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Results

Recognition, activation and targeted degradation of protein kinases clients by the HSP90-molecular chaperone 10 Apr 2018

Many oncogenic protein kinases depend on interaction with the HSP90 molecular chaperone, mediated by the co-chaperone CDC37, for their cellular stability and oncogenic activity. Inhibition of HSP90's conformationally-coupled ATPase mechanism leads to the ubiqtuitylation and degradation of these protein kinase 'clients'. Consequently HSP90 is an important target for therapeutic intervention in cancer. Although there has been substantial progress in this field, important issues remain unresolved. In particular we wish to understand : How protein kinase clients are specifically and selectively recognised by the CDC37 co-chaperone, and recruited to HSP90 ? What structural and biochemical changes are elicited in the client protein by recruitment to HSP90 and by its conformationally-coupled ATPase cycle ? How dephosphorylation of CDC37 by the HSP90-targeted protein phosphatase PP5 regulates client protein release ? How protein kinase clients are targeted for proteasomal degradation when HSP90's ATPase is inhibited ? To address these questions we will use cryoelectron microscopy, X-ray crystallography, NMR spectroscopy, and a range of biochemical and biophysical approaches, to determine structures of key complexes along the pathway from initial client recognition to release or ubiquitylation, and define the structural and biochemical transitions that connect them.

Amount: £2,027,915
Funder: The Wellcome Trust
Recipient: University of Sussex

Expression and purification of ApolipoproteinE4 - A potential target for Alzheimer's disease therapeutics 01 Apr 2016

The purpose of my project will be to express and purify the human recombinant ApoE4 isoform as the basis for conducting subsequent structural analysis and small molecule screening in an early-stage drug discovery project. In the first instance, I will attempt to reproduce previously published data with so-called "structural correctors" that convert the morphology of the "bad" ApoE4 isoform into the more benign "good" ApoE3 isoform. More specifically my aims will be: 1. Small-scale expression tests of human ApoE4 cDNA in various standard strains of bacteria (E. coli) 2. Large-scale (2-5L) expression of ApoE4 under optimal conditions identified in Step 1. 3. Isolation and purification of ApoE4 using affinity, size and/or ion exchange chromatography and fast-protein liquid chromatography (FPLC) Stretch objectives (if all goes well) include: 4. Crystallography trials and thereafter X-ray crystallography 5. Development of an ApoE4 strucutural conformation assay using a previously-published fluorescence resonance energy transfer (FRET) assay

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University of Sussex

Biomedical Vacation Scholarship 23 Jun 2014

Not available

Amount: £9,000
Funder: The Wellcome Trust
Recipient: University of Sussex

Validating a combined geo-epidemiological approach to sampling for a geo-chemical disease 06 Dec 2012

Podoconiosis (endemic, non-filarial elephantiasis) is a common but under-researched condition found predominantly in tropical Africa. A strong research program has been developed over six years through collaboration between academics from Addis Ababa University and Brighton & Sussex Medical School, and a podoconiosis Patient Association in southern Ethiopia. Through the research described below, we intend to expand the program to include geological and mineralogical research into the environmental trigger to complement further genetic studies. We plan first to use stored blood samples from patients and controls in southern Ethiopia to confirm the association between Class II HLA genes and susceptibility to podoconiosis. In parallel with this, we will collect salivary DNA samples from400 cases and 400 controls in a recently described endemic site in North West Cameroon. We will genotype the top 80 single nucleotide polymorphisms (SNPs) identified by our earlier GWAS and perform HLA fine mapping on all samples, and do HLA typing and sequencing in a subset. Finally, in an eight-site comparative study in four regions of Ethiopia, clinical, epidemiological, geological and topographical informationwill be gathered and linked using GIS methods, and soil and water samples taken for mineralogical and chemical analysis.

Amount: £161,412
Funder: The Wellcome Trust
Recipient: University of Sussex

A Multi-Site Study of Socially Engaged Art in Public Health Research within Low Income Settings. 02 May 2013

There is increasing pressure for those working in community-based biomedical research to engage more with outside communities. This is justified by statements around democratising science and supporting two-way dialogue. Still, the underlying beliefs and assumptions driving engagement in practice are rarely explored and are not always understood by those involved, and the impacts of these activities are not always captured. Socially engaged art (SEA) may provide a unique space in which genuine e ngagement can take place. The aim of this research is to identify the impact and potential of SEA as a tool for community engagement (CE), allowing for open dialogue and addressing power imbalances between researchers and communities. This aim will be addressed by using two/three in-depth studies of SEA practice within the context of biomedical community-based research across different social, cultural and political contexts. Ethnographic and participatory methods will be used to explore the behaviours and attitudes of researchers, artists and other participants in the process and how these interact. As well as exploring the creative process the research will investigate the reactions and interpretations of the outputs of these works on local audiences. Outputs will hold relevance to research governance, research programmes, funders, NGOs and engagement practitioners.

Amount: £94,364
Funder: The Wellcome Trust
Recipient: University of Sussex

Institutional Strategic Support Fund 07 Sep 2016

Not available

Amount: £900,000
Funder: The Wellcome Trust
Recipient: University of Sussex
Amount: £2,026,044
Funder: The Wellcome Trust
Recipient: University of Sussex

Bacterial RNA profiling to predict tuberculosis treatment failure 15 Aug 2016

At present there is no way of accurately predicting tuberculosis (TB) treatment failure and relapse to active disease. This results in the over-treatment of many patients, who might safely stop the toxic six-month therapy earlier, and necessitates lengthy and costly clinical trials to assess new therapies, thus creating a bottleneck to progress. This innovative project will test whether the transcriptional response of TB isolated from patient sputa during the first few days of treatment will predict relapse months later. Building on the applicant’s recent study demonstrating that sputa TB mRNA signatures differ between patients and reflect clinical/microbiological measures of disease, this proof-of-concept prospective patient study will for the first time define markers of relapse. TB RNA from patient sputa will be assayed by targeted and genome-wide profiling techniques at diagnosis and at multiple timepoints after the start of drug therapy. RNA yields and gene expression signatures will be analysed to determine key methodological parameters concerning the collection and detection of sputa TB RNA and to assess applicability in the UK and Cameroon. Finally, TB mRNA signatures from relapse and successfully-treated patients will be compared using this novel discovery approach to identify biomarkers that predict relapse, transforming the management of TB.

Amount: £99,201
Funder: The Wellcome Trust
Recipient: University of Sussex

Synaptic computation in the visual system. 03 Dec 2013

How does a circuit of neurons process sensory information? And how are transformations of neural signals altered by changes in synaptic strength? These questions will be investigated in the context of the visual system. A distinguishing feature of our approach will be the imaging of activity across populations of synapses - the fundamental elements of signal transfer within all brain circuits [1-5]. Our guiding hypothesis is that the plasticity of neurotransmission plays a major part in controlling the input-output relation of sensory circuits, regulating the tuning and sensitivity of neurons to allow adaptation or sensitization to particular features of the input [6-9]. We will focus on computations carried out in the visual system because these are defined in sufficient detail to allow a quantitative analysis of the underlying circuitry and are also likely to have parallels in other brain regions [10-15]. How does a population of connected neurons detect the different temporal frequencies in a fluctuating input? Or the direction of motion of a moving object? Or the orientation of that object? In parallel, we will ask how these computations are modified in response to i) changes in the visual input that lead to adaptive changes in processing, and ii) neuromodulators that alter circuit function on longer time-scales.

Amount: £2,659,024
Funder: The Wellcome Trust
Recipient: University of Sussex

Taking treatment of chronic lifelong conditions to scale: applying the positive deviance approach to health programme management. 25 Mar 2014

In sub-Saharan Africa, and in South Africa in particular, there are significant numbers of people living with HIV/AIDS. Increasingly, there are growing numbers of people who are also living with non-communicable disease such as diabetes and heart disease. Although HIV is infectious and diseases like diabetes are not, they share similarities in that they require lifelong management to ensure health. HIV treatment requires a consistent regimen of antiretroviral therapy (ART), while diabetes may require a change in diet as well as regular medication. For policy makers planning health care in South Africa, it is a big challenge to make sure that the state health system has a cost-effective plan to keep these people on treatment and accessing care throughout their lifetime. Although the South African government has made ART available free of charge, recent studies have indicated that many with HIV stop taking the drugs over time. This problem has worsened as the programme has expanded. This is dangerous for their health and is also worrying from a public health standpoint as it could lead to strains of the disease that are resistant to ART as well as increasing the chance of them passing the virus on. Significantly, some clinics dispensing ART have much higher rates of people continuing to pick up their treatment. This study aims to fill knowledge gaps about the factors that influence whether people stay in care, focusing on the ART programme in the Western Cape Province of South Africa. The results of the research will help us work with policy makers in the Department of Health and leaders of community-based organisations to design a larger project that will involve implementing a country-wide programme to achieve more continuous care for people with chronic lifelong conditions. The study will involve researchers from different disciplines who are trained in medicine, the analysis of health systems and policies, social anthropology, public health and pharmacy. We will adopt a method that analyses existing numerical data monitoring how regularly people are collecting the ART drugs at clinics, and other HIV-related data. This will be used to identify which health facilities are performing better than others in terms of keeping people on treatment and engaged in their clinical care. We will focus our work on facilities serving poor populations who are socially marginalised. We will then go on to do more in-depth research in a few facilities which we have assessed as "good performers" and "bad performers" respectively. We will look in more detail at the information about HIV care and also look at indicators of whether people with diabetes are staying in care, using diabetes as an example for non-communicable disease. We will also collect information by observing practices in clinics, and interviewing staff and patients. Interviews will be conducted with decision-makers in the provincial and national Departments of Health. We will investigate the reasons for differences in performance and identify constraints to positive performance. We suspect that the facilities that are managing to keep patients in care, have more innovative organisational practices and have in addition forged partnerships with community-based organisations. This can then help to better support people to take part in managing their chronic illness themselves as well. Such "selfmanagement" is an important factor in poorer settings where the health system cannot provide intensive support from health professionals. We will identify generic factors that are helping to keep people on ART in care and that, if adopted more generally, could contribute to improving care for other chronic conditions also. We will have a workshop with the Department of Health and other stakeholders to discuss how the lessons learned can improve the programmes for chronic disease at national level. This will assist in the design of a bigger intervention and a further research proposal.

Amount: £24,123
Funder: The Wellcome Trust
Recipient: University of Sussex

Open access publishing costs 2014/15. 15 Sep 2014

Not available

Amount: £21,256
Funder: The Wellcome Trust
Recipient: University of Sussex

Analysis of vertebrate cyclin dependent kinase function in genome maintenance by chemical genetics. 26 Jun 2007

I am planning to investigate how Cdks coordinate DNA replication and repair to ensure the maintenance of a stable genome. Cdks are known to trigger DNA replication, but little is known on Cdk function at later stages of S-phase. To address this question I have established a vertebrate cellular model system, in which S-phase is controlled by a single allel of a mutant Cdk1, that can be instantly turned off by the addition of a mutant-specific inhibitor. Using this system I would like to investiga te how Cdks contribute to replication fork progression in the absence or presence of DNA damage; I would also like to address the control of DNA double strand break repair by Cdks. Furthermore I am planning to combine this chemical genetics system with a proteomics approach to identify the relevant targets of Cdks in these pathways. If successful this study will clarify how the major pathways of genome maintenance are coordinated by Cdks to ensure a successful duplication of the genome during th e S-phase of vertebrate cells.

Amount: £696,889
Funder: The Wellcome Trust
Recipient: University of Sussex

The ergonomics of electronic patient records: an interdisciplinary development of methodologies for understanding and exploiting free text to enhance the utility of primary care electronic patient records. 16 Jul 2008

Electronic patient records contain a mixture of coded information and free text. We will develop generalisable methods for the identification and interrogation of potentially important data concealed in free text, use the results to enhance coded data, and evaluate the utility of this approach. Through user centred methods, we will explore what influences clinicians in the balance between recording free text vs using standard codes (e.g. 002.23 Appendicectomy), and how information needs to b e stored for it to be useful to and retrievable by clinicians. Natural Language Processing (NLP) will be used to search the free text of large quantities of anonymised free text patient records, and to enhance coded data with pseudo-codes. Statistical methods will be used to explore the impact of integrating the additional information on (a) prevalence estimates (rheumatoid arthritis), and (b) estimates of dates of first relevant presentation (ovarian cancer). A visualization tool for the int egrated graphical display of coded and NLP generated data will be developed. It will be used to validate the novel data through clinician and researcher review, and thus to explore the value of these techniques in improving the quality and accessibility of information in electronic patient records.

Amount: £672,034
Funder: The Wellcome Trust
Recipient: University of Sussex

Neurodegeneration and aging: roles for DNA single-strand break repair. 23 Jun 2008

The SSBR proteins TDP1 and Aprataxin are mutated in two distinct neurological diseases; spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) and ataxia oculomotor apraxia-1 (AOA1). The goal of this proposal is to (1) Characterise mechanisms of SSBR in primary neural cells using a combination of in vitro biochemical assays (employing synthetic oligonucleotide substrates) and cellular chromosomal DNA repair assays (employing the alkaline comet assays). I propose to define the intermediates that accumulate in neural cells that are defective in SSBR using biochemical approaches and to characterise novel factors in this pathway using yeast 2-hybrid and co-immunoprecipitation experiments. (2) Elucidate the impact of un-repaired SSBs on neural cell fate, with emphasis on transcriptional competence and survival of primary neural cells. (3) Evaluate the neuroprotective effect of SSBR in vivo, by measuring specific behavioural and physiological end points in wild type and SSBR-defective mouse model systems.

Amount: £653,466
Funder: The Wellcome Trust
Recipient: University of Sussex

Vacation Scholarships 2008. 27 May 2008

Not available

Amount: £5,760
Funder: The Wellcome Trust
Recipient: University of Sussex

Open Access Award. 31 Oct 2006

Not available

Amount: £10,000
Funder: The Wellcome Trust
Recipient: University of Sussex

Mechanisms of client protein activation and regulation by the Hsp90 molecular chaperone system. 10 May 2011

The Hsp90 molecular chaperone plays an essential role in the stabilisation andactivation of a wide range of client' proteins, including some of the most important proteins required for cell maintenance and regulation in eukaryotic organisms from yeast to humans. Hsp90 itself is regulated by a plethora of co-chaperone proteins that modulate its essential ATPase coupled conformational cycle, and/or act as adaptors facilitating recruitment of specific client proteins to the Hsp90 machinery. Involvement of Hsp90-dependent clients in the development and progression of cancer, has led to enormous interest in Hsp90 as a drug target, and an emerging realisation of Hsp90 involvement in viral and and parasitic infections, suggests that Hsp90 is important in many other diseases. Although much of the biochemistry of the Hsp90 system has been unravelled in recent years, central questions of Hsp90 biology remain unanswered. To address this, we propose to define at the structural level the molecular mechanisms by which the Hsp90 molecular chaperone system contributes to the activation, stabilization and regulation of its selected client' proteins in eukaryotic cells

Amount: £2,804,975
Funder: The Wellcome Trust
Recipient: University of Sussex

Veterinary science, transboundary animal diseases and markets: pathways for policy in Southern Africa. 28 Feb 2006

Key to the future of livestock production in Africa - and constraints on meeting the high hopes of a 'livestock revolution' as a spur to stagnant agricultural sector growth - are the presence of transboundary animal diseases and the consequent escalating costs of regulation and meeting export standards. Focusing on the case of foot and mouth disease (FMD) in southern Africa - and specifically Botswana, Nambia, South Africa and Zimbabwe - this research will explore the economic, social and political trade-offs arising from disease control strategies focused on promoting commercial beef exports which are premised on the ability to separate a 'disease free' commercial sector from endemic areas through strictly enforced buffer and surveillance zones, and movement control. The key question is: given limited resources and capacities and growing costs, does it make sense to persist with this status quo and ensure disease freedom? Or are there alternatives that benefit a wider group of producers, are easier to implement, yet maintain access to important export markets and so foreign exchange revenues? Four country-based teams, coordinated by IDS and supported by project advisors, will investigate the policy processes in each country: how choices are made and by whom and with what criteria, to uncover the different scientific and economic arguments, policy actors and interest positions involved. The project will then bring the different players together in a series of policy dialogue workshops to explore different future policy scenarios (and their trade-offs), through a deliberative and participatory process. The main audience for both the analysis and methodological approach will be national and regional (SADC) level policymakers working on the intersections of animal health/disease control and marketing/trade policy. The policy dialogues will engage diverse stakeholders - livestock producers, regulators, processors, exporters and scientists - with a view to encouraging dialogue across usually divided sectors and across the region.

Amount: £148,704
Funder: The Wellcome Trust
Recipient: University of Sussex