- Total grants
- Total funders
- Total recipients
- Earliest award date
- 14 Dec 2005
- Latest award date
- 30 Sep 2016
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
This application follows an invitation from Wellcome staff to apply for a small grant to support costs relating to the development of our shortlisted outline application for the Hub award Created Out of Mind: Changing perceptions of dementia through art and culture. The proposed costs will be used to cover project management of our bid, art design and branding input from creative members of our hub bid team, and travel expenses relating to a series of meetings and workshops designed to build relationships, develop conversations and discuss key questions and proposed projects within and between existing and new team members.
Investigating the neural odometer function of entorhinal grid cells in rats navigating a multi-planar environment. 01 Apr 2016
It has been proposed that the grid cell system in the medial entorhinal cortex acts as a ‘neural odometer’, encoding both distance travelled and an animal's position in space. These features may be necessary for spatial computations such as path integration, but the relationship of grid cell firing patterns to behaviour remains speculative. In not-yet-published work, it has been shown that for a rat climbing a wall with its body plane aligned vertically the grid fields are expanded, as if the cells underestimate distance travelled. If grid cells support spatial computations then rats should also underestimate distances in this plane. To test this hypothesis rats will learn a distance match-to-sample task leading to triangle completion while both sample and choice phases are in the same plane (both horizontal or both vertical). In probe trials, the sample will be horizontal but the choice vertical. Distance underestimation in the probe trials (walking too far on the vertical wall to achieve a match to the horizontal sample) will link grid cells to behaviour, while the basic distance-matching task will serve as a springboard for neurobiological studies investigating the role of grid cells in odometry generally.
We will investigate how a newly discovered mutation to the GABA-A receptor alpha 1 subunit gene (GABRA1) is causing epilepsy in a young child. A single mutation has been identified, which resides in the receptor's first transmembrane domain. This is near the previously identifed neurosteroid binding site from which endogenous neurosteroids can positively modulate GABA-A receptor activity. To investigate the implications of this mutation we have formulated the following aims that will be addressed using heterologous expression of GABA-A receptors in a cell line: 1. To establish the effect of the mutation on GABA concentration response curves and current voltage relationships for typical synaptic and extrasynaptic-type GABA receptors. 2. To determine if known allosteric modulators of GABA-A receptors are affected by the alpha1 subunit mutation. 3. To deduce if the expression levels and receptor mobility at the cell surface are affected by the alpha 1 subunit mutation. To achieve these goals, we will use a combination of patch clamp electrophysiology and single particle imaging techniques. This should establish whether the mutation is causing a gain- or loss-of function, or affects receptor trafficking.
Blastema formation and skeletogenesis during arm regeneration of the brittle star Amphiura filiformis: cellular and molecular characterization. 17 Jan 2014
The aim of this research project is to understand the initial stages of brittle star arm regeneration in terms of stem cell involvement, cell specification and the earliest activation of the skeletogenic gene regulatory network. The brittle star is a marine organism with a unique capability for regenerating whole arms post-amputation or after injury. To determine whether the regenerative blastema, a mass of proliferative cells giving rise to the entire structure, is composed of stem cells or dedifferentiating cells, molecular tools will be employed for their characterization. Stem cell markers and lineage tracing techniques will be used to identify the nature of the cells, their origins and migratory behaviour. The regenerating arm of the brittle star is contains several skeletal structures and the second aim of this project is to understand the cohort of signalling pathways involved in the early specification of the cell lineages which will develop into this adult tissue. This will be achieved by using molecular techniques and a candidate gene approach for studying the genes that have already been well-characterised in the closely-related sea urchin, , for which a complete gene regulatory network for the embryonic development of skeletogenic cells has been published.
Public Engagement Provision 03 Dec 2014
The James Lind Alliance recently identified their 'Top 10' research prioritiesaccording to what stroke patients and their carers want. Cognitive therapies, long-term consequences of stroke and aphasia therapy were the top three priorities. My proposal will address all of these. Stroke patients with anomia and their families will be therefore be the main public beneficiaries of knowledge arising from this research. The results will inform them about brain and language recovery after stroke and potential new treatments that will directly improve their communication and quality of life.
Description of the project and its relevance Jebel Moya is a combined cemetery and settlement locality in the south-central Sudan which was excavated in the early 20th century by the founder of the Wellcome Trust, Sir Henry Wellcome. The excavation was overseen by different field directors, employing variable excavation, recording and surveying techniques, over the course of the four seasons from January 1911 - April 1914. Plans for further expeditions were first placed on hold by the outbreak of World War I and subsequently ended by Sir Henry's death in 1936. Around a fifth of the estimated 10.4 hectares of deposits were excavated. It still stands as one of the largest British excavations ever undertaken in Africa and one of the largest cemeteries yet excavated in North-East Africa. Overall, 2792 graves were excavated and recorded. A site report was eventually published by Frank Addison in 1949, followed by Ramkrishna Mukherjee, C. Rao and J. Trevor's 1955 analysis of the osteological remains. Limited re-analyses have since been conducted. Rudolf Gerharz (1994), Isabella Caneva (1991) and Joel Irish (2007). Gerharz only utilised the information contained in Addison's 1949 report, particularly the limited Registrar of Graves, to propose a new tentative chronology; he never re-examined any of the excavation records and materials firsthand. Caneva examined a small sample of pottery, curated at the British Museum, from the earliest settlement period. Irish looked at the remaining teeth to test Mukherjee's hypothesis on population heterogeneity. No previous study has re-examined the excavation records and materials to test the validity of the original site reports, and to re-analyse the social implications of the individual burial assemblages and distribution of graves. Furthermore, there has been no attempt to ascertain the probability of conducting radiometric dating on either the osteological or pottery remains, for example using Accelerator Mass Spectrometry (organic materials) and Thermoluminescence (inorganic materials, including pottery). My accompanying paper from Sudan & Nubia (2009) provides a critical overview of the previous publications mentioned above, details my investigations to date, demonstrates that there remains much information to glean from studies of the materials - both skeletal and associated artefacts - and presents preliminary ideas resulting from analysing the grave card data which I am cataloguing into the first ever electronic database for the site. In addition, I am re-examining the excavated grave, settlement and skeletal materials firsthand. The majority of the grave objects? positions are recorded on the grave and anatomical cards, and also in Addison's register of graves. These factors are also being entered into the database under together with data on the strata, attitude of the burials and the condition of the skeletal remains. Furthermore, Dr Kevin MacDonald (Institute of Archaeology, UCL) will be assisting me in the Petrie and British Museums to analyse the associated settlement and grave pottery which is of chronological, spatial and social interest; this has never been comprehensively undertaken before. Moreover, as a result of research presented at the May 2009 Sudanese Archaeological Research Society's conference (British Museum), Professor Abdel Rahman Ali extended an open invitation to visit the National Museum of Sudan (Khartoum) and work on the housed Jebel Moya materials which remain unstudied. The accompanying Table 1, derived from Frank Addison's registrar of graves in his 1949 publication, summarises the distribution of the artefacts from Wellcome's expedition which are primarily held in museums in Cambridge, Khartoum and London.I will also be using the information provided in the archived records on the skeletal and associated grave artefacts to reconstruct behavioural patterns, social structures and population histories. The previous Jebel Moya publications did not adequately integrate different subsets of data, resulting in an incomplete reconstruction of the social and biological transformations which occurred over the millennia. Theoretical modelling of social and biological evolution has advanced considerably in the 60 years since Addison's publication. Mortuary systems can provide information on social variability through analysing spatial dimensions, in comparison with biological and cultural affiliations: human (biological) bodies are loci of identity at individual and group levels, and are situated within the wider culturally constructed landscape. Places were defined and made significant not just by their physical location but also by materiality, including the skeletal remains. There are two additional avenues which my research encompasses: bone chemistry and DNA analyses. The human skeletal and faunal remains are curated in the Duckworth Laboratory, Cambridge, and some are in a condition where bone chemical analyses could be attempted. Such analyses, if successful, would help shed light on marriage patterns and possible migratory patterns by disentangling intra-site and regional relationships, and also provide information on diet. DNA would help test previous hypotheses of genetic closeness in, for example, the proposed elite cemetery from the late first millennium BC. Dr Tamsin O'Connell (Wellcome Trust Research Fellow, MacDonald Institute) and Professor Martin Jones (Department of Archaeology) will be approached for their assistance. A third avenue, that of disease, could be looked at as a possible future research question. Therefore, the interdisciplinary approach which I employ involves interpreting the relationships between mortuary behaviour, memory and material culture by utilising aspects of bioarchaeology (such as radiocarbon dating and isotopic studies), ethnography, Wellcome's expedition records and the archaeological artefacts housed in different museums. The re-examination of the nature of burial distributions will assist in establishing relative chronologies of graves, cultural histories, patterns of pastoral migrations and interactions with the surrounding regions. There is also the possibility of conducting radiometric dating on appropriate skeletal remains in order to arrive at a firmer chronology than what is currently available. These avenues for research are also detailed in the sub-section 'What can be done with the data' in my accompanying paper.
Volunteers in Biomedical Research: Social Science Perspectives The aim of this meeting is to bring together academics who are specifically interested in exploring what it means to be a volunteer from the volunteers' perspective. While many of the researchers in the field are London-based, there has been little opportunity for all to meet in a single forum. The workshop will develop ideas and collaborative links for future work, build capacity in the UK social science community, and explore how this area of research can engage with current debates in science policy and research governance. Although UK government policy now puts a strong emphasis on public participation in research governance, there remains little discussion on the participatory role of volunteer human subjects. There are questions too about how adequately current codes of medical ethics function in practice and how they can accommodate the idea of more actively participative volunteers. The proposed workshop and its outputs could contribute to moving forward these issues. Topics to be addressed will include: the researcher-subject relationship; volunteers' understandings of research design and the implications for informed consent; volunteer motivation to participate; historical perspectives on volunteers' self-understanding; the significance of discourse around the 'volunteer', 'participant' or 'subject'; the possibilities for volunteers to influence the design and development of research. The meeting fits specifically with the objective of the Wellcome Biomedical Ethics programme to "build and enhance national capacity in the field". Some of the invited participants are working specifically within the programme's focus, looking at volunteering in relation to genetics (especially genetic databases) and neuroscience (especially brain imaging); others are working on the role of volunteers in a diverse range of the biomedical sciences. This meeting is specifically concerned with qualitative studies of volunteers' own experiences and understandings, and to this extent we are not aware of any recent meetings on this emerging field of science.
My own work, using fluorescent imaging techniques during the rotation project, showed that Ab increases ROS generation by activation of the NADPH oxidase in BV2 cells and that inhibition of the CLIC1-mediated chloride conductance - with IAA-94, by transfecting cells with an siRNA against the CLIC1 protein or by substitution of Cl with non-permeant anions almost completely prevents that response. We propose that the activity of the NADPH oxidase is limited by charge compensation and that the chloride conductance plays a key role in augmenting the activity of the enzyme by providing a route for the compensation of electron flow across the membrane. CLIC1 is also expressed in astrocytes, but at present we have no data regarding its possible functions. The functions of this CLIC1-mediated chloride conductance, its mode of activation, the means by which its inhibition can reduce ROS production and neuronal death and its potential ubiquity and general importance in glial cell physiology will form the basis of the research to be undertaken during the course of this PhD.
The grant requested is intended to support a series of seminars to be hosted jointly by the Centre for the History of Medicine and the Department of Neuroscience, Physiology and Pharmacology at University College London. The aim of the series is to present a series of papers on themes relating to the history, sociology, and philosophy of the neurosciences from distinguished scholars in these fields. Although attendance will be open to all, the series is particularly directed at research and mast ers students in the neurosciences with a view to providing them with a broader historical perspective upon and a sense of the wider social and ethical implications of their specialized fields of study. We hope thereby to encourage a genuine interdisciplinary exchange of ideas and insights.
Management and rehabilitation of patients with socially incompatible personality disorders at Broadmoor Hospital. Secondly an audit into the outcomes of people bought into the emergency department by police who are under the influence of methamphetamine and have suicidal ideation, at St Vincents Hospital in Sydney.
Structural Basis of Gabapentinoid Drug Action 01 Apr 2016
Gabapentinoids are blockbuster drugs used to treat conditions including neuropathic pain and epilepsy. They act by binding alpha2delta voltage-gated Ca2+ channel subunits. The focus of this summer project is to investigate the structure of alpha2delta to help understand its role in presynaptic Ca2+ entry and reveal the molecular basis of gabapentinoid binding. We have developed constructs for alpha2delta expression in High5 insect cells and HEK293T eukaryotic cells. We will express and purify different regions of alpha2delta, taking advantage of enzymes at our disposal for modifying glycosylation and pre-protein cleavage. Co-crystallisation screens will be set up with natural and synthetic small molecules including pregabalin and gabapentin. Successful crystal hits will be tested for x-ray diffraction using an in-house x-ray source. In the final fortnight of reserach, the student will perform crosslinking coupled to mass spectrometry experiments to determine the interaction sites of different subunits within the calcium channel complex, depending on the progress of crystallisation experiments.
Modern brain imaging contains vastly more information than historical radiographs, yet its clinically informative output has remained the same: a radiologist’s verbal report. As the information content of imaging increases, a void has opened between what we expensively collect and what we actually use.This is both a lost opportunity, and an obstacle to the continued growth of brain imaging. Technology being developed by Dr Parashkev Nachev and colleagues at University College London seeks to close this gap by applying novel computer-assisted algorithms so as to exploit much more of the information in each scan than a verbal report contains. An automatic “anomaly map” for each scan, indexing the deviation from normality of each point, will assist radiological reporting, allow the application of computer systems that predict clinical outcomes from patterns of anomaly, and guide radiological triage and resource/performance management. The project aims to demonstrate the feasibility, robustness, clinical, and managerial value of the approach using a large collection of standard brain imaging, and to deliver a pilot system capable of translation into a full clinical product. Without changing any clinical pathways or adding new investigations, the system will improve radiological reporting and optimise radiological triage and management, while creating a scalable major new platform for computational imaging analysis.
Pathophysiological consequences of mutations affecting the mitochondrial calcium uptake pathway 01 Apr 2016
Mitochondrial calcium uptake plays critical roles in cellular energy homeostasis. Alterations both in mitochondrial function and in cellular calcium signals play major roles in the pathophysiology of many major diseases, including ischaemic injury, neurodegenerative and neuromuscular diseases. The very recent discovery of the proteins mediating mitochondrial calcium uptake provides a new opportunity to understand the physiological roles of the pathway and pathological consequences of its dysfunction, as seen in patients with mutations of MICU1 described by the host lab. The patients have learning difficulties, muscle weakness and a progressive extrapyramidal motor disorder. The mechanism whereby mutations of MICU1 cause this particular constellation of symptoms are not understood. We will use iPS cells which we have generated from patient derived fibroblasts, differentiated into neurons and myotubes – the tissues most affected in the patient – and explore the consequences of MICU1 mutations for mitochondrial calcium signalling and for mitochondrial bioenergetic function. The project will illuminate the underlying mechanisms causing symptoms in the patients and point the way to therapeutic strategies.
Positron emission tomography (PET) has become an invaluable tool for diagnostic imaging and medical research as it allows quantification of biochemical processes in vivo with unsurpassed sensitivity and specificity. Due to its near ideal physicochemical properties fluorine-18 is the radioisotope of choice for imaging applications with PET, yet the lack of efficient and practical methods for the incorporation of 18F limits the availability of clinically relevant radiotracers. In particular, late stage labelling of compounds bearing functional groups that are prerequisite to biological activity remains challenging. The Arstad group have recently developed a new radiochemical strategy for aromatic labelling of drug-like small molecules based on the unique reactivity of sulfonium salts with fluoride-18. In this project, we aim to investigate the structural requirements for labelling with 18F and to broaden the scope of the existing method by establishing complimentary synthetic routes. To demonstrate clinicalapplicability, the strategy will be used to simplify radiosyntheses of existing radiotracers, to improve the imaging properties of established tracers, and to develop novel diagnostic imaging agents. The work has the potential to open up new prospects for imaging applications with PET. Ultimately, the development of new diagnostic agents can lead to improved human health.
A cross-cohort comparison of unhealthily low BMI in early adolescence – a feasibility study and development of research protocol 31 Jan 2016
Childhood thinness (unhealthily low body mass index) has been linked to poorer health and development but has received relatively little research attention in high income countries. Contemporary routine data reported by the National Child Measurement Programme (NCMP) point towards a possible U-shaped socio-economic gradient in thinness in 10-11 year olds (whereby those living in the most and least deprived areas have elevated rates of thinness). However, since the main focus of the NCMP is overweight and obesity, this social patterning in thinness has not been emphasised or further investigated. The U-shaped socio-economic distribution in thinness may be explained by food poverty in more disadvantaged areas, and issues of body image and eating disorders in more advantaged groups. UK cohort studies provide an untapped resource for examining this issue, because they contain rich, individual-level data, spanning different time periods (exposed to different social and economic contexts). However cross-cohort comparisons can be challenging and require a lot of input at the planning stage. This proposal therefore comprises of a feasibility study for a cross-cohort investigation of individual-level socio-economic inequalities in thinness in young people (and possible reasons behind them).