MRI (qMRI), translate these tools so they can be applied across clinical sites and in other neurodevelopmental and neurological disorders. I propose to build a continuous time-space model of brain development using large population MRI data from typically developing children. Using this model, I will test the specificity of abnormality maps in individual patients to confirmed epileptic pathology in a training- and test-dataset from two large epilepsy neurosurgery programmes. To generalise this model to standard clinical sequences, I will collect qMRI and synthesise scanner-independent MR images to tailor this growth model to any local protocol. Finally, I will extend these structural findings to identify networks associated with focal epilepsies, and investigate whether they can predict a successful outcome from surgery.
Insulin-like peptides (ILPs) play evolutionarily conserved roles in many physiological processes, including development, ageing, and neural function. Humans and other species possess multiple ILPs, and cross-regulation between ILPs is important for biological function. Here we exploit the stereotyped anatomy of C. elegans to dissect the regulation between two ILPs: ins-3 and ins-6. ins-3 negatively regulates ins-6 expression during the control of larval development. ins-3 is expressed in three identified neurons, while ins-6 is expressed in two identified neurons. Our key goal is to map out the regulatory connections from ins-3 neurons to ins-6 neurons. We will determine in which neurons is ins-6 affected in an ins-3 knock-out mutant using an ins-6::mCherry transcriptional reporter. We will next determine from which neurons ins-3 acts from, by examining ins-6 expression in a set of ins-3 mutant strains where wild-type ins-3 is selectively restored to each of its three neurons. All of the above strains have been made and will be analysed with an automated system for fluorescence microscopy to measure ins-6 reporter expression. This work will provide insights into cross-regulation between ILPs at single-cell level, and show how ILPs mediate communication in the nervous system.
The proposed Centre in Medical Engineering focuses on medical imaging, and is a renewal of our existing Centre. Our vision is to bring together teams from multiple scientific disciplines to identify and solve complex multi-factorial challenges, focusing on the most important clinical and biological issues. By combining expertise in biomedical and clinical research with excellence in underpinning sciences of imaging engineering & physics, computational and mathematical approaches and imaging chemistry, we will deliver impact that improves the understanding, diagnosis and treatment of neuropsychiatric, oncological and cardiovascular diseases. The Centre will have a unique combination of characteristics that allow delivery of this vision. The current critical mass of imaging scientists combines with cutting-edge facilities across multiple imaging modalities, strong industrial links and our location within a major hospital campus to create an exciting, synergistic environment where the most challenging questions can be addressed. In addition to producing world-leading outputs, the Centre infrastructure will accelerate translation to clinical benefit and industrial uptake. The Centre will act as a focus for recruitment of leading international talent and training of the next generation of research leaders, enhancing excellence. We will make a major contribution to public engagement, enhancing the strong current activity.