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Funders:
The Wellcome Trust

Results

Elucidating the function and requirement of insulator protein CTCF in transcriptional regulation in the mouse. 17 Jan 2014

Regions of open chromatin referred to as DNaseI hypersensitive sites co-localise in mammals with putative cis-regulatory regions that include promoters, enhancers and CTCF binding sites. Of these, the function of CTCF binding sites is the least well understood, although roles in chromosome folding, partitioning and transcriptional regulation have been identified. Our aim is to identify the function of CTCF binding sites in the regulation ofgene transcription and the establishment of the local chromatin architecture. To achieve this, we will explore two methods to study the effects of differential CTCF binding on gene regulation; the disruption of CTCF binding by TALEN-mediated mutagenesis and the study of differential CTCF binding events between inbred mouse strains. The effects on local chromatin and transcription will be assessed by chromosome conformation capture techniques, chromatin immunoprecipitation and expression analysis of local genes. In support of these strategies, we will characterise the binding of several knownCTCF binding partners to sub-classify CTCF binding sites. Thus, we aim to use a combination of functional studies and genome-wide approaches to elucidate the role of CTCF binding sites in gene transcription and chromatin organisation.

Amount: £64,140
Funder: The Wellcome Trust
Recipient: University of Oxford

Trauma, gender and the treatment of epilepsy 1870-1948. 13 May 2014

This project will examine the growing understanding of the causes of epilepsy during the period 1868-1948. It will examine the patient experience at the Crichton Royal Asylum, Scotland, from its emergence as a private asylum to the eve of National Health Service control. This project will utilize both asylum records and the records of the David Lewis Epileptic Colony, Ewell Epileptic Colony and the Charlfont Colony before 1948. Gender and class will be analysed to differentiate patient experienc e within the asylum and open communities, in particular with regard to the medical perception of trauma and madness. The project aims to develop an understanding of personal trauma in civilian patients and the medical understanding of trauma as a cause of epileptic seizures. In particular, it will consider the relationship between trauma and the physical manifestation of stress. The influence of gender on this understanding of trauma will underline the projects discussion of both the medical and public perception of epilepsy in this period. Regional differences will be explored to question the influence of medical specialists on the care of patients outside England and, within England, outside the jurisdiction of the Institute of Neurology.

Amount: £81,037
Funder: The Wellcome Trust
Recipient: Glasgow Caledonian University

Biomedicalization of Death: The Social Impact of Life Support Technology in Bangladesh. 14 May 2014

This project aims to understand the biomedicalization (Clarke et al 2003) of death in the cultural context of contemporary Bangladesh. This study will carry out by ethnographic research to explore biomedical and social practices in four hospitals in Chittagong and Dharka. Recent developments in biotechnology have resulted in the production of new forms of life and death. Life-prolonging technologies encompass the possibility to modify elementary processes of life leading to redefinitions of he alth, illness, and death and also have made the determination and definition of death difficult and controversial. A seemingly insoluble tension exists in relation to the life prolonging technologys relationship to the dying patients family members. This research will explore how family members manage the end-of-life decision of close kin who are on life support in hospitals and how do class, gender, religion and morality impact on this decision-making? This research also focuses on how econom ic status affects access to different levels of technological intervention and therefore shapes different experiences of death.

Amount: £113,108
Funder: The Wellcome Trust
Recipient: Lancaster University

Growing Well: Dirt, Health and Domestic Horticulture in Britain, 1900-1970. 13 May 2014

My project examines tensions between cultural practices of domestic hygiene and the organic movement's view of healthy soil (i.e. dirt) as fundamental to human health. I will detect subtle changes in a broad range of representations of domestic food growth, purchase and preparation between 1900 and 1970. I will look at whether vegetables were portrayed as dirty, clean, wholesome or perishable, and at who was seen as responsible for their production, purchase or preparation. Paternalist commercia l organisations will be a major focus as these both encouraged domestic horticulture and presented particular images of products as wholesome and/or hygienic. My research will assess the impact of the take up of mains drainage on cultural attitudes to domestic soil husbandry, and to the organic movement, for whom the return of wastes to the soil was central. My thesis will argue that the construction of a notion of hygienic domesticity in part explains the marginalisation of the organic movement and the decline in domestic vegetable cultivation after 1945. My key goals, alongside my thesis, are to produce two articles, for Medical History and Social History of Medicine, and a number of public engagement activities.

Amount: £92,105
Funder: The Wellcome Trust
Recipient: University of Warwick

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

The Plurality of Prevention: Medical Superintendents and the Practices of Compulsory Sterilisation in Californian State Institutions, 1909-1960. 13 May 2014

This project will examine institutional records related to the distinct practices of compulsory sterilisation in Californian State hospitals between 1909-1960. By developing an awareness of the institutional organisation of compulsory sterilisation in California, this project will generate a nuanced understanding of how state policy was interpreted and implemented differently by medical superintendents. Highlighting these clinical practices will assist in evaluating whether superintendents t ruly believed in the law's therapeutic mandate. Furthermore, California's impact on British eugenicists will be highlighted. This project will prompt a significant scholarly re-evaluation of compulsory sterilisation in the North American and international context. The aims of this project are therefore: 1. To understand how state medical authorities understood and implemented the practice of compulsory sterilisation in the psychiatric institutions under their control. 2. To understand th e extent to which superintendents believed that sterilisation benefited the patients 3. To examine the overlooked role of hospital superintendents in the practice of compulsory sterilisation in Californian prisons. 4. To highlight the knowledge exchange between Californian superintendents and British eugenicists and physicians. 5. To advance a new methodological explanation for the decline of compulsory sterilisations in California during the 1950s and thereafter.

Amount: £88,016
Funder: The Wellcome Trust
Recipient: Oxford Brookes University

Birth, Marriage and Sex in Eighteenth Century Wales. 13 May 2014

My proposed research will examine the social, cultural and medical history of childbirth in eighteenth-century Wales. My focus will be on the experience of reproduction and childbirth for unmarried mothers and on perinatal mortality, which I believe can be linked to a diverse typology of illegitimacies that carried varying levels of acceptability which influenced perinatal survival rates. My key goals will include investigation of the following: - What forms of courtship, cohabitation and p re-marital conjugal union were acceptable within communities? - Did rates of infant mortality vary for illegitimate births resulting from both acceptable and unacceptable sexual unions? - What childbirth customs and practices existed in eighteenth-century Wales and were they different for unmarried parturient women? - To what extent were there regional variations between in childbirth customs and practices, and in the role of midwives in England and Wales? - Did the largely rural nature of Welsh settlements affect accessibility to the services of a midwife and did this affect mortality rates? - What impact did medical advances in childbirth in the eighteenth century have on Wales?

Amount: £84,588
Funder: The Wellcome Trust
Recipient: University of Exeter

Wellcome Trust PhD Programme for Clinicians at the University of Cambridge. 15 Sep 2014

Parkinson's disease (PO) is common, affecting between 2-3% of people over the age of 65 with over half of patients developing dementia within ten years. This causes a decline in function and often leads to nursing home care. The involvement of the immune system in PO has been well described but it remains unclear whether this is an epiphenomenon. I hypothesise that the immune response to PO associated pathology contributes to disease progression, increasing the risk of dementia. My PhD will look at the role played by 8 lymphocytes as most research has focused on T lymphocytes or the innate immune system. I aim to characterise the 8 lymphocyte response associated with alpha synuclein pathology in both the mouse and human brain and to identify whether there are perturbations in the systemic 8 cell compartment in patients at high risk of dementia versus those who have a low risk. Using two mouse models of PO I will manipulate B cells to see whether 8cell depletion, antibody depletion or manipulation of 8 cell regulatory activity alters disease course thereby confirming causation in an animal model.

Amount: £216,904
Funder: The Wellcome Trust
Recipient: University of Cambridge

Wellcome Trust PhD Programme for Clinicians at the University of Cambridge. 15 Sep 2014

Traumatic axonal injury of the brain (TAlB) is a common and devastating type of acquired brain injury. The injury is mediated through direct axonal damage and a cascade of secondary injury factors including local inflammatory response and energy failure. Understanding the response of axons is important in order to try and salvage injured axons from cell death and prevent progressive neurodegeneration. Hypotheses to be tested: - An in vitro primary culture/organotypic injury model can accurately represent the structural and functional changes found in human TAIB. - TAIB impairs Axonal transport, resulting in o axonal varicosities o failure to deliver axon survival factors resulting in Wallerian degeneration o aberrant protein expression - TAIB induced a proinflammatory cascade of signalling that o Contributes to axonal transport defects o mediates persistent neurodegeneration - Altering the inflammatory/microglial response can o promote neuronal survival and salvage injured neurons o mitigate varicosity formation o terminate aberrant protein expression and long-term neurodegeneration - TAlB triggers a progressive neurodegenerative process I will use stretch models of injury and/or addition of pro-inflammatory cytokines and cytokine blockade in variety of culture subtypes, including dispersed cortical cultures, organotypic slices and cortical explants. I will examine live-iimaging markers of transport in various injury states.

Amount: £223,710
Funder: The Wellcome Trust
Recipient: University of Cambridge

Wellcome Trust PhD Programme for Clinicians at the University of Cambridge. 15 Sep 2014

CTCF is a DNA-binding protein that regulates enhancer-promoter interactions and defines transcriptional and chromatin domains. CTCF-binding elements and the location of its chromatin binding sites are much more highly conserved across species than other transcription factors, supporting an integral role of CTCF in genomic stability. Indeed, CTCF has been implicated as a tumour supressor gene: Ctcf haploinsufficient mice develop multiple spontaneous tumours, and CTCF mutations have been identified in human malignancies.My study will investigate how altering the genomic concentration of a major chromatin organising factor impacts genome organisation, stability, and unltimately cancer formation. To accomplish this we will analyse chemically induced tumours in a genetically engineered mouse model using functional genomics and proteomics.In aim 1 we will explore which tumour suppressors and oncogenes are near CTCF binding sites and are sensitive to CTCF depletion. In aim 2 we will explore which chromatin organisation machineries are directly dependant on proper CTCF expression by whole proteome analysis. In aim 3 we will use a chemical carcinogen N-nitrosodiethylamine to examine the effect of CTCF loss on hepatocarcenogenisis. Together my Aims will help reveal the mechanisms by which CTCF controls the genome organisation required for tissue homeostatsis and which molecular players facilitate carcinogenisis.

Amount: £211,204
Funder: The Wellcome Trust
Recipient: University of Cambridge

Biophysical and biochemical properties of heterotrimeric phosphofructokinase complexes 15 Sep 2014

Regulation of phosphofructokinase is integral to the control of glycolytic flux and glycolytic biosynthesis.In humans, phosphofructokni ase mutations are associated with neurological dysfunction (Tarui's disease) and control of glycolysis is thought to be important for synaptic development and function. A greater understanding how phosphofructokinase is regulated will provide new insights into controlof glycolysis. Biological modulation of phosphofructokinase activity is achieved by multiple methods,although the precise mechanisms remain poorly characterised.Mammals have three isofomns (M,L, and P) of phosphofructokinase, which are postulated to form heteromeric structures with each other and with other enzymes as glycolytic complexes (metabolons). This project will explore the functional consequences of heteromeric complexes of phosphofructokinase Human phosphofructokinase isoforms will beinvestigated as follows: - Phylogenet c analysis of mammalian phosphofructokinases - Biophysicalanalysis of human phosphofructokinase - Human enzyme kinetics and the effects ofinhibitors and activators - Construction of structure-activity relationships for heteromerlc and homomeric complexes - lsoform localisation within different tissue/cell types in humans and mice

Amount: £217,482
Funder: The Wellcome Trust
Recipient: University of Edinburgh

The role of rumination in post-natal depression and its impact on sensitivity to infant cues. 29 Aug 2014

Postnatal depression (PND) is a major public health issue that confers risk for a range of negative effects on child development. Many of these effects are mediated by disturbances in mother-infant interactions. There is therefore a need to develop interventions that effectively target these interactions. Recent research highlights the importance of maternal cognitive processes, particularly rumination, in PND. Rumination comprises persistent negative thoughts and narrowed focus of attention, which impairs the ability to attend and respond to the outside world. It therefore provides a possible mechanism through which PND impairs maternal responsivity to the infant. The proposed research will examine mechanisms through which rumination in PND affects maternal responsivity. The specific goals are to establish the ways in which rumination affects perception of infant facial and vocal cues and to test whether cognitive training procedures improve responsivity to these infant cues. The project will also elucidate whether any improvements in maternal responsivity to these cues in laboratory tasks generalise to improvements in mother-infant interactions. Finally, neuroimaging will be used to examine neural mechanisms of infant facial cue processing before and after induced rumination, in non-depressed adults.

Amount: £205,573
Funder: The Wellcome Trust
Recipient: University of Oxford

Risk factors for and spatio-temporal distribution of acute encephalitis syndrome in Nepal 15 Sep 2014

Acute Encephalitis Syndrome (AES) causes high rates of morbidity and mortality in Nepal, particularly in children. Despite the introduction of a vaccine against Japanese encephalitis virus (JEV) (a major cause of AES), numbers remain high, and there are many cases of AES where the cause is unknown. The majority of these are in the low-altitude, densely irrigated, southern Terai region and coincide with the wet season. This suggests that many cases may be due to vector-borne pathogens. The primary goal of the study is a) to identify the environmental, socio-demographic and behavioural risk factors associated with known and unknown causes of AES using a case-control study and b) to assess the extent to which these factors explain the observed spatio-temporal distribution of AES. This will improve knowledge of the epidemiology of AES, provide guidance towards the cause, and help disease control methods. Secondary goals are: 1. To estimate and map the residual, unexplained spatio-temporal variation of AES and to produce a model which aims to estimate the population-based risk of AES. 2. To analyse the contact patterns and daily activities of healthy participants living in districts of high AES incidence, and produce models of exposure to risk factors associated with vector-borne diseases. This will be an exploratory aim.

Amount: £332,360
Funder: The Wellcome Trust
Recipient: University of Liverpool

Emergency care re-attendance for acute childhood asthma in a low-resource setting: The Childhood Asthma Re-attendance Assessment (CARA) Study 10 Feb 2014

Asthma is the most common chronic disease in children. Its prevalence in LatinAmerica is now as high as in traditionally high prevalence countries and is still rising. Asthma exacerbations are common, cause great anxiety in patientsand are associated with potential severe complications, risk of death, loss oflung function, and high direct and indirect costs. A tool to enable cliniciansidentify asthmatic children at a greater risk and help patients understand their risk of suffering acute exacerbations is lacking. Such a tool could helpoptimise treatment and address modifiable risk factors, preventing future asthma attacks. Research question: What factors are associated with emergency care re-attendance for acute asthma exacerbations in children in the city of Esmeraldas, Ecuador? A cohort of children treated for an asthma exacerbation at the emergency department will be followed-up to study factors (demographics, history, symptoms and knowledge, comorbidities, environmental exposures) and biomarkers(blood eosinophilia, atopy, nasal eosinophilia, exhaled nitric oxide and lung function) associated with the time to a subsequent asthma exacerbation requiring emergency re-attendance during the following 6 months following. We will then combine these factors into a risk score and evaluate its practicality and applicability through a qualitative study involving patients and health-care workers.

Amount: £359,019
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Understanding the Pharmacokinetics of Antiretroviral Drugs in Breastfeeding Mother-Infant Pairs. 18 Jun 2014

Despite evidence that perinatal use of antiretroviral therapy (ART) can reduce the rates of mother to child transmission (MTCT) of HIV to less than 1%, approximately 430 000 children are infected annually. Consequently, WHO recommends commencing pregnant HIV+ women on lifelong ART irrespective of CD4 count or clinical stage. Whilst benefits are likely, this strategy carries several potential risks; increasingly, infants will be exposed to ART in utero and through breastmilk (BM). Several recent studies highlight both toxicities and the risk of multi-class drug resistance should the PMTCT fail. My aim is to characterise ARV accumulation in BM, relative infant dosing and systemic absorption following feeding. Sparse pharmacokinetic sampling from postpartum women receiving ARVs in Kampala will evaluate covariates (eg gestational age, birth weight, nutritional status, pharmacogenetics, maternal CD4) of infant ARV exposure. Clinical outcome measures will include HIV viral load in mothe r, BM and infant, drug safety, and vertical transmission. A population pharmacokinetic (and pharmacodynamic) model will characterise ARV exposure and efficacy in mother-infant pairs, and simulate outcomes with alternative dosing regimens and combinations. I have developed novel dried blood and dried BM spot methodology for some first line ARVs in support of this Fellowship.

Amount: £423,408
Funder: The Wellcome Trust
Recipient: University of Liverpool

Does enhanced PI3K signalling render APDS patients susceptible to infections by interfering with B cell development and activation?. 18 Feb 2014

Aberrant B cell activity can initiate or aggravate both immunodeficiencies and autoimmunity, and lead to lymphoproliferative disorders. PI3delta (phosphoinositide 3-kinase) is key in the signaling pathways regulating many immune cells, including B and T cells. We have identified patients with a dominant mutation in PI3delta (phosphoinositide 3-kinase ) catalytic subunit, a novel primary antibody immunodeficiency accompanied in some cases by lymphoproliferation. The basis for the phenotype is unknown. We speculate that overactive PI3Kdelta impairs B cell functions downstream of AID (activation induced cytidine deaminase), with failure in the production of protective high affinity class-switched antibodies and promoting cell division. We will investigate patients and mouse models harboring the activating mutation in PI3Kdelta , with emphasis on the effect on B cell functions (cell autonomous and as a result of T regulation) monitoring PI3K activity and expression and function of down stream targets, eg AKT, FOXO1, BLIMP1 and AID. We will test selective PI3Kdelta inhibitors to modulate PI3Kdelta activity and its functional consequences in the context of the activating mutation. We expect that the B cell dysfunction will be reversed by administration of the PI3Kdelta inhibitor in mouse models, and eventually in patients.

Amount: £363,305
Funder: The Wellcome Trust
Recipient: University of Cambridge

Poxvirus immune evasion strategies 08 Jul 2014

The objectives of this research are to understand how vaccinia virus, the prototypical poxvirus, suppresses the host innate immune response to infection, and how this impacts on virus virulence and the adaptive immune response that follows. This investigation will provide fundamental information about the host-pathogen interactions, how the innate immune response functions and influences the adaptive response, how the innate immune system can be inhibited, and how this information can be used to develop more immunogenic and safer poxvirus-based vaccines. It is also a goal to obtain co-crystal structures of the vaccinia virus proteins with their cellular binding partners to understand in molecular detail how inhibition of the innate immune system is mediated and in the long term to use this information to develop small molecule inhibitors of innate immunity that will have anti-inflammatory therapeutic value.

Amount: £2,216,660
Funder: The Wellcome Trust
Recipient: University of Cambridge

Coated vesicle adaptors. 29 Aug 2014

Adaptors select cargo for inclusion into different types of coated transport vesicles. The best characterised of the adaptors are the AP-1 and AP-2 complexes, which are associated with clathrin-coated vesicles (CCVs) budding from intracellular membranes and from the plasma membrane respectively. We plan to look for new cargo sorting signals using libraries of random cytoplasmic tails, and for new sorting machinery using a combination of CCV proteomics and genome-wide siRNA library screening. In teractions between sorting signals and candidate adaptors will be investigated both structurally (in collaboration with David Owen) and functionally, using a number of novel assays such as CCV profiling and rapid inactivation of CCV machinery by rerouting to mitochondria. Questions we will address include how the GGA pathway interfaces with the AP-1 pathway, how SNAREs are sorted into CCVs, whether GGA-mediated trafficking contributes to the pathology of Alzheimer's disease, and how HIV-1 Nef hi jacks adaptors to down regulate MHC Class I and CD4 from the surface of virally infected cells. E

Amount: £25,047
Funder: The Wellcome Trust
Recipient: University of Cambridge

Genetic, neurological and cognitive determinants of success and failure in learning a first language. 08 Jul 2014

Overarching question: What are the origins and functional significance of cerebral lateralization for language? Subsidiary questions: Can lateralization for different aspects of language be dissociated? How does atypical cerebral lateralization relate to language impairment? Is cerebral lateralization significantly heritable?

Amount: £305,883
Funder: The Wellcome Trust
Recipient: University of Oxford

Molecular mechanisms controlling polarised secretion at the immunological synapse. 01 Apr 2014

The aim of my research is to understand the molecular mechanisms that govern polarized secretion at the immunological synapse. We will use the CTL model with a clear trigger (TCR) and end-point (target cell death) to identify and characterize proteins that play a role in polarization and secretion as the immunological synapse is formed. Our specific aims over the next 5 years will be to (i) Map the order of events leading to secretion at the immunological synapse using rapid microscopy to compare the sequence of events leading to secretion in wild-type versus mutant CTL. (ii) Identify novel mechanisms contributing to polarised secretion in CTL by identifying genes up-regulated by Hh signaling that facilitate centrosome polarization; analyzing CTL derived from ciliary mutations that disrupt Hh signalling, gene-deletion mice from the Sanger screen and using proteomics to identify interactions with known proteins. (iii) Determine whether the lysosome itself plays a role in controlling polarization and secretion at the immunological synapse by asking whether TFEB regulates gene expression of proteins required for CTL secretion, and whether localized release of calcium from lysosomes via TPC1 and TPC2 controls any of the steps leading to polarized secretion from CTL.

Amount: £3,479,056
Funder: The Wellcome Trust
Recipient: University of Cambridge