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Results

TwinsUK Genetic Epidemiology Resource. 16 May 2006

This project aims to build on the existing TwinsUK resource. The currently held Wellcome FGI has funded development of the twin resource and the creation of a website and open access by researchers to limited twin data. We plan to ensure that the resource is investigated as thoroughly as possible, answering specific questions in a variety of fields, using well-designed studies in a cost-effective manner. In addition to maintaining and studying the existing phenotypes we plan: - Collection of new and longitudinal phenotypes eg. Adipose tissue, eye data, inflammatory markers - Linkage Study and statistical analysis on 2,500 pairs - Maintenance and consolidation of twin resource - Extending the use of the database and website development Key goals include: 1.Maintenance and consolidation of the twin resource by ensuring that the biological samples and phenotype databases are safely stored and available for widespread use; to retain motivation of the cohort through regular contact. 2. Make greater use of the resource by strengthening current relationships and forging new links with scientific collaborators and providing controlled access to the full genotypic information and selected phenotypes via the internet. 3. Extend the scientific utility of the resource by collecting new questionnaire data and biological samples.

Amount: £1,063,464
Funder: The Wellcome Trust
Recipient: King's College London

The X11 adaptor proteins and Alzheimer's disease. 27 Feb 2006

Work from our and a number of other laboratories has demonstrated that X11a an d X11b inhibit APP processing and Ab production. However, the molecular mechan isms that underlie this effect are not known. This project is to gain insight into these mechanisms. Release of Ab from APP involves proteases termed secret ases and one key goal of this project is to determine whether theX11s influenc e secretase function. A second key goal is to determine whether X11 inhibition of Ab production involves altered trafficking of APP and/or APPsecretases. Fi nally, we have found that the X11s are involved in neuronal copper metabolism and that one of the secretases (BACE1) is a copper binding protein. Disruption to copper homeostasis is believed to contribute to Alzheimer's disease. The f inal goal is to understand further how copper is delivered to BACE1 and whethe r it influences BACE1 function and Ab production.

Amount: £918,022
Funder: The Wellcome Trust
Recipient: King's College London

Depression, disability and socio-economic position among older adults 'Left behind' by out-migration: a multilevel study in Kanchanaburi Province, Thailand. 01 Nov 2005

It is suggested that the high level of out-migration of young adults from rural areas in many low-income countries may have negative impacts for older adults (OA). These may include loss of social, instrumental and economic support role for OA which may lead to poor health and social outcomes. If contrast, if migration is effective in diversifying family risks, it should benefit both migrant and non-migrant family members. It is not known whether out-migration of youth is associated with loss of support for OA, or an increased risk of depression or disability. The goals of this study are: 1) To use a historical cohort study to assess the extent to which the risk of depression, disability and low socio-economic position in OA is associated with previous out-migration of one or more of their co-resident children 2) To establish a population cohort of OA to examine the 12-month onset and maintenance of depression and disability, and the 12-month change in socio-economic position, in relation to 'left behind' status and social support 3) To explore any influence of contextual factors on the risk of depression and disability.Kanchanaburi province provides an ideal setting, given a high level of out-migration of youth from family households, and the systematic collection of longitudinal multilevel data between 1999 and 2004 from a representative sample of households as part of the Kanchanaburi Demographic Surveillance Survey.

Amount: £119,367
Funder: The Wellcome Trust
Recipient: King's College London

The role of retinoic acid in the spatiotemporal patterning of dorsal embryonic hindbrain. 04 Jul 2006

We will investigate how retinoic acid influences the development of late-born dorsal structures in the hindbrain. These comprise both the cerebellum and the precerebellar and noradrenergic neurons of the hindbrain. From preliminary evidence we believe retinoic acid plays a role in both the induction and maintenance of these vital nuclei. To test this hypothesis, we have devised a comprehensive programme of research utilizing avian and mammalian models to accomplish four aims. We will 1) fully ch aracterize the expression of retinoic acid pathway members in the late hindbrain. Using both molecular markers and the analysis of neuronal migration and projections, we will then test the effects of 2) blocking retinoic acid receptors through overexpression of dominant negative constructs (chick) or targeted conditional knock-outs (mouse). In a complementary strategy we will, 3) focally block the production of retinoic acid by transplantation of quail material from Vitamin A deprived embryos in to chick hosts. Finally 4), we will examine the long-term dependence of these cell groups on choroid plexus derived retinoic acid using a Vitamin A deficiency model.

Amount: £219,123
Funder: The Wellcome Trust
Recipient: King's College London

Modulation of vasomotor tone by hypoxia in the pulmonary circulation. 07 Nov 2005

Hypoxic pulmonary vasoconstriction (HPV) is an adaptive mechanism which diverts blood from areas of alveolar hypoxia, thereby optimising ventilation-perfusion matching. However, with global hypoxia, (e.g. in COPD), HPV causes detrimental increases in pulmonary artery pressure, increasing morbidity and mortality. The mechanisms causing HPV are controversial. The prevailing hypothesis is that HPV is caused by K+ channel inhibition, leading to depolarisation and Ca2+ influx through voltage-gated Ca2+ channels. Recently, we have been instrumental in developing an alternative model, which proposes that HPV is due to Ca2+ influx via non-selective cation channels and an endothelium-dependent Ca2+ sensitisation. We have also presented evidence that mitochondria act as the O2 sensor, although the intermediate signalling pathways remain obscure.Our major goal for the Programme is to define the Ca2+influx, release and homeostatic pathways involved in HPV. In particular we will explore the involvement of Trp channels, membrane depolarisation, and themitochondria. Our second goal is to establish the mechanisms underlying Ca2+

Amount: £498,929
Funder: The Wellcome Trust
Recipient: King's College London

Believing and colluding in conversion disorder. 02 Mar 2006

Conversion disorder is a very common and highly disabling psychiatric condition, where it is thought psychological distress is in some way 'converted' into neurological symptoms such as paralysis or blindness. Thoughthe psychogenic model is the orthodox view, no neuroscientific basis has been found for it; indeed, faced with the lack of a convincing model, and the paradoxical features of the disorder, some may be tempted to conclude the patient is simply feigning (known as Factitious disorder). The neurologist who sees such a patient is put in a very awkward position. Thoughthey have determined the patient to be neurologically normal, as far as current medical knowledge goes, the patient is still disabled, and the only treatments are psychiatric. Attempts to explain this, however - that they have a Conversion or Factitious disorder, and would benefit from psychiatric help - will probably be fiercely opposed by the patient, who may complain, seek alternative opinions, or simply leave, consigning themselves to lifelong disability. Faced with these likelihoods, and in the interests of eventual successful treatment, the neurologist may be inclined to misrepresent his view, in the hope that the patient may one day accept a psychiatric referral. Though some neurologists have long maintained this avoidant position - telling their patients one thing, and their colleagues, and the notes, another- this clearly raises ethical questions, for it may be considered collusion. It is also directly challenged by current and imminent changes to clinical practice. The requirement that clinic letters are now copied to patients and the introduction of the National Patient Electronic Record means that diagnosis will be forced into the open, or driven more deeply underground. And now the very diagnostic basis of Conversion - the Diagnostic and Statistical Manual (DSM) - is due for revision, with some arguing that the psychogenic label should be removed from these disorders entirely, largely to ease this situation. This study aims to inform that debate, and to present directly to the DSM committee. Firstly I shall delineate the models employed in conceptualising Conversion by philosophical analysis. Guided by this, using a mixed-methods approach, I shall explore which models neurologists believe, what they tell their patients, and why - in a qualitative analysis ofin-depth interviews, and quantitative analysis of a national questionnaire. Lastly, I shall explore the ethical and policy implications of the current position, the imminent changes, and the proposed revisions.

Amount: £188,616
Funder: The Wellcome Trust
Recipient: King's College London

Assessment of Exeter Partnership NHS Trust records. 20 Sep 2006

The Devon Partnership NHS Trust, providing mental health and learning disability services for Devon has decided to discard a substantial number of individual patient records, together with at least two different card indices. These materials appear to date mainly 1930s - 1960s and are to be destroyed unless archived. They represent an important resource for researchers and for the engagement of scientific and historical scholarship with the wider public. The Devon Archivist has accepted the need to house these materials on a temporary basis until an effective means of sampling and retention can be found. The rationale for retaining these materials and developing a clear model for sampling what is a collection of some ten thousand patient files can be simply stated. Earlier deposits of health records, in particular those relating to mental health, have provided a foundation for major research initiatives at the Centre, including detailed studies of mental services in south west England before 1939. Relatively few collections of patient records for the post-1918 period have survived, though they complement studies of the nineteenth century which have drawn largely on such materials. The present proposal is for a brief (approximately 3 months) investigation of the medical records to assess their scope and organisation, and to identify an appropriate strategy for future sampling. The proposal envisages funding for one member of staff (a Research Assistant) under the direction of Dr Jo Melling (the applicant), in collaboration with the Devon Archivist, but housed in the Devon Record Office. John Draisey (Devon County Archivist) has agreed to the Research Assistant using office space, telephone facilities and associated resources at the Devon Record Office. Management will be arranged by monthly meetings, with reports prepared by the Research Assistant.

Amount: £8,823
Funder: The Wellcome Trust
Recipient: University of Exeter

Regulating technologies. 22 May 2006

Title of meeting: "Regulating Technologies" There are four reasons why a conference of this kind is both timely and needed. First, although there are research centers in the UK that focus on the regulation of particular technologies (mainly IT and biotechnology), hitherto no one has tried to bring together these particular research lines to draw whatever generic lessons might be learned. Secondly, hitherto, no one has attempted to join up thinking about the regulability of technology with the potential of technology to function as a regulatory tool. Thirdly, the context for regulation and technology is increasingly international. A gathering of interested parties from North America and Europe presents an opportunity to begin building an international research network. Fourthly, any useful thinking about this topic must open itself to all relevant disciplines. Again, the conference presents an opportunity to begin building an interdisciplinary network. The principal topics to be covered are: - the regulation of today's technologies (principally biotechnology and ICT); - the regulation of tomorrow's technologies (principally nanotechnology and neurotechnology); and - the potential of technology (all the above technologies) as a regulatory tool.

Amount: £5,000
Funder: The Wellcome Trust
Recipient: King's College London

Conference entitled 'In the age of al-Farabi: Arabic thought in the 4th/10th Century'. 22 Nov 2005

In the Age of al-Farabi: Arabic Thought in the 4th/10th Century The proposed conference is one of a series of events focusing on philosophy in the Islamic world (we use the phrase "Arabic Philosophy" since some of the philosophers to be discussed were in fact Christian and Jewish). Previous events in this series have had a broader focus, dealing with a range of topics throughout the history of Arabic thought. But in order to produce as coherent an event as possible, this conference will focus more tightly on the most philosophically vibrant and historically important century in Arabic thought: the 10th century (the 4 century of the Islamic calendar). The purpose of this conference is to look at al-Farabi and other philosophers within the complex intellectual context of the 10th century itself. This involves two basic tasks: First, we will take account of the full range of philosophical schools and traditions of this time period. The most famous of these is the Aristotelian school in Baghdad; the Muslim al-Farabi was a member of this school, but most of these Aristotelians were in fact Christians. Several papers will be devoted to this school: those by Black, Eggert, Ferrari, Giannakis, Rashed, Reisman and Urvoy. A rival development were the more Platonist philosophers who lived and worked further east in the Islamic empire. The papers by Adamson, Biesterfeldt and Wakelnig will discuss these thinkers. Meanwhile, there are philosophical movements that are harder to classify - one of the goals of the conference will be to explore how other thinkers relate to the major trends of the period. Thus Fenton will speak on Jewish thinkers of the time, and there will be papers on the enigmatic "Brethren of Purity" and other authors with Shiite Ismaili leanings. Second, we will consider intellectual developments that were related to philosophy, without however involving thinkers who would necessarily have described themselves as "philosophers". There are three such developments to be explored: science, and especially medicine; the trend of refined literary authors who show knowledge of and interest in philosophical texts; and perhaps most importantly indigenous Islamic theology, or "kalam".

Amount: £516
Funder: The Wellcome Trust
Recipient: King's College London

The performance of medicine : researching the historical writings on the ritual of tarantism. 13 Jul 2008

The project for which this grant is being sought, is for proposed archival research into specific aspects of medical history relating to the phenomenon of tarantism. The grant will allow for detailed examination of documents and sources contained within two libraries, the Wellcome Trust Library, London, and the Bodleian Library, Oxford, both of which hold significant material relating to the historical study of the medical writings concerning tarantism, which date from the 15th Century through to the present. The key goals of this archival research are that it will contribute toward the writing of a monograph, Ritual, Rapture and Remorse: the dance of the spider in Salento, under contract with Peter Lang, which is a study of the history of tarantism through different disciplinary perspectives, and includes discussion of the extensive amount of documentation within the field of the history of medicine. This will make an important contribution to dissemination of these writings, each of which demonstrates the shifts in approaches to the body, medicine and scientific and philosophical paradigms, most particularly in Renaissance and Early Modern Italy, but also moving through to the developments in psychiatric medicine during the 20th Century.

Amount: £1,297
Funder: The Wellcome Trust
Recipient: University of Exeter

Student Elective Prize for Ms Elizabeth Boleat 29 Aug 2008

Gender Issues related to spaceflight

Amount: £1,000
Funder: The Wellcome Trust
Recipient: King's College London

High Performance Liquid Scintillation Facility. 12 Oct 2006

The applicants research programmes fall into discrete themes with distinct objectives. Dr Thomas s area of research is focused on understanding the physiology and pathophysiology of the blood-brain and blood-cerebrospinal fluid interfaces and how this relates to drug delivery to the brain. Dr Francis has two themes to his studies, firstly biochemical investigation of neurotransmitter correlates of cognitive, non-cognitive and neuropathological change in Alzheimers Disease and secondly the use of model systems to answer fundamental questions that arise from the human studies. Dr Malcangio has a major interest in the study of the positive and negative modulation of synaptic transmission at the first pain synapse. Professor McMahon has had a long standing interest in somatosensory systems and runs a large laboratory actively engaged in work ranging from molecular biology to electrophysiology to human psychophysical studies. Dr Rattray primary research interest concerns the properties and functions of transporter proteins in the central nervous system, and in particular their importance in neurodegeneration. Other work is to understand the intracellular events underlying neurodegeneration and neuroprotection. All these research programmes, and the specific funded projects detailed in this application, require access to liquid scintillation counters, hence this application to modernize and expand this central resource.

Amount: £48,997
Funder: The Wellcome Trust
Recipient: King's College London

MA in Medical History. 31 Aug 2007

The mind and its inexorable relationship to the early modern body caught my imagination specifically, and my dissertation was influenced as such. 'Lovesickness' became the core focus of my thesis. Not only did I discover a historiographical lacunae in this field of medical history, but, surprisingly, an incredible amount of source material relating to this disease in both popular and medical tracts of the seventeenth century. Through my research I began to establish the hypothesis that it was this period that witnessed the articulation of the female body as that primarily affected by this disease. Discovering that it was associated with sexual appetite and mental instability, I concluded that lovesickness was grounded deliberately in the fundamental characteristics of the female anatomy in order to posit her gender as sexually and mentally volatile. As such, a diagnosis of 'lovesick' served perfectly to validate a young women's exclusion from the public and intellectual domains, thus supporting the common early modern paradigm of female subjection. Yet while this may have implied the historical fiction of lovesickness, I believe that my analysis also elucidated a genuine disease that may have inspired the invention. Indeed diary entries, newspaper articles, and the predominance of the lovesick maid in popular ballads inferred that real women experienced the tumults of love both physiologically and psychologically. If permitted what I would like to investigate is the disparity in representation between the male and female versions of the disease. Was male lovesickness as much of a cultural phenomenon as the female version, or was it simply a literary relic deriving from the Middle Ages (when the term Amor Heroes implied the masculinity of the disease, as attested by the historian Mary Wack)? Did male lovesickness reside in a different area of the body to that of female lovesickness, and did love enter the body through the same channels? Was the male less, and the female more susceptible to the disease due to their humoral characteristics? Was female lovesickness more innately sexual that male? In medical accounts of authors such as Jacques Ferrand, he seats the disease potentially in the testicles, yet does not link this explicitly to sexual appetite, whilst with the seating of the disease in the womb, he does. Was the male sufferer, therefore, more prone to the melancholic rather than the erotic stage of lovesickness? And as in female accounts of the disease, was the male sufferer always young? And finally, I would like to investigate whether genuine cases of lovesickness inspired the fictive accounts of the male malady, as they did the female. Thus there are an incredible number of avenues to research in this field, if indeed I am granted the opportunity to do so.

Amount: £20,153
Funder: The Wellcome Trust
Recipient: University of Exeter

Lentiviral vector delivery of shRNA to study pain related gene function. 20 Dec 2006

To develop a lentiviral vector system to be capable of transfecting cells of the PNS and CNS to stably express transgenes To use these vectors to deliver shRNA to sensory neurones in vitro and knock down the expression of specific target proteins To use these vectors to deliver shRNA to sensory and spinal neurones in vivo and knock down the expression of specific target proteins

Amount: £20,080
Funder: The Wellcome Trust
Recipient: King's College London

Early recurrent pain and its effect on adult pain processing. 20 Dec 2006

This project therefore takes a multidisciplinary approach by combining psychological and behavioural assessment of children with recurrent pain together with an animal behavioural study of the effects of recurrent pain in juvenile rats. The student will therefore be primarily supervised by Prof. Maria Fitzgerald with psychological supervison from Prof Amanda Williams, Reader in Clinical Health Psychology at UCL.

Amount: £19,150
Funder: The Wellcome Trust
Recipient: King's College London

Assessment of mental capacity in individuals with psychiatric disorders. 19 Sep 2007

The project builds on previous work funded by Wellcome. Mental capacity is a cornerstone in the process of giving informed consent. The prevalence, associations and consequences of mental incapacity have not been sufficiently studied in clinical populations. Our first project involved acutely ill general hospital in-patients, and we determined that approximately 40% lacked mental capacity to make key treatment decisions. These patients were older and more cognitively impaired than patients who had mental capacity. We used transcripts of semi-structured interviews to determine that experts rating the interviews had good inter-rater reliability (mean kappa = 0.76). Our second study funded by Wellcome was the pilot study for the present proposal, and indicated firstly that two psychiatrists performing a semi-structured interview 1-2 days apart had good inter-rater reliability (kappa = 0.78). It also indicated that the proposed project is feasible, with satisfactory participation rates. The main aims are (1) To determine the prevalence of psychiatric in-patients who lack capacity to make key decisions regarding their treatment; (2) to test a series of hypotheses linking mental capacity with the use of the Mental Health Act, perceived coercion and the presence of cognitive impairment or delusions and (3) to describe the proportion of mentally incapacitated individuals who regain capacity by the time of discharge from hospital. A consecutive sample of 270 psychiatric in-patients will be approached and interviewed using the capacity interview, as well as measures of insight, perceived coercion, and clinical status. It will be possible from this study to determine the proportion of patients judged to lack mental capacity to make decisions regarding their current treatment. All incapacitated patients will be re-interviewed at the point of discharge, or six months following admission, to determine the proportion in whom capacity is regained over this period of time. Participants who are judged to lack capacity will be compared with those who are thought to have capacity on a range of clinical and demographic characteristics. We will then use univariate and multivariate statistical methods to compare these groups in terms of their legal status under the Mental Health Act (1983), their perception of coercion, and their insight into their condition.

Amount: £26,062
Funder: The Wellcome Trust
Recipient: King's College London

Characterization of a neurogenic programme activated by the proneural factor Mash1. 03 May 2007

Our first aim in this application is to characterize the neurogenic programme activated by the proneural bHLH protein Mash1 in neural stem cells. We will use an inducible Mash1-expressing neural stem cell line to identify on a genome wide basis the sequences bound by Mash1 and the genes associated with these sequences. To achieve this aim, we will use the ChIP-PET technique in collaboration with the Genome Institute of Singapore, complemented by expression arrays, bioinformatic analysis and hybridization of chromatin immunoprecipitation products to genomic microarrays (ChIP on chip). Our second aim is to characterize the mechanisms that underpin the regulation of Mash1 target genes in differentiating neural stem cells. Hybridization of expression arrays at different time points will define the time course of expression of Mash1 targets. ChIP on chip experiments with antibodies to Mash1, to various histone modifications and to candidate Mash1 co-factors will determine the contribution of Mash1 binding site occupancy, cofactor recruitment and histone acetylation and metylation to the regulation of Mash1 targets, and particularly to their timing of expression. We will validate the results obtained in cultured neural stem cells by performing chromatin immunoprecipitation experiments with embryonic brain material.

Amount: £134,651
Funder: The Wellcome Trust
Recipient: King's College London

Characterisation of the functional role of the Batten disease gene, cln3, in Drosophila. 03 May 2007

Batten disease/NCL is an inherited neurodegenerative disease of childhood characterised by the accumulation of abnormal autofluorescent material within lysosomes. The most common form, Juvenile NCL, is caused by mutations in the Cln3 gene. A role in endosomal/lysosomal function has been suggested in non-neuronal cells but it is uncertain if Cln3 plays the same function in neurons. We aim to increase our understanding of Cln3 function by investigating its role in Drosophila. Our preliminary work has revealed that Drosophila Cln3 shares many features with the human protein. Our data and that of others suggests a role for Cln3 in membrane trafficking. We will utilise our experience in study of the Drosophila nervous system to investigate (i) the cell biology of Cln3 both in vivo and in vitro, (ii) the functional requirement for Cln3 and the pathological role of modified Cln3 proteins and (iii) partner proteins that function with Cln3 within the nervous system. We hope to establish the pr ecise compartment within the neuron where Cln3 is expressed and identify the functional pathway in which it acts. Additionally we will follow and characterise the pathology that occurs when the protein is absent or non-functional and characterise the cells that require Cln3.

Amount: £318,672
Funder: The Wellcome Trust
Recipient: King's College London

Investigation of genetic susceptibility to inflammatory bowel disease. 16 May 2007

The inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC) are chronic disorders that are associated with severe inflammation of parts of the gastrointestinal tract. The underlying causes are unresolved, but may involve chronic bacterial infection and a dysregulated immune response. Epidemiological studies indicate that both genetic and environmental factors contribute to pathogenesis, and the NOD2/CARD15 gene has been identified as a susceptibility gene for CD. The W ellcome Trust has funded a genome-wide case control association study to identify susceptibility loci for common diseases, including CD. A major goal of this proposal is to develop the leads from that study by fine mapping and identification of the associated susceptibility genes and causal variants. The case control data will also enhance our current work to define the genes and causal variants at the CD susceptibility loci on chromosome 5q31 and 6p21. Follow-up of ongoing genome-wide and a gen e-based scans for susceptibility genes for UC will also be undertaken. Two further key goals are to examine the effect of causal variants on gene function in cells from patients of defined genotype, and to investigate their contribution to disease risk and to disease behaviour.

Amount: £107,008
Funder: The Wellcome Trust
Recipient: King's College London

Identification of upstream regulators of Pax6 in sensory organ formation. 06 Feb 2007

Sense organs and sensory ganglia form the cranial sensory nervous system, crucial parts of which arise from placodes outside the CNS. We have recently found that all placode precursors share common properties and are initially specified as lens. When cultured in isolation, cells that normally never contribute to the lens undergo normal lens development. They rapidly begin to express Pax6 and other lens-specific genes culminating in the formation of crystallin+ lentoids. These findings provide a unique opportunity to study the molecular mechanisms that control Pax6 initiation in the future lens ectoderm. We have designed a differential screen using strict parameters to compare expression profiles of four different cell types. Taking advantage of a well defined biological system in which Pax6 expression is initiated within a short period, the screen considers timing of gene action as well as presence or absence of a certain set of markers genes. Using these stringent criteria we aim to identify only a few direct regulators of Pax6. Their function will then be assessed in gain- and loss-of-function approaches. The project will provide new insights into the specification of lens precursors and of progenitors that form the sensory nervous system.

Amount: £210,329
Funder: The Wellcome Trust
Recipient: King's College London