- Total grants
- Total funders
- Total recipients
- Earliest award date
- 18 Apr 1991
- Latest award date
- 02 Apr 2019
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
The HIV pandemic continues to be the overwhelming health problem in southern Africa. In the Africa Centre Demographic Surveillance Area (ACDSA) HIV seroprevalence is 22% for all adults, and is over 50% in women 25-29 years. Half of all deaths are due to AIDS. During the coming five years, the Africa Centre will have as its major objectives: 1) Characterising the HIV epidemic and risk factors for infection; 2) Understanding how to better prevent and treat HIV and AIDS; and 3) Understanding the effects of the epidemic at the individual, household, and population level, including its effect on social structures. The Centre will use its Demographic Information System to track changes in the epidemiology of HIV; to determine behavioural and genetic risk factors for infection; and to develop models for projecting the future behaviour of the epidemic. The Centre will take part in international trials to test microbicides and vaccines for preventing HIV infection, and will design and propose a multi-component intervention for preventing HIV in adolescents. The Centre will support the ART rollout of the District Health Services, and will model ART delivery programs that use non-professional staff to deliver the majority of care. It will determine the effect of ART rollout on life-expectancy in the ACDSA, and assess how best to follow persons who are HIV-infected but don't yet need therapy; how to detect important clinical complications of therapy; and the importance of nutrition on response to therapy, and therapy on nutritional state. The Centre importantly will be able to determine factors associated with adherence to ART, and design interventions to improve adherence. The effect of the HIV epidemic on the functioning of households and individuals, including effects on employment and income, on development and education of children, and on health care utilisation, will be continuing themes of the Centre's research. The Centre will begin to study chronic non-infectious disease, with a focus on factors causing the metabolic syndrome and how to prevent it; and will start discussions to determine if a biobank should be established using ACDSA as a base. Lastly, the Centre will work to increase training opportunities for young South African scientists, especially those from previously disadvantaged backgrounds.
Congenic cell bank for pigmentary mutations 17 Oct 2005
The Wellcome Trust Functional Genomics Cell Bank holds a large collection of mammalian cell lines, especially mouse melanocyte and melanoblast lines carrying specific pigmentary mutations, and provides these to researchers as a service, together with advice on melanocyte culture. We request funds to continue this service for a second quinquennium. We will establish additional lines of mutant mouse and human melanocytes known to be of current research interest. We will also use cells from the collection ourselves, in research on two main areas. One is the mechanism of cell determination from pluripotent precursors, using the melanocyte lineage as a model. We will use our pluripotent neural crest-like cell lines, and existing and new melanocyte and melanoblast lines deficient in key transcription factors, especially the putative master controller Mitf. We will examine the dynamics of changes after induction of (exogenous) Mitf expression, and effects of different levels of the factor. Global mRNA and protein analyses by microarrays and DIGE will be followed by focussing on changes in candidate regulators, then building and testing of model(s) integrating available knowledge. The other area is that of the regulators and effectors involved in the synthesis of pheomelanin (red/yellow pigment), still very poorly understood.
The Newcastle Clinical Ageing Research Unit (CARU): a new facility for integrative and translational research on early assessment and treatment for older people. 11 May 2006
We will establish an innovative Clinical Ageing Research Unit (CARU) as part of the Newcastle Campus for Ageing and Health (CAH), which will focus on developing early assessment and intervention strategies targeted at age-associated degenerative conditions. Research on ageing and age-associated disease is a Department of Health priority. Newcastle is one of the world's leading centres for ageing research with our researchers attracting over £38m in awards over the last 8 years and more than £12.5m in the last year. CARU will be intimately linked with cutting-edge research on underpinning mechanisms of ageing, including physical and functional links with the newly constructed Magnetic Resonance Centre that comprises a world class MR physics team and is being directed by a clinician with wide experience of MR research. This will optimise focus on clinical research whilst harnessing cutting edge development of MR techniques. CARU will provide exceptional opportunities for translational studies. Demographic trends mean that age-related health problems command increasing clinical attention. For the majority of these health problems, age itself is the single biggest risk factor. It is therefore of key importance to understand why the aged cell or organ becomes more vulnerable to pathology and what can be done to intervene at early stages before the less tractable end-stage pathology has developed. CARU is needed to provide the necessary specialist clinical research infrastructure for the expanding major research hub of the Institute for Ageing and Health (IAH) at Newcastle General Hospital, including extensive research on dementia and brain ageing. The CAH already includes the Henry Wellcome Laboratory for Biogerontology Research, IAH Research Laboratories (with Newcastle Brain Tissue Resource and aged animal units), and the MR Centre. CARU will support research in three of the UKCRN research networks (dementia and neurodegenerative diseases, diabetes and stroke) and have close links with the Directors of the Stroke and DeNDRoN Research Network National Coordinating Centres (Ford, McKeith).
A new era of translational research in Birmingham: Expansion of our Clinical Research Facility. Director's Discretionary Fund. 11 May 2006
The Wellcome Trust Centre for Research in Clinical Tropical Medicine, University of Oxford, proposes to continue its role in coordinating and facilitating the large programme of research carried out by the Oxford Tropical Network. This programme aims to improve the prevention, diagnosis and management of important tropical diseases through a better understanding of their pathogenesis, pathophysiology, genetics and epidemiology and the development of new treatments and vaccines. The main areas of interest are the major infectious diseases causes of morbidity and mortality in the developing world; malaria, pneumococcal disease, tuberculosis, HIV associated opportunistic infections , melioidosis, typhoid, tetanus, rickettsial diseases, dengue and viral encephalitides, as well as emergent western diseases such as hypertension and type II diabetes mellitus, thalassaemias and non-infectious problems such as poisoning and envenomation. As in previous years related basic science research will be carried out in the Nuffield Department of Clinical Medicine, the University Department of Paediatrics, and the Institute of Molecular Medicine, in support of epidemiological and clinical investigations in the Oxford-linked Wellcome Trust Tropical Units in Thailand, Viet Nam and Kenya and other overseas investigators and collaborators. Close links will be developed with the department of Public Health. The main role of the Oxford Centre is to provide administrative and logistic support for the overseas units and to identify, recruit, encourage and support the training of outstanding young clinical scientists in Oxford and in its linked tropical units. Continuing support for the Oxford Centre is justified by the achievements of the Oxford Tropical Network which, over the past five years, has yielded more than 400 peer-reviewed publications which have been influential in changing health policy and medical practice, and has trained 22 young medical scientists.
This application requests part funding for real-time PCR and Luminex bead array equipment, to support several research groups who are focussing on the molecular pathogenesis of human disease utilising patient- and population-based approaches underpinned by proof of concept laboratory biomedical studies. The following research programmes will be supported: (1) Role of epithelial and endothelial barrier dysfunction in the pathogenesis of inflammatory bowel disease and the development of sepsis. (2) Inflammatory responses in the brain and their role in the pathology of stroke and Alzheimers disease. (3) Identification of genetic markers and cellular processes involved in micro-and macrovascular disease. (4) Identification of genetic risk factors in neurodegenerative disease. The primary goals common to all these programmes are: (i) understanding the molecular basis of disease pathogenesis, (ii) investigating how biomarkers can be used to inform the diagnosis and management of di sease and (ii) to identify new therapeutic targets. Understanding these complex pathologies at the molecular level depends increasingly on the ability to rapidly quantify multiple genes, proteins and other biomarkers at levels sensitive enough to allow translation into clinical settings. The requested equipment will provide such facilities and, greatly enhance not only existing programmes of research but also new and emerging areas.
University of Sheffield Centre for BioImaging 31 Oct 2005
We aim to establish a high-resolution light microscopy facility to enable researchers in the Departments of Biomedical Science (BMS) and Molecular Biology and Biotechnology (MBB) (both rated as 5* in the last RAE) at the University of Sheffield, to carry out direct visualisation of biological molecules, and their interactions, in their natural cellular, tissue or organismal environment. The principal applicants already have funding in place to pursue fundamental biological questions that require such sophisticated imaging but it is envisaged that this will be a multiuser facility available to many other scientists in BMS and MBB, which will be run on an equitable basis. Bringing the apparatus under one roof with a dedicated postdoctoral worker in place to manage the facility will greatly enhance productivity, facilitate the development and implementation of state-of-the-art technologies in light microscopy and provide access to such technologies to less experienced users. The bid includes requests for multi-photon, confocal and DeltaVision microscopes and the facility will also include a TIRF microscope (already purchased by BMS). This combination of microscopes will provide the necessary flexibility so that each user can visualise samples under optimum conditions. Given the rapid technological developments in this area, this facility will also promote the dissemination of information and ideas.
The further development of medical history in Ireland as an established discipline. The research focus of the project concentrates on aspects of medical marketplace in Ireland and is rooted in the expertise of the core staff. The main focus is an interrogation of medical practices and practitioners, formal and informal, in Ireland, with allied projects on child health and birth control and maternal health. They address the Wellcome Trust's priority of 'Medical Markets and Health Care Systems' and allow an exploration of the history of medicine in Ireland within the different cultural contexts, north and south of the island. Key goals: · The research prioritises output through publication. Each theme aims to produce one research monograph and articles. Other outputs include seminars, conferences, public lectures, etc. These will incorporate public outreach activities. · Research training (BA, MA, PhD and post-doctoral) of future medical historians to develop Irish medical history. · To raise the profile of the discipline in Ireland among academics, medical professionals and the public at large. · Future appointments in medical history, including a Wellcome Trust University Award at University of Ulster. · UCD and UU will work together as principal and co-equal partners to develop a joint research culture.
Identification and characterization of a susceptibility gene or genes for congenital heart disease and oesophageal atresia at human chromosome 17q21.3- q23.3. 12 Jul 2006
Congenital heart defects (CHD) are present in nearly 1% of all newborns and continue to be a significant cause of death in infancy. They may occur in isolation or in association with other birth defects, as with the 22q11 deletion syndrome, for example. Case reports from the human cytogenetics literature point to a susceptibility locus for CHD together with oesophageal atresia at human chromosome 17q21.3-q23.3. This evidence is supported by the finding that mice with a chromosomally engineered deletion within this region,6.8 Mb in size, have CHD, though not oesophageal atresia. The aim of the proposed research is to identify the susceptibility gene for congenital heart defect at human chromosome 17q21.3-q23.3 using further mouse chromosome engineering, BAC 'rescue' of a smaller nested deletion and then targeted mutagenesis of selected candidate genes. In parallel, DNA samples from patients with CHD and oesophageal atresia will be studied by array-based comparative genomic hybridization, with a view to refining the critical region for both of these defects. Subsidiary aims of the project are the identification of the gene responsible for oesophageal atresia at chromosome 17q21.3, and the identification of othersusceptibility loci for CHD and oesophageal atresia elsewhere in the human genome.
Unilateral cochlear implantation (CI) restores partial hearing to patients: they often understand speech, but only in quiet conditions, and have severe sound localization deficits. Normal listeners hear speech-in-noise and localize sounds better with two ears, utilizing interaural level differences (ILDs) and interaural time-delays (ITDs). For these reasons, bilateral CI has been trialled. Bilateral implantees show improved localization and ILD sensitivity, but moderate ITD thresholds, with highly variable results. Effects of auditory experience, age at hearing loss or deafness duration may account for this variability. We have developed an animal model of bilateral CI, with the aim of maximizing binaural benefits of CI in humans, whilst utilizing CI as a tool to study the development and plasticity of the neural mechanisms underlying binaural processing. Ferrets will be deafened, bilaterally implanted and chronically stimulated in infancy. Once they are mature, we will assess their ability to localize sound and to process binaural cues using behavioural and electrophysiological techniques that are currently in use in this laboratory. We will then examine the effects of age at hearing loss and duration of deafness on the development of these measures. Lastly, potential benefits of auditory training and an experimental processing strategy, designed to better-preserve ITD cues, will be assessed.
The role of mitochondria in the dysfunction of oligodendrocyte lineage cells: implications for the pathogenesis of multiple sclerosis. 06 Dec 2005
Objectives: To investigate the role of mitochondria in the dysfunction of oligodendrocyte lineage cells in multiple sclerosis (MS), I will determine the(1) presence of mitochondrial dysfunction at biochemical, protein and genetic levels in oligodendrocyte lineage cells in acute (pattern II and III), active and chronic MS lesions. (2) neuropathological features of inherited mitochondrial disorders with primary demyelination. (3) effects of mitochondrial DNA (mtDNA) abnormalities on the development, function and survival of oligodendrocyte lineage cells in vitro (MO3, HOG, Ntera2 and mouseES cells).Design: (1) Histochemistry and immunohistochemistry will be performed on post-mortem brain tissue from MS and mitochondrial disorders. (2)Molecular biology techniques (laser micro-dissection, real-time PCR and mtDNA sequencing) on dissected oligodendrocyte lineage cells from frozen MS tissue will be used to identify evidence of damaged mtDNA. (3) transmitochondrial hybrids containing inherited abnormal mtDNA and cell lines containing acquiredabnormal mtDNA (IFN-gamma and TNF induced) will be used in vitro to assess migration, proliferation, differentiation, myelination and survival using time-lapse microscopy, proliferation markers, electron microscopy for ultrastructure, immunocytochemistry for myelin proteins and apoptosis using flow cytometry.
This programme will investigate pathophysiological mechanisms of disordered information processing in dementia using the paradigm of complex sound. It will integrate complementary fMRI, structural MRI, and behavioural (psychoacoustic) measures in clinically, radiologically and genetically-defined populations with the most common cortical degenerative dementias, Alzheimer's disease and frontotemporal lobar degeneration, and in age-matched healthy controls. Mechanisms of elementary auditory pattern analysis will be probed using fMRI, and brain activation profiles will be correlated cross-sectionally and serially with psychoacoustic and other behavioural measures of complex sound processing and with structural MRI. By comparing structural with functional imaging data, and imaging data with behaviour, it will be possible to assess these complementary techniques in relation to one another and in combination. The correlation of complementary disease measures will determine how pathophysiology maps onto structural damage, whether regional brain dysfunction predicts the rate and distribution
Accurate assessment of multiple sclerosis pathology using high-field magnetic resonance and quantitative histology. 30 Aug 2006
Using quantitative high-field magnetic resonance (MR) applied to post mortem multiple sclerosis (MS) brain tissue this project aims to establish accurate non-invasive measures for three fundamental pathological features of MS that are potentially of importance for the development of disability and recovery of clinical symptoms in people with this condition: (i) remyelination, (ii) lesions in the grey matter and (iii) gliosis. Furthermore we will explore the possible link between Glutamate as assessed by high-field MR spectroscopy (MRS) and quantitative histological measures (glutaminase activity, axonal count) in MS. Results from this project will have significant impact for the optimisation of MR studies in patients with MS in vivo. It will also facilitate the understanding of the mechanisms that cause disability in MS. T2-weighted (T2W) MR imaging (MRI) of the brain and spinal cord at a field strength of 1.5Tesla is sensitive in the detection of MS white matter (WM) lesions and thereby useful for diagnosis. However, T2W MRI is not specific for the individual pathological substrates of MS, e.g. demyelination, remyelination, axonal loss, gliosis, inflammation. Quantitative MR (qMR) techniques have the potential to be more specific for certain pathological components in MS brain and may therefore improve the monitoring of patients in natural history studies and treatment trials. In order to establish the specificity of qMR measurements, research into the pathological substrates of qMR measures is much needed. Several studies using standard magnetic field strengths have explored the relationship between signal changes detected on MRI and histopathological findings by investigating brain or spinal cord specimens of MS patients. However, the assessment by MR techniques of important aspects of MS pathology, such as lesions in the grey matter or the detailed investigation of WM lesions for signs of remyelination is limited, mainly by the low image resolution at 1.5T.
In humans, the main pathway over which voluntary motor signals are carried from the brain to the spinal cord is the corticospinal tract. Insults to the "upper motor neurons" that constitute this tract can result in a clinical picture of spastic paralysis. The hereditary spastic paraplegias (HSPs) are single gene disorders in which the axons of the corticospinal tract show progressive, length-dependant, distal degeneration after initially normal development. Functional characterisation of the responsible genes is therefore likely to reveal cellular processes that are important in long tract axonal maintenance and perhaps of relevance to common neurological diseases. More than 20 HSP loci exist and 9 of the responsible genes have been identified. Until recently, there was no discernable common underlying cellular pathological mechanism for groups of HSP conditions. However, several lines of evidence now point to defects in intracellular traffic as being the underlying cause of several different genetic types of HSP. This evidence includes the known functional role of KIF5A, a gene that I have identified as being involved in HSP, and preliminary experimental data that I have generated that implicate spastin and spartin in intracellular membrane traffic events and suggest a possible functional relationship between them. This proposal focuses on spastin and spartin and its aims are to test the hypothesis that the two proteins are functionally related components of an intracellular membrane traffic pathway that is disrupted when they are mutated. I will test this hypothesis by: a) examining whether the tissue and sub-cellular expression patterns of spastin and spartin overlap, b) further investigating preliminary experimental data that suggest physical interactions between spastin, spartin, and 2 other proteins, CHMP1.5 and gp25L2, that I identified in a yeast two-hybrid screen using spastin as bait, and which are known to be involved in intracellular membrane traffic events, c) examining in cultured mammalian cells whether knocking down expression of spastin or spartin, controlled expression of wild-type spastin or spartin, or controlled expression of mutant forms of spastin or spartin, results in any morphological or functional abnormality of intracellular membrane traffic pathways or components.
The role of cardiac myocyte apoptosis in the transition from compensated hypertrophy to dilated cardiomyopathy. 03 Apr 2006
Cardiac myocytes undergo hypertrophy in response to haemodynamic overload, an adaptation that initially maintains systolic cardiac function. Over time, however, the hypertrophied ventricle often becomes thin-walled, dilated and hypocontractile. Mechanisms that mediate this transition are poorly understood but work over the past 5 years has documented increased - yet quite low - levels of cardiac myocyte apoptosis in human hearts with dilated cardiomyopathy (0.1-0.3% vs 0.001-0.002% in controls). Moreover, Kitsis et al have demonstrated in transgenic mouse models that low levels of cardiac myocyte apoptosis (0.08-0.023%) are sufficient to generate dilated cardiomyopathy. In prior work, I investigated the role of heme oxygenase-1 in angiotensin II-induced hypertrophy and apoptosis using cultured neonatal cardiac myocytes. I now wish to continue to study the relationship between cardiac myocyte hypertrophy and apoptosis in an in vivo setting. I propose to test the importance of cardiac myocyte apoptosis in the development of overload-induced compensatory hypertrophy and the transition to cardiomyopathy in vivo. I will compare the molecular, cellular, structural and phyhsiological responses of wild type mice subjected to transthoracic aortic constriction with those of two transgenic models developed in Dr. Kitsis' lab in which cardiac myocyte apoptosis has been potently suppressed. These studies will test whether cardiac myocyte apoptosis plays a causal role in overload-induced hypertrophy and the transition to cardiomyopathy, an important clinical scenario in which the role of cardiac myocyte apoptosis is yet to be defined. Third generation pan-caspase pseudosubstrate inhibitors are currently in Phase I clinical development (Idun Pharm.) and Dr. Kitsis has successfully used one of these to attenuate ventricular dysfunction and dilatation in 2 different genetic cardiomyopathy models. I plan to also perform aortic constriction on wild-type mice and test the effect of this pharmacological agent on the trasition from hypertrophy to cardiomyopathy. Mosst of this work will be carried out in Dr. Kitsis' lab (Albert Einstein College of Medicine, NY) for the first 2½ years of this 3-year fellowship. All animal procedures will be done in Dr. Kitsis' lab and I will continue experiments with animal tissue collected from the aim 3 of the project (Caspase Inhibitor) in Cambridge.
Identification and functional characterisation of a rheumatoid arthritis susceptibility gene mapping to chromosome 17q24. 03 Apr 2006
Background: Based on collaboration with the Karolinska Institute, Sweden, linkage to regions syntenic to those identified in animal models of inflammatory arthritis (IA) have been investigated in rheumatoid arthritis (RA) affected sibling pair (ASP) families previously. Linkage and association to 17q24, syntenic to a region linked to 2 rate models of IA, has been detected and replicated in independent data sets. Objectives: To identify and characterise putative RA disease gene mapping to the region of linkage on chromosome 17q24. Design: Fine mapping studies will be performed using SNP markers with a density of 1 marker per 50Kb across the 5.5Mb region of linkage. Association will be investigated in test and replication data sets of RA affected sibling pair cases and controls in order to define a minimal region of association. Allele and haplotype frequencies will be compared between cases and controls and haplotype analysis will be used to determine the pattern of LD across the region. Expression patterns for genes mapping to an associated block of LD will be examined to determine the RA disease gene mapping to chromosome 17. Systematic examination to determine all SNPs mapping to the gene will be undertaken and the likely functional SNP(s) identified according to knowledge about their position within the gene. Polymorphisms within the disease gene wil be investigated with regard to function to identify the disease variant/s and their role in the aetiology of RA. The functional studies will depend on the disease gene identified and the position of likely variants within the gene but may include techniques such as reporter gene, gel shift and protein binding assays. Material: DNA is available from 400 RA ASP and 500 single-case families, over 1,000 sporadic RA cases and controls. Outcome: Identification and functional characterisation of RA susceptibility genes.
Human T lymphocyte trafficking in large airways and alveoli: the role of lymphocyte adhesion, the epithelial cytoskeleton and the Rho family of GTPases. 05 Jun 2006
In healthy individuals there is a continual flux of leukocytes to and from the alveoli and large airways and this constitutive trafficking is increased in response to infectious and allergenic stimuli. Although much is known of leukocyte adhesion to the vascular endothelium and transendothelial migration. By comparison, little is known of leukocyte interactions with the basal surface of the epithelium or of subsequent passage across the epithelial barrier. Epithelial integrity is maintained by the apically placed tight junction together with the more basally placed adherens junction which, linked via the cytoskeleton, together form the functional apical junction complex (AJC). It is across the AJC that transmigrating leukocytres must pass. Data suggest that leukocytes can interact with epithelial cells to influence the AJC but it is not clear which signalling pathways are involved; although there appears to be a requirement for integrin-mediated adhesion of the leukocyte to the epithelium. Accumulating evidence suggests that the Rho-family of small GTPases (Rho-GTPases) can alter AJC permeability both indirectly, via their known effects on the actin cytoskeleton, and directly via effects on epithelial junctional molecules. In addition, there is evidence that Rho acts downstream of the integrin ligand intercellular adhesion molecule (ICAM)-1 on endothelial cells. We propose that adherent leukocytes interact with epithelial adhesion molecules to initiate downstream signalling events that involve the Rho-GTPases and result in alterations in the actin cytoskeleton and the AJC to facilitate and regulate leukocyte passage. This project will combine the candidate's previous experience in integrin-mediated adhesion, T cell biology and the respiratory epithelium with the expertise of the proposed host laboratory in signalling, cytoskeletal rearrangements and the Rho family of GTPases to address a fundamental question in cellular immunobiology.
The role of redox potential regulation in the molecular pathogenesis of congenital adrenal hyperplasia. 12 Jul 2006
Congenital adrenal hyperplasia (CAH) is the commonest inborn metabolic diseaseand clinical consequences include adrenal insufficiency, genital ambiguity, metabolic syndrome and infertility. Mutations in the electron donor enzyme P450 oxidoreductase (POR) were recently shown to cause a novel form of CAH. Importantly, POR mutations illustrate the differential impact of redox potential regulation on the function of P450 enzymes crucially involved in steroidogenesis and requiring electron transfer from POR. Current results indicate that this CAH variant may be the second most common after 21-hydroxylase deficiency. We will perform genetic analysis in a large CAH cohort, also analysing the impact of genetic variations in the POR gene on thephenotypic expression of CAH caused by 21-hdyroxylase deficiency. We will employ functional in vitro assays to investigate the impact of POR on steroidogenesis in further detail, specifically aiming to explore the pathogenesis of the multiple bone malformations that are a unique feature in this CAH variant. Many of the affected girls also suffer from treatment resistant polycystic ovaries and we will investigate underlying mechanisms by generating a gonad-specific POR deletion in a mouse model. This could provide invaluable insights into polycystic ovary syndrome in general, a condition affecting 10% of the female population.