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Results

Student elective for Suzanne Gaskell 19 Jul 2006

Colorectal cancer (CRC) accounts for 9% of all cancers making it the third most common cancer worldwide. CRC is accountable for around 7% of all cancer deaths, with approximately 60% of these being in developed countries. Although mortality rates have been slowly declining in many countries, the disease remains unacceptably common. It has thus become a high health priority for many developed countries. In America and Canada, where CRC screening for CRC is encouraged, there is a wide variation in the patterns of utilization of screening services among populations. An study found that almost twice the number of people aged 50 and older reported recent colorectal cancer screening with an endoscope procedure than screening with an FOBT; 40.4% versus 21.8% respectively. IN the same year, 50% of Americans aged 50 years and older reported that they had not had any colorectal cancer screening. Between 1997 and 2001 there was a 21% increase in annual FOBT and a 29% increase in 5- yearly lower endoscopies, amongst persons at average risk. Compared with the use of other cancer screening tests, colorectal cancer screening rates are low. The problem of too many average risk adults not being screened persists. Reasons for this include a lack of an efficacious screening method, low engagement by health care providers in recommending screening to their patients, and low awareness of the public about the need for and importance of screening. The objective of this retrospective cohort study is to analyze whether certain patterns of health services utilization lead to early (TNM stage I) versus late (TNM stage II-IV) diagnoses, and if these patterns impact survival.

Amount: £1,000
Funder: The Wellcome Trust
Recipient: University of Liverpool
Amount: £4,800
Funder: The Wellcome Trust
Recipient: University of Liverpool
Amount: £18,304
Funder: The Wellcome Trust
Recipient: University of Liverpool

Understanding Research Ethics Committees: The New Regime. 14 Dec 2005

Title of meeting: Understanding Research Ethics Committees: The New Regime Topics to be covered include: Consistency in decision-making, assessing whether such disparities are necessarily a flaw in operating procedures or whether they represent a valuable form of divergence; Inter- and Intra-group dynamics, assessing the relationships between LRECs and MRECs and the individual personalities within groups which may have a bearing upon decisions reached; The need for "Ethics Plus", assessing the role of ethical oversight bodies in genetic research and their relationship with established Review Committees; International oversight, assessing whether the current initiatives comply with the ICH-GCP and whether an internationally centralised system of oversight is achievable; Overview of the National Patient Safety Agency (NPSA, charged with overall responsibility for COREC as part of the DoH "Arm's Length Bodies" review) and how to navigate the process of application for ethical approval; Critical analysis of the changes being implemented in the light of past criticisms and an assessment of the value of the new regime for the future; Assessment of applying for approval from the perspective of an applicant and whether the new regime represents an improvement on a practical level to past experience.

Amount: £2,244
Funder: The Wellcome Trust
Recipient: University of Liverpool

VALUE IN PEOPLE AWARD. 30 Aug 2006

Not available

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

The role of microparticle-associated endothelial protein C receptor in disseminating activated protein C function. 07 Nov 2005

Activated protein C (APC) was recently shown to significantly reduce the relative risk of death in patients with severe sepsis. The mechanisms of its protective effects are not fully understood and treatment carries serious bleeding risks. In treated patients, we have made the novel observation that APC induces endothelial microparticle release into the circulation. The microparticles contain APC bound to its endothelial receptor to enable expression of anticoagulant activity. We hypothesise that this mechanism of disseminating APC could be harnessed into more efficient strategies for delivering APC to cell surfaces to prevent overlying thrombus formation and protect endothelial cell integrity, especially under inflammatory conditions. We therefore propose to examine for these effects in vitro and in vivo using clinical samples from patients and a mouse model of sepsis, through gene microarrays, flow cytometric, functional, histological and electron microscopic studies. The potential benefits of such an approach would includeo Improved understanding of the mechanisms underlying the protective effects

Amount: £153,858
Funder: The Wellcome Trust
Recipient: University of Liverpool

The immunological consequences of metabolic drug activation by dendritic cells. 31 Dec 2005

Drug hypersensitivity is an important problem during drug development and in the clinic. The immune system is thought to be involved in the pathogenesis, although the key steps leading to drug-specific T cell activation have not been fully elucidated. The aim of the proposed research is to test the hypothesis that metabolism of compounds within dendritic cells can be an important step in the immunopathogenesis of drug hypersensitivity. This will involve characterisation of (a) stable and chemically reactive metabolite formation in dendritic cells; (b) co-stimulatory and antigen-specific interactions between dendritic cells and T-cells; and (c) whether this is altered in hypersensitive patients. The studies will be undertaken using sulfamethoxazole as a paradigm because of its well characterised clinical, toxicological and metabolic profile.Dendritic cell metabolism will be evaluated using a combination of established bioanalytical and immunological techniques. To explore the relationship between metabolism and dendritic cell activation, drug-treated cells will be analysed using immunological and molecular approaches such as flow cytometry, ELISA, EMSA and focussed microarrays. Moreover, the interaction between dendritic cells and T-cell clones from patients will be evaluated using established cell culture methodologies. This integrated approach will provide insight into how drugs can cause tissue injury in man.

Amount: £204,727
Funder: The Wellcome Trust
Recipient: University of Liverpool

Defining the molecular basis of arthropod transmission of Bartonella species: identifying essential bacterial genes using a neo-natural experimental system and signature tagged mutagenesis. . 24 Apr 2006

Bartonella species are arthropod-transmitted haemoparasites of medical importance that exploit mammals (including humans) as reservoir hosts. Although early experimental studies concluded that the infectiousness of bartonellae towards their reservoirs was augmented by arthropod transmission, contemporary investigations of the molecular mechanisms underlying bartonella persistence in their vectors, particularly those underlying this apparent preparedness for infection, are lacking. To begin to ad dress this shortfall, we will develop a near-natural experimental transmission system in which Bartonella birtlesii infections will be established and monitored in captive Apodemus sylvaticus (the wood mouse, a natural reservoir host) and will be transmitted by fleas that comprise the natural wood mouse fauna (fleas are primary vectors for B. birtlesii). We will identify B. birtlesii genes that are required for bacterial persistence during inter-host transmission by determining the performance o f members of a library of signature tagged transposon mutants of B. birtlesii using the near-natural system. Mutants in which transmission-essential genes are disrupted will be identified by their absence in newly infected animals, then characterised.

Amount: £333,409
Funder: The Wellcome Trust
Recipient: University of Liverpool

The chemical and molecular basis of the prevention of drug-induced liver injury by Nrf2. 03 May 2006

Drug-induced liver injury (DILI) is a major public health concern. Many drugs and chemicals, including the widely used analgesic paracetamol undergo metabolic activation in the liver to toxic metabolites. The human liver has evolved multiple systems to protect itself from chemical stress induced by chemicals and their metabolites. It has been proposed that a major mechanism for the up regulation of proteins that catalyse the bioinactivation of drugs (and their toxic metabolites), such as paracet amol, involves the redox sensitive Keap1-Nrf2-ARE signalling pathway which is thought to be activated by chemical modification of critical cysteine residues in Keap1. The purpose of our work is to understand the chemical and cellular signalling systems that determine DILI, from the initial contact of ultimate chemical toxin with target protein(s) through to pathological outcome. In this study we will focus on the earliest, dose-dependent, chemical interaction of paracetamol, and other relevant h epatotoxins with Nrf2 and Keap1. We will define the chemical and molecular mechanisms of protein modification that regulate the Nrf2-Keap1-ARE pathway and the consequent levels of defence gene induction, in relation to the level of chemical stress and the subsequent modulation of toxicological outcome.

Amount: £260,394
Funder: The Wellcome Trust
Recipient: University of Liverpool

Efficacy and impact of a health and welfare education programme for horse and donkey livestock owners in Ethiopia. 18 Aug 2006

The ways in which livestock owners use and acquire information is of great importance to animal health, welfare and productivity, particularly in developing countries. However, limited published work is available which evaluates the impact of educational interventions. We propose a project which will develop an education and knowledge dissemination programme for equid owners, using novel methods to determine the most effective way of delivering this education programme. This education programme will then be implemented to a wider audience with the aim of improving horse and donkey health, welfare and productivity of working equids in Ethiopia, a country with an equid population over 5.5 million. We will identify the most important areas of health that impact on equid productivity in the study area, and we will then evaluate the effectiveness of different knowledge dissemination interventions for increasing equid health care knowledge and promoting uptake of recommended new practices by owners. To achieve this we have several objectives Identification and prioritisation of areas of draught horse and donkey health that impact on productivity. This will involve engagement with various stakeholders including livestock keepers and animal health practitioners. Development of a variety of knowledge dissemination interventions for educating horse and donkey owners in Ethiopia. Interventions will be selected after consultation with stakeholders, but may include village meetings, visits to individual farmers and diagrammatic handouts. A randomised controlled trial (RCT) to evaluate the effectiveness of the different knowledge interventions for increasing the knowledge of livestock owners Identification of sources of information regarding horse and donkey care currently used by Ethiopian farmers and estimation of their relative importance. Implementation and widespread delivery of the most appropriate and effective knowledge dissemination intervention in an education programme aimed at improving horse and donkey health, welfare and productivity in Ethiopia.

Amount: £124,774
Funder: The Wellcome Trust
Recipient: University of Liverpool

The pharmacology of Nevirapine in Malawian patients: Implications for dosing and understanding of hypersensitivity reactions. 23 Mar 2006

The NNRTI nevirapine is used in Malawi in combination with stavudine and lamivudine for the treatment of HIV. Nevirapine is associated with a 6-10% risk of hypersensitivity in Caucasians, most reactions typically occurring within the first 3 months of therapy. Initial observations in Malawi, since the start of the national ARV Programme, suggest that the prevalence of adverse reactions is at least as high as in Caucasians.The mechanism of, and risk factors for, nevirapine hypersensitivity are not well understood. In Caucasians, female gender, high CD4 counts and MHC genotype increase risk. Factors such as ethnicity, co-infection with hepatitis viruses, micronutrient status and differences in drug exposure, may also be important. However, none of these factors have been investigated in Malawi.The aims of this project are to characterize the clinical pattern of nevirapine hypersensitivity in Malawi by longitudinal assessment of a patient cohort. This cohort will also be utilized to identify the environmental and genetic factors predisposing to nevirapine hypersensitivity; this will be underpinned by immunological and pharmacokinetic assessments in a subset of patients. These studies will provide insight into the mechanisms of nevirapine hypersensitivity, with a potential in the future to develop better diagnostic and preventive strategies.

Amount: £438,229
Funder: The Wellcome Trust
Recipient: University of Liverpool

Regulation of tissue inhibitors of matrix metalloproteases (TIMPs) expression in the gastric epithelium. 20 Sep 2006

The aim of this project is to define the mechanisms by which H.pylori infection increases expression of tissue inhibitors of matrix metalloproteases (TIMPs) in gastric mucosal cells, and to determine the consequences for the mucosal remodelling that occurs with infection. The experimental plan is based on our capacity to culture human primary gastric epithelial cells and myofibroblasts transfected with promoter-reporter constructs, to study Helicobacter responses in mice (and determine if they are an useful model) and to identify putative substrates using 2-DG cells and mass spectrometry of selected spots (5,6,7).

Amount: £6,396
Funder: The Wellcome Trust
Recipient: University of Liverpool

Analysis and decoding of the language of cells (A Royal Society Exhibition). 19 Jul 2006

Analysis and decoding of the language of cells (A Royal Society exhibition) A proposal for the above exhibit has been selected for the Royal Society Summer Exhibition (July 2006) and the 2006 Glasgow Science Exhibition (September). There is no funding associated with acceptance for these prestigious events. Both events attract a large number of scientists, politicians, policy makers and members of the public. They represent a major annual opportunity to increase awareness of important scientific topics and breakthroughs. We will show how timelapse microscopy using proteins from fireflies and jelly fish has transformed cell biology. This will involve a luminescence practical demonstration and demonstrations using pictures and videos. We will use the NF-kappaB signalling system to demonstrate the problem that each mammalian cell has in sensing its environment and in making correct decisions regarding the cell's fate. We will show our new data that suggests that this signal works in a different way from that previously suspected. Rather than being a simple switch, we have found that NF-kappaB proteins move repeatedly (oscillate) between the cytoplasm and the nucleus of the cell. These oscillations control the switching on (and off) of a large number of genes. It now seems likely that the timing of these oscillations encodes the message. This concept, developed using systems biology approaches, changes the way that we think about cell signals suggesting that period (FM) may be as important as the amplitude of a signal (AM). We will demonstrate how this relates to cell division, cell death, cancer (particularly neurobalstoma in children) and inflammatory disease.

Amount: £6,975
Funder: The Wellcome Trust
Recipient: University of Liverpool

Attentional mechanisms in colour-defined motion perception. 04 Jul 2006

In visual environments, motion direction and colour of parts of an object are usually correlated. Human motion perception does not seem to automatically benefit from this correlation: motion discrimination performance in a random dot kinematogram (RDK) where all signal dots are associated with a particular colour and all noise dots are associated with another colour is not better than if no association between motion direction and colour exists. If observers have prior knowledge of the signal co lour and attend to it, motion discrimination performance increases. Two mechanisms have been proposed to explain this facilitation: a feature-based mechanism, wherein attention increases the gain of the chromatic motion signal, or, alternatively, a surface-based mechanism, wherein attention performs colour-based surface selection hence restricting the motion discrimination task to a specific colour plane. The purpose of this project is (1) to validate a novel paradigm that allows us to discrimi nate between these two mechanisms and (2) to establish their corresponding neural markers. We will exploit the fact that, for a large range of parameters, short-wavelength-sensitive (S) cones do not contribute to global motion perception, while altering the appearance of the stimulus, hence enabling surface segmentation without changing the input into the motion mechanism itself.

Amount: £62,105
Funder: The Wellcome Trust
Recipient: University of Liverpool

Investigation of the humoral immune response to pneumococcal polysaccharides and the role of a conjugate pneumococcal vaccine in secondary prevention of invasive pneumococcal disease in HIV-infected Africans. 09 May 2006

Invasive pneumococcal disease (IPD) is the only important HIV-related problem in sub-Saharan Africa which is potentially vaccine preventable. Conservative estimates suggest 1 million cases of adult IPD occur annually in this region as a consequence of HIV-infection. In our recent efficacy trial in Uganda, the 23-valent pneumococcal polysaccharide vaccine (PPV) increased the risk of IPD/pneumonia. The efficacy and role of the newer conjugate pneumococcal vaccines (CPV) remains unknown. I aim to investigate potential mechanisms of vaccine failure and harm associated with the use of PPV, and assess the response to and efficacy of CPV in a randomised controlled trial. CPV will be used to probe for defects in serological response to polysaccharides in a) previous PPV vaccine recipients b) individuals with past IPD, to describe and categorise the prejudicial effects of exposure to vaccine-purified or natural polysaccharide. A double-blind, randomised placebo controlled trial of CPV as secondary prophylaxis to prevent recurrent IPD will be performed in HIV-infected Malawian adults. Proven efficacy of the vaccine as secondary prophylaxis will be a fair indicator of potential as primary prophylaxis. Initial studies of the B-cell mechanisms that underpin altered or deleterious serological response will commence with validation of appropriate and "field-friendly" methods for the isolation of polysaccharide responsive B-cells, for future molecular-based descriptions of B-cell populations and dynamics.

Amount: £58,552
Funder: The Wellcome Trust
Recipient: University of Liverpool

Core support for the Wellcome Centre for Research in Clinical Tropical Medicine - supplement for an administrative meeting in Kilifi, 18-20 Sept 2006 19 Jul 2006

The Trust established its 'Centres in Clinical Tropical Medicine' in 1995 to generate the cadre of senior clinical scientists needed to strengthen Tropical Medicine in the new Century. Application for 'Centre Status' was a competitive process, with letters of invitation being sent to many Institutions of Higher Education in the UK. The same national competition was held again in 2000. Over the last 10-years we think that we have successfully (a) built a thriving Research programme in Malawi ('MLW'), (b) attracted high-quality clinical researchers into Clinical Tropical Medicine and (c) ensured their optimal output, through careful scientific and logistic support. The Appendix lists our Fellowships to date, and up to 5 of their major research publications. The Liverpool Centre has its closest overseas ties with the Trust's MLW Programme, but also manages Fellows in the Trust's Kenya and SE Asia Programmes. MLW is a strong North-South partnership between the Universities of Malawi and Liverpool (including the Liverpool School of Tropical Medicine). The present application is for core support to the WTTC, not for a specific scientific project. But it is important to appreciate that WTTC is the hub of research in clinical tropical medicine in Liverpool, and that the present application underpins many separate projects.

Amount: £3,820
Funder: The Wellcome Trust
Recipient: University of Liverpool

Value in People Award. 18 Jul 2007

Not available

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

Plague epidemiology and risk in the heterogeneous rural landscapes of Madagascar. 19 Mar 2007

The project will determine how plague risk in rural Madagascar is determined by the abundance and movement of its principal, and susceptible, reservoir host. It will integrate field studies, genetic analyses and epidemiological modelling to quantify patterns of rat abundance and movement and investigate their relative contribution to the transmission of vectors and plague. Within the endemic plague region, I will use data on spatial genetic structuring to compare and contrast the scale and frequency of historical dispersal by host, vectors and pathogen. At the local scale of a village and its surrounding area, I will investigate what factors influence patterns of rat abundance and movement, using field and molecular approaches. Analysis of genetic structuring of flea populations will reveal flea dispersal patterns. Molecular typing of archived plague samples, together with information on mutation rates and host movement, will be used to investigate transmission dynamics wit hin local outbreaks in humans. A spatial model will be developed, parameterised with field data and used to determine (1) the relative importance of host abundance and movement for local plague dynamics and (2) the efficacy of control strategies. Liaison with Malagasy authorities will ensure relevant findings inform plague control policy.

Amount: £485,942
Funder: The Wellcome Trust
Recipient: University of Liverpool

Investigation of store operated calcium entry in pancreatic acinar cells. 19 Jul 2006

An increase of the cytosolic Ca2+ concentration is a key signal in virtually every cell type, regulating a vast number of processes ranging from short term responses, such as contraction or exocytosis, to long term events like gene expression or cell division. Cytosolic Ca2+ signals can be generated by Ca2+ release from intracellular stores and by Ca2+ influx through the plasma membrane. In physiological conditions Ca2+ release from intracellular stores is transient. Ca2+ is cleared from the cytosol by uptake into organelles and by extrusion from the cell by Ca2+ exchangers and pumps. The loss of cellular calcium is compensated by Ca2+ influx from the extracellular solution.

Amount: £132,687
Funder: The Wellcome Trust
Recipient: University of Liverpool