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The Wellcome Trust
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Birkbeck University of London

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Results

Structure and Action of the Metazoan Disaggregase Complex 31 Jan 2017

The metazoan Hsp70 disaggregase system is the only known human protein complex capable of resolubilising aggregated protein, conferring a protective phenotype for a range of pathologies. Disaggregation occurs through the dynamic assembly of a Hsp70/110 complex, initiated by J-protein recruitment of substrate. The structure of the active complex is currently unknown, as is the mechanism of disaggregation. This project will employ an interdisciplinary approach to structurally characterise the disaggregation of alpha-synuclein amyloid fibres in vitro by the human proteins DNAJB1 (J-protein), Hsc70 (Hsp70) and Apg2 (Hsp110). There will be a primary focus on understanding two particular elements of disaggregation. Firstly, how do J-proteins recruit substrate to activate disaggregation? This will be investigated using electron tomography, taking advantage of the recent "resolution revolution" in the electron microscopy field. Secondly, what is the mechanism of the active disaggregase complex as it is resolubilising aggregates? To answer this, we aim to track individual alpha-synuclein fibres by atomic force microscopy and total internal reflection fluorescence microscopy as they are solubilised during disaggregation. Given the role of aggregation in a broad range of debilitating diseases, increasing the understanding of disaggregation in humans has the potential to eventually lead to significant public health benefits.

Amount: £0
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Timestamping Integrative Approach to Understand Secondary Envelopment of Human Cytomegalovirus 28 Nov 2017

The mechanisms facilitating the assembly of Human cytomegalovirus (HCMV) in the cytoplasm of infected cells, a complex process termed ‘secondary envelopment’, are poorly understood. Our goal is to identify in-situ the identity, position, and interactions of all the essential proteins involved in this critical stage of the viral ‘lifecycle’. Despite decades of research, it has been difficult to dissect the complexity of secondary envelopment, as bulk assays only show ensemble averages of populations of viral particles. To study these intermediates that are formed when cytoplasmic capsids acquire tegument proteins and their envelope membrane, we will develop a novel approach that separates these intermediates in time and space. We will provide their spatio-temporal models by integrating complementary cutting-edge techniques and expertise within this collaboration, including flow-virometry, correlative (fluorescence and electron cryo) microscopy, crosslinking and ion-mobility mass spectrometry-based proteomics, and computational modelling. Specifically, we aim to: -Identify key players in tegument assembly on capsids/membranes. -Elucidate the order and spatial organisation of tegument assembly. -Validate the interactions in vivo and analyse capsid tegumentation in vitro. -Integrate the information into a spatiotemporal model. This will significantly improve our understanding of herpesvirus assembly in general, a crucial step towards identifying new therapeutic targets.

Amount: £673,700
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Establishing objective measures for identifying children with Autism Spectrum Disorders using eye-tracking technology in the UK and India 09 Nov 2016

Autism Spectrum Disorders (ASD) contribute significantly to total years lived with disability globally. Most people with ASD in low-income countries are belatedly or never diagnosed, mainly due to the paucity of mental health specialists - hence critical years for treatment are missed. Objective measures for ASD detection are needed. Multiple cognitive markers of ASD have been identified using eye-tracking technology; testing these markers in combination holds promise for effective identification of children with ASD. This proposal aims to establish objective measures for identifying children with ASD using eye-tracking technology in high and low-income settings. Stage 1 will analyse existing eye-tracking data from the British Autism Study of Infant Siblings, to establish a combination of eye-tracking tasks that has the highest probability of identifying children with an ASD diagnosis. Stage 2 will be a case control pilot study to determine whether the same combination of markers identifies children with an ASD diagnosis in India. The feasibility and acceptability of these eye-tracking tasks will also be assessed in an Indian context. Establishing effective, acceptable and feasible methods for objectively identifying children with ASD will improve detection in these settings and translate into a greater number of children benefiting from early interventions worldwide.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

After the End of Disease conference 31 Dec 2015

This conference brings together historians of medicine and global public health, anthropologists and sociologists with policy makers to challenge conventional linear narratives of epidemics and diseases in general. The overall aim of the event is to bring multiple perspectives and analyze what happens when diseases are decreed to be over. This work will offer a robust analytical framework and will inform current global health policies of eradication and epidemic management. In turn, it will bring the experiences of practitioners in global public health to provide insight and further the understanding of the historical and social trajectories of these phenomena. The key goals of this conference are: 1. Understand and identify historical trajectories and challenges associated with post-outbreak periods. 2. Create a critical knowledge mass to equip future policy-makers with the necessary tools to address post-outbreak issues. 3. Build a network of scholars and policymakers that can be mobilised in future global health crises to advise how to better tackle post-outbreak moments.

Amount: £9,860
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Fatigue in Britain: Work, Medicine and Society, 1914-1945. 13 May 2014

This project looks at fatigue and work in Britain from 1914 to 1945. It examines how political and economic concerns influenced the production of medical knowledge of fatigue, and how concepts of fatigue in turn penetrated ways of thinking about society. In contrast to a postwar period in which fatigue has increasingly been seen as a matter of individual responsibility or pathology, from the First World War and through the interwar period, I argue, workers' fatigue was an issue of major publi c significance. The working body became a symbolic focus for discourses over national efficiency, productivity and the welfare of the population. The fatigued working body became a point around which anxieties over the state of the nation were organised, and a key locus for the production of medical knowledge. The key goals are: to establish the contexts in which fatigue emerged as an issue of public significance and an object of medical and political inquiry; to examine the physiological and psychological models of fatigue developed in this period; to determine how the fatigue of workers was contested politically; to determine the effect of World War Two on the medical conceptualisation and social significance of fatigue.

Amount: £88,078
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Institutional Strategic Support Fund 07 Sep 2016

Not available

Amount: £900,000
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Institutional Strategic Support Fund Phase2 FY2014/16 27 Oct 2014

The Wellcome Trust has recently awarded the University of Aberdeen £600,000 in funding to support a range of strategic research activities that fall within the Wellcome Trust's remit. Projects must fall within the remit of the Wellcome Trust and be within the strategic remit of the Aberdeen ISSF including; Infection, Immunity and Inflammation, particularly Medical Mycology Understanding the molecular basis of obesity for the development of interventions Applied Health Sciences, particularly through our Chief Scientist Office-funded Health Economics Research Unit and Health Services Research Unit. The support strategy for the fund is to: Facilitate more interdisciplinary research across the schools and institutes Enhance research impact through its translation into practice and dissemination through public engagement Enhance our Career Development Support in biomedical research

Amount: £600,000
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

The reception and application of degeneration theory and the concept of atavism in Scandinavian racial sciences, literature, cultural debate, and satire, 1880-1922 10 May 2016

The objective of my doctoral thesis will be to examine how degeneration theory, as both a scientific and cultural concept, was received and disseminated into Scandinavian racial biology and anthropology, literature, cultural debate, and satire. I will contend that degeneration theory may be viewed as a prism reflecting the relationship between nineteenth- and early twentieth-century science and culture: culture popularising science through periodicals, satire, and literature, and science examining and diagnosing culture. Furthermore, this project aims to broaden the geographical and cultural scope of degeneration studies by delineating the unique character of Scandinavian degeneration theory, strongly emphasising heredity over environment as the main cause of degeneration. I will also juxtapose the notion of late nineteenth-century British, French, German, and Italian degenerationist thought as closed systems of knowledge with a wider, more inclusive network of mutual contributions between European scientists, critics and authors. I will be focusing on the time period between 1880 and 1922, as the spectre of degeneration began to emerge in Scandinavian debate in the 1880s, and the study will conclude with the founding of the Swedish National Institute for Eugenics in 1922, which positioned Scandinavia at the forefront of European research into the mechanisms of racial heredity.

Amount: £89,829
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

“Balint Groups” and the Patient-Doctor Relationship: The Social History of a Psychoanalytic Contribution to the Medical Sciences 11 Jan 2016

The project studies the emergence of "Balint groups", initiated by the medically trained psychoanalyst Michael Balint in the 1950s. In the groups, psychoanalysts encountered medical doctors to discuss the latter’s difficulties with their patients. This encounter has unexplored consequences for the understanding of illness and the formation of medical doctors. I propose a multi-method social history of "Balint groups" and I ask two questions: how can we understand this complex psychoanalysis-medicine conversation and what does this case have to say about what psychoanalysis can offer to medicine, with respect to making sense of illness? The project has four dimensions of research: theoretical, examining Balint’s innovative relational conception of illness; historical, analysing the importance of Balint’s embeddedness in the Budapest School of psychoanalysis; epistemological, looking at the forms of boundary-work between psychoanalysis and medicine that characterised the emergence of Balint groups and reflecting on the collective and transdisciplinary knowledge produced in the groups; ethical, discussing the non-hierarchical modes of relationality in the groups. The project relies on archival research and brings to light the novel material contained in the Balint Archive, held by the British Psychoanalytical Society since 2014. The research will also involve in-depth interviewing of psychoanalysts and medical doctors.

Amount: £195,829
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Waiting Times: Waiting and care in the time of modernity. 08 Apr 2015

Seed funding is sought for the development work that will lead to a joint Investigator Award Application by Lisa Baraitser (Birkbeck) and Laura Salisbury (Exeter) that investigates waiting time in relation to mental health, clinical contact time, and care. The project will bring together perspectives from medical humanities, medical history, psychosocial studies, literary studies, and new studies of temporality, to think critically about waiting times in mental healthcare provision, the time-spa ce of the GP encounter, and practices of care for the very elderly. Using an emerging scholarship that reformulates the speed and mobility commonly associated with modernity by emphasizing slowness and stilled, impeded or suspended time, the project investigates contemporary experiences of waiting in clinical and care encounters in what are felt to be increasingly frenetic times. Seed funding will enable a) a scoping study to be completed on the history of managing waiting in the NHS, from 1948- present day; b) the development of the conceptual resources on temporality that will underpin the Investigator Award Application through teaching buy-out, meetings, networking and conference attendance by the two co-investigators; c) the development of partnerships with those who will have a stake in the research outputs of project.

Amount: £27,039
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Alternative Psychiatric Narratives: a 1.5 day conference. 31 Mar 2014

We propose a 1.5 day conference at Birkbeck in London for postgraduate and early career researchers to explore the theme of alternative psychiatric narratives. This aims to investigate new approaches to histories and experiences of psychiatry in its broadest sense, by considering overlooked stories, new sources and approaches, and the very question of narrative in psychiatry itself. We anticipate that researchers across the humanities and social sciences will engage with the topic, that the narratives under consideration will include a range of styles and media, and that there will be challenges to the constructions and uses of psychiatric narratives themselves. We will also welcome discussions of psychiatric encounters occurring outside formal psychiatric spaces, and the engagement of those who fall outside the doctor-patient dyad, such as non-medical staff and activists. The event will include a keynote speech given by an established academic, Dr Mathew Thomson, followed by presentations from junior scholars and a networking reception in the evening. If funding allows, this traditional conference format will be enhanced by a concluding roundtable discussion of invited participants and a final event open to the public.

Amount: £2,509
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Biomedical Vacation Scholarship 25 Jun 2012

Not available

Amount: £4,560
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Biomedical Vacation Scholarship. 20 May 2011

Not available

Amount: £1,520
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Protein quality control: Chaperone-substrate interactions and cellular aggregates. 26 Jun 2009

This project is concerned with molecular and cellular aspects of protein quality control. We will carry out structural analyses of molecular chaperones at different stages of protein folding or disaggregation by cryo electron microscopy and single particle analysis. To understand the mechanism of assisted folding and the structural basis for substrate selectivity in bacterial and archaeal chaperonins, proteins trapped or folding inside chaperonin complexes will be imaged. We will also investigat e complexes of the yeast chaperone Hsp104 with model and physiological substrate proteins. Hsp104 is one of a unique group of chaperones capable of dissolving aggregates, and is essential for the propagation of yeast prions. A new approach initiated by the PI s sabbatical is cryo electron tomography of vitrified cell sections to study the three-dimensional structure of yeast prions in situ. In parallel, biochemically isolated prion aggregates will be examined by tomography, along with prion fi brils reconstituted with the Hsp100 and the Hsp70 system chaperones involved in their propagation. We will then apply these methods to neuroblastoma cells stably infected with mouse prions, the causative agent of transmissible encephalopathies. The approaches developed should eventually be applicable to vitrified sections of brain tissue of animal models of neurodegenerative disease.

Amount: £1,062,536
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Insights into pore-formation from studies of Clostridium perfringens Epsilon-toxin. 01 Oct 2009

Clostridium perfringens epsilon-toxin is uniquely lethal and exquisitely specific. It causes pulpy kidney disease which in unvaccinated livestock can devastate herds in a few days. Pathological changes associated with epsilon-toxin occur mainly in the brain, and it binds MDCK and rat brain synaptosomal cells. Our structure of the monomeric proto-toxin revealed that it is a beta-pore-forming toxin. This family generally shows activity against a broad range of cell types with much larger lethal doses than epsilon-toxin. Understanding why epsilon-toxin shows this atypical behaviour could help the design of a specific, efficient cytolytic agent. We will study oligomerization and receptor interaction. Micro-array analysis has revealed candidate genes for epsilon-toxin sensitivity. We will use siRNA to suppress expression of these genes in MDCK cells and assess their contribution to toxin recognition. We will mutate residues previously identified by structure comparison and conser vation analysis to assess their involvement in receptor interaction. We will determine the heptamer structure by cryo-electron microscopy and crystallography. We already have promising negative stain EM images. Residues revealed to be in the heptamer interface will be mutated and any changes in oligomerization investigated. Non-oligomerizing variants will be used in models of disease to assess their suitability as molecular vaccines.

Amount: £308,240
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Open access award. 22 Sep 2009

Not available

Amount: £30,000
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Value in People Award. 17 Oct 2007

Not available

Amount: £200,000
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Biomedical vacation scholarship. 29 May 2009

Not available

Amount: £3,040
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Open Access Awards. 16 Sep 2008

Not available

Amount: £20,000
Funder: The Wellcome Trust
Recipient: Birkbeck University of London