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Funders:
Paul Hamlyn Foundation
The Wellcome Trust
Recipients:
University College London
Amounts:
£500 - £1,000
Award Year:
2007

Results

Value in People award. 18 Jul 2007

Not available

Amount: £300,000
Funder: The Wellcome Trust
Recipient: University College London

Survey estimation of sexual behaviour, HIV/STI prevalence and development of an HIV prevention intervention in male migrant workers in Surat, India. 19 Feb 2007

Survey estimation of sexual behaviour, HIV/STI prevalence and development of a HIV prevention intervention in male migrant workers in Surat, India Aims: 1) To estimate HIV/STI prevalence and obtain other relevant data to inform the development of targeted interventions to decrease HIV and STI transmission in migrant men working in diamond and textile industries in Surat. 2) To evaluate the efficacy of locally developed syndromic management using laboratory-based diagnoses. Hypothesis: Survey estimates of sexual behaviour, STI and HIV prevalence will guide the development of targeted HIV and STI prevention interventions. Expected outcome: HIV prevalence in migrant men is expected to be at least 5%.

Amount: £19,854
Funder: The Wellcome Trust
Recipient: University College London

Genomic and biochemical analysis of ageing and age-related disease. 18 Jul 2007

A recent discovery is that mutations in single genes can extend healthy lifespan in laboratory organisms. Furthermore, these effects are conserved over large evolutionary distances, opening the opportunity to use simpler organisms with much shorter lifespans to understand human ageing. Mutations in insulin/IGF-like signalling (IIS) genes can extend lifespan in the worm Caenorhabditis elegans, the fruit fly Drosophila and the mouse. Our collaborative research programme has three aims: 1. Our previous work has both demonstrated robust conservation of the effects of IIS on lifespan in Drosophila and produced a new, robustly long-lived mutant mouse. We shall unravel the signalling mechanisms involved, essential for identification of possible drug targets. 2. We shall identify and manipulate the biochemical processes by which IIS slows ageing, the key to understanding how ageing-related damage is generated and how normal longevity is assured by defence and repair systems. We shall focus on detoxification, autophagy and the proteasome. 3. Ageing is the major risk factor for predominant, lethal diseases: cardiovascular disease, cancer and neurodegenerative disease. We shall test the idea that ageing-related diseases are caused by the same accumulation of molecular damage that drives the ageing process, focussing upon neurodegenerative diseases in the model organisms and humans.

Amount: £5,127,323
Funder: The Wellcome Trust
Recipient: University College London

Neuroesthetics. 12 Sep 2007

The development of powerful techniques for imaging brain activity has ushered in an interest in the neurobiology underlying artistic creativity and aesthetic appreciation, in fields as diverse as art, literature, music and mathematics. The new field of neuroesthetics studies these subjects and relies on contributions both from neurobiology and the humanities. This application aims to promote the study of neuroesthetics in the UK, where the concept was born. The main goal is to produce world clas s research addressing issues that have long been debated in the humanities concerning the nature of art and beauty, the relationship of both to the atavistic impulses of love, and the role of reward, judgment, affective states, knowledge and concepts in the creation and appreciation of works of art. Other goals are to train future generations of researchers to tap knowledge acquired in the humanities to develop questions amenable to scientific experimentation; to educate undergraduate students a nd the public about the relevance of neurobiological studies to issues of concern to science and society. Finally, it will provide a framework within which to unite the apparently disparate fields of neurobiology and the humanities in the common pursuit of understanding the human brain and the human condition.

Amount: £1,128,963
Funder: The Wellcome Trust
Recipient: University College London

'The importance of medical history: Transnational and cross-cultural perspectives on a multi-faceted discipline' conference to be held in Mumbai, India from 15th to 17th November 2007. 23 Mar 2007

The importance of medical history: Trans-national and cross-cultural perspectives on a multi-faceted discipline The proposed meeting will be the first of its type in the South Asian sub-continent - dealing with the important questions of historical method and historiography, from trans-national and cross-disciplinary perspectives; it will allow the audience access to a plethora of perspectives on how to study HOM. The projected audience will be university and college teaching, research and administrative staff of all grades, we well as undergraduate and post-graduate students, doctors, print and TV journalists, and independent researchers. A number of well-known scholars have agreed to attend the meeting, as they acknowledge the usefulness of an event like this in popularising HOM in an important education centre in Asia. These academics, who are attached to a number of Wellcome Trust-funded units, will draw upon an important item of their research - dealing with Europe, North America, Asia and further afield - to develop trans-national perspectives of how to study HOM. This meeting will engender a lot of discussion, which is critically important for an endeavour that seeks to provide new insights to post-and under-graduate teachers about important international developments in the discipline, and the most effective ways of teaching and carrying out research. Themes to be covered: History of pharmacology; Anatomy; Global trade and medicine; Medical genetics and gender; Medicine in the early modern period; Public health in 19th and 20th centuries; Global health programmes and disease eradication; War and medicine; International perspectives on rabies; Scottish doctors and British empire; Obstetrics and surgery; Cross-disciplinary perspectives on leprosy and empire; Hospitals; Medicine and 'witchcraft' in the early modern period; Healthcare in colonial Mumbai/India; Health of industrial labour; Oral histories of contemporary medicine and biological science; History of medical practice and multiple meanings of health.

Amount: £5,000
Funder: The Wellcome Trust
Recipient: University College London

Structure function models of language and its recovery. 26 Jun 2007

My proposal is to establish a functional anatomical model of language that predicts how speech and reading are lost and recovered following neurological damage. The novel aspect of this model rests on my hypothesis that distinct language tasks can be sustained by several different neuronal systems. Crucially, this means that when one system dysfunctions, recovery can be meditated by a surviving system. The neuronal systems engaged by each task will be identified by combining data from neuropsych ological and functional imaging studies. Validating the model involves structural neuroimaging and behavioural assessments in patients with acquired brain damage in the regions identified. This will determine how the impact of damage in one system depends on the integrity of another. The model will then be used to formulate and test predictions for recovery using functional imaging studies of patients who recover their language skills despite damage to the areas engaged by normal subjects. The ability to anticipate which brain systems emerge, during rehabilitation, may be important for targeting various therapies or, at least, in helping the patient anticipate his or her course of recovery.

Amount: £1,275,779
Funder: The Wellcome Trust
Recipient: University College London

Physiological regulation and pathological dysfunction of the nitric oxide receptor soluble guanylate cyclase: role in cardiovascular homeostasis and disease 12 Jun 2007

Soluble guanylate cyclase (sGC) is a heterodimeric haemoprotein that represents the intracellular receptor for nitric oxide (NO). Activation of the enzyme facilitates formation of the second messenger cyclic GMP and it is this molecule that mediates the majority of biological actions attributed to NO. Due to its ubiquitous nature, inappropriate sGC activity may be fundamental to the aetiology of a wide variety of disease states, exemplified in the cardiovascular system by conditions such as stroke, atherosclerosis and septic shock. Therefore, agents that can modulate sGC function selectively will have considerable therapeutic potential, particularly in the treatment of cardiovascular disease. However, understanding of the expressional, biochemical and pharmacological regulation of sGC under physiological and/or pathological conditions is poor. Therefore, the current proposal is designed to test the hypothesis that regulation of sGC expression and activity is a key determinant of the biological actions of NO and that enzyme dysfunction may contribute to the pathogenesis of vascular disease. The programme of research will comprise a multi-disciplinary approach from molecular studies, in vitro and in vivo pharmacological characterisation to evaluation in humans. Molecular & biochemical studies: Regulation of enzyme expression will be studied by analysis of the promoter regions of the human sGC genes (by luciferase reporter assay) which contain NF-?B, oestrogen, hypoxia and shear stress response elements (each believed to be involved in cardiovascular homeostasis and/or disease). Expression of recombinant human sGC isoforms will yield sufficient quantities of purified protein for studies examining biochemical regulation and enzyme kinetics. In vitro/in vivo pharmacology: Determination of the expression and sensitivity of sGC by pharmacological evaluation using cells in culture, in vitro organ bath/myograph techniques and in vivo studies will provide functional correlates for the molecular and biochemical studies. Relevance to human disease: The presence of polymorphisms within the human sGC genes will be investigated to provide potential links between altered sGC activity and human disease. Studies of platelet aggregation (an index of sGC activity) will be conducted and related to genotype. Polymorphisms identified in the coding region will be expressed as recombinant proteins and enzyme kinetics evaluated; variations in the promoter region will be genetically-engineered and evaluated in the promoter-reporter studies. In summary, the results of this proposal are likely to have important implications for the understanding of the regulation of expression and activity of sGC in health and disease and perhaps provide the rationale for the design of novel therapeutics.

Amount: £313,528
Funder: The Wellcome Trust
Recipient: University College London

Transthyretin depletion for treatment of hereditary systemic and senile cardiac amyloidosis 03 May 2007

Systemic transthyretin amyloidosis is a fatal late onset disease caused by tissue deposition of amyloid fibrils composed of variant and wild type transthyretin. The objective of the project is to construct compounds to trigger the accelerated clearance of plasma transthyretin molecules by the liver by synthesising palindromic ligand-linker-ligand compounds capable of cross-linking transthyretin molecules or oligosaccharide-ligand conjugates that direct hepatic clearance, which could be used as drugs for treating and preventing acquired and hereditary human systemic transthyretin amyloidosis. The aim is to optmise the design, synthesis, and properties of a transthyretin depleting drug and complete the comprehensive safety and efficacy evaluation required prior to administration of a validated candidate compound in humans.

Amount: £931,387
Funder: The Wellcome Trust
Recipient: University College London

The functional effects of alterations in the human voltage-gated P/Q-type calcium channel. 26 Mar 2007

Mutations in the P/Q-type voltage-gated neuronal calcium channel are responsible for a diverse range of episodic and progressive neurological disorders. In humans, three allelic disorders, namely episodic ataxia type 2, familial hemiplegic migraine and spinocerebellar ataxia type 6 (SCA 6) have been identified. However, mutations in this gene are increasingly emerging as a cause or susceptibility factor for other phenotypes including epilepsy. I propose to study the effects of mutations and s pice variants of the alpha 1A subunit of the P/Q- type calcium channel on calcium currents and channel kinetics in neurons. My goals are as follows. Firstly, I will identify and clone the dominant splice variants from the hippocampus, the cerebral cortex and the cerebellum. These areas were chosen as obvious aetiological substrates for disorders such as epilepsy, migraine and ataxia. Following this I will introduce mutations into these splice variants and study their biophysical properties. I n parallel with this I am working on constructing a viral vector for expression in neuronal cultures. I also propose to collaborate with other researchers in the group, who are developing new optical methods to relate presynaptic calcium signalling to transmitter release kinetics within individual nerve terminals.

Amount: £111,824
Funder: The Wellcome Trust
Recipient: University College London

The evolution and impact of HIV-1 resistance following the public health rollout of antiretroviral therapy in Africa. 19 Mar 2007

There around 40.3 million HIV infected people worldwide with 3.1 million deaths in 2005 (half a million were children). Antiretroviral therapy (ART) has been shown to increase survival, and therefore providing ART has been identified as a global public health priority. HIV treatment in the industrialised world is accompanied by regular virological monitoring to limit the emergence of high level resistance, thus optimising response to subsequent therapies. This monitoring is not feasible in the developing world. Maintaining patients on therapy despite viraemia risks the development of more extensive resistance and may compromise choices for second line therapy. Children experience higher viral loads and slower responses to ART. This greater viral turnover provides the potential to develop resistance more rapidly than in adults. We aim to describe the emergence of resistance in African children and to explore relationships with virological fitness and clinical disease. Then we a im to translate these findings to assess the likely efficacy of WHO second-line therapy at a population level. Given that research into optimal sequential therapies for children in the developing world is limited, there is an urgent need for such real life resistance data to inform the evidence-based approach to public health rollout of ART.

Amount: £225,608
Funder: The Wellcome Trust
Recipient: University College London

Learning to cooperate: decision making in cooperative and competitive social exchanges. 12 Jul 2007

This project aims to investigate how people learn to cooperate in strategic social interactions and, more specifically, the neural processes underlying this capacity. The general hypothesis I will test is that the neural processes underlying learning and decision-making in single-agent situations are extendable to multi-agent contexts, and that they can be used to understand action selection in game theoretic paradigms involving competitive and cooperative options. The project will involve pr oposing and developing theoretical models of decision-making applicable to tasks such as the sequential Prisoners Dilemma and Public Goods games. In particular, these models will be based on the computational framework provided by reinforcement learning (Year 1). The validity of these models will then be tested experimentally, using a combination of statistical model fitting and model-based functional magnetic resonance imaging (Years 2 and 3). The emphasis will be on understanding the role of l earning in these tasks, such as how reputations are formed and the impact of observation in games that involve punishment. More generally, this should lead to a theoretical understanding of how humans actually solve the game-theoretic problems (algorithmically) and how this is implemented in the brain.

Amount: £161,752
Funder: The Wellcome Trust
Recipient: University College London

Regulated SAP gene transfer for correction of X-linked lymphoproliferative disease. 12 Jul 2007

X-linked lymphoproliferative disease (XLP) is a genetic disorder resulting in immunedysregulation, typically following Epstein-Barr virus (EBV) infection. Affected boys suffer from fulminant infectious mononucleosis, malignant lymphoma or hypogammaglobulinaemia. The defective gene is SH2D1A, which encodes for SAP protein (SLAM associated protein, involved in regulation of immune cell signalling) expressed in T and NK cells but not in primary B cells. Current management involves haematopoietic stem cell transplant but success is dependent on a good donor match and absence of active infection at transplant. Somatic gene therapy can correct certain forms of immunedeficiency and offers a potential cure for XLP. However, dysregulated gene expression is potentially harmful. In this study we aim to develop vectors expressing SAP in a regulated manner allowing correction of the disease phenotype without untoward side effects. Lentiviral vectors will be generated encoding SAP under the regulation of recently defined SAP promoter elements or the CD2 promoter. These vectors will initially be tested for physiological patterns of expression and function prior to use in correcting cellular models of SAP deficiency and to recomplement SAP in an siRNA knockdown SAP deficiency model. We also aim to correct a murine model of XLP using the optimal SAP lentiviral construct.

Amount: £225,029
Funder: The Wellcome Trust
Recipient: University College London

The Sloane printed books project. 18 Jul 2007

The project will make available for research and public use a database of the books once belonging to Sir Hans Sloane (1660-1752), which after his death formed one of the foundation collections of the British Museum Library but which have since been dispersed into the Library's general collections and into the collections of other research libraries. Sloane's library of approximately 40,000 volumes will be identified by further investigation into the BL's collection and the collections of other libraries. The bibliographical information will be enhanced with information about pre-Sloaneprovenance, annotations and condition. The information accumulated will be made available to the public through a web-accessible database that will be maintained by the British Library, while various supplemental materials and ongoing maintenance will allow additional books once owned by Sloane to be identified and added to the database in future years. The body of work produced by the project will form a significant research resource for medical and intellectual historians of the period. This resource will be launched at aconference and through publications. The key goals of the project are: " Identification of Sloane's books, their provenances and other associations " Presentation of the findings as a public resource for research " Communication of the findings through a conference and papers

Amount: £83,844
Funder: The Wellcome Trust
Recipient: University College London

The Relationship of Visual Perception and Perceptual Binding to Single Cell Activity. 19 Sep 2007

The research project will be to record from the pulvinar nucleus of the thalamus in alert animal models trained to perform a classical conjunction search' task, where the target item is a unique combination of two features (e.g. blue & tilted amidst a display of orange tilted and blue vertical bars, say). Correct performance of the task demonstrates that the target features blue' and tilted' have been correctly bound to each other (and/or to the corresponding object location in space). Individual pulvinar neurons are notexpected to demonstrate pronounced selectivity for either colour, or orientation (although, if they do, the course of the experiment and its validity are not affected). The single unit response, local field potential (LFP - recorded from the same electrode) and the spike-LFP coherence will be monitored while either a target or nontarget is present within the receptive field. The task difficulty will be varied while recording at the same site, inorder to obtain a measure of the neural-behavioural correlate in terms of % correct performance.

Amount: £15,547
Funder: The Wellcome Trust
Recipient: University College London

The Consequences and Outcomes of Convulsive Status Epilepticus in Children. 06 Feb 2007

The central hypothesis of this study is that convulsive status epilepticus (CSE) is associated with brain injury, particularly to the hippocampus, which predisposes individuals to subsequent development of epilepsy and associated neurodevelopmental and/or behavioural dysfunction. CSE is the most common medical neurological emergency in childhood with an incidence of 18-20/100,000 children per year. The possible adverse outcomes from childhood CSE include subsequent epilepsy, permanent neurol ogical, developmental or cognitive deficits, or death. The proposed study will characterise structural brain abnormalities and identify early predictors of adverse outcomes, with particular emphasis on the hippocampus and mesial temporal sclerosis (MTS). Understanding the genesis of MTS would provide a framework for development of strategies that could reduce morbidity associated with MTS. My previous studies have shown evidence of hippocampal oedema and evidence of longer-term hippocampal injur y 6 months following CSE, although not all of the magnetic resonance criteria for MTS have been met. In the work proposed, the natural history of MTS and other structural brain abnormalities will be investigated using longitudinal quantitative magnetic resonance imaging in children with CSE. Prediction of morbidities based on magnetic resonance parameters will allow early identification of children who would develop an adverse outcome and promote early treatment.

Amount: £310,759
Funder: The Wellcome Trust
Recipient: University College London

Dopaminergic and cholinergic neuromodulation of novelty encoding in humans. 06 Feb 2007

The ability to memorize preferentially novel stimuli is essential for survivalin a changing environment. The cognitive and neuromodulatory brain mechanisms behind this preference are still unclear. On the basis of our recent work, we take the view that motivation, reinforcement and prediction-errors are key factors in the preferential encoding of novelty. We hypothesize that when a novel stimulus is detected, brain networks specializing in processing motivationally relevant and potentially rewarding stimuli are activated, that includes dopaminergic and cholinergic circuitry. The resulting dopaminergic and cholinergic activation modulates long term plasticity in memory-relevant structures such as the medial temporal lobes. On the basis of these hypotheses, we now aim to identify the mechanisms and cognitive processes through which dopaminergic and cholinergic modulation improve long-term memoryformation for novel stimuli. To that end we will use multimodal pharmacological imaging (functional magnetic resonance imaging and magnetoencephalography) involving dopaminergic and cholinergic drugs in experiments that allow us to contrast the influence of novelty with reinforcement-value and prediction-error, and assess how they interact in memory formation in healthy adults. The results may help in understanding and treating memory impairment associated with neuromodulatory dysfunction in aging and neurodegenerative neurological conditions.

Amount: £154,193
Funder: The Wellcome Trust
Recipient: University College London

The mitochondrial permeability transition pore plays a central role in cardioprotection: an investigation using the cyclophilin D knockout mice. 22 Feb 2007

Novel interventions are required to protect the myocardium against ischaemia-reperfusion injury. In this regard the cardioprotective interventions of ischaemic preconditioning (IPC) and ischaemic postconditioning (IPost), which describe the application of brief episodes of sub-lethal ischaemia either prior to the lethal ischaemic insult or at the time of reperfusion respectively, limit myocardial infarction. Studies suggest that the mitochondrial permeability transition pore (mPTP), a non-specif ic pore of the inner mitochondrial membrane, which is believed to open in the early minutes of reperfusion, is central to the cardioprotection induced by IPC, IPost and several pharmacological cardioprotective agents. Previous studies investigating the role of the mPTP have relied on pharmacological manipulation, however in the present proposal we are able, for the first time, to study the role of the mPTP in ischaemic and pharmacological preconditioning and postconditioning using a transgenic m odel in which cyclophilin-D has been genetically knocked out and therefore unable to form a functional mPTP. We will examine the cardioprotective interventions of ischaemic and pharmacological preconditioning and postconditioning in this animal, using an in vivo model of myocardial ischaemia-reperfusion injury in order to assess the role of the mPTP and its interaction with the survival kinases (Akt and Erk1/2) in these settings.

Amount: £144,844
Funder: The Wellcome Trust
Recipient: University College London

Engineered derivatives of Hepatocyte Growth Factor in the prevention and treatment of liver disease. 22 Feb 2007

In experimental systems Hepatocyte Growth Factor/scatter factor induces hepatocyte proliferation and prevents apoptosis; in animal models (HGF/sf) can prevent and reverse acute and chronic liver damage. Native HGF/sf is a large complex protein; we have engineered truncated forms which are smaller, and potentially much more attractive molecules to develop for therapeutic purposes, reflecting their less complex tertiary structure and ease of production. We shall therefore characterise their effe cts in two sets of studies. Firstly we will assess the activity of wild-type and engineered forms of hgf/sf on human liver cells in order to confirm that they elicit the same biological responses as they do on rodent cells, and identify the most active engineered form. Secondly we will explore the activity of the proteins in established and validated pre-clinical models of (i) acute liver failure, (ii) chronic, progressive liver disease and, (iii) survival and recovery from large surgical resec tion. The two sets of studies should provide the data necessary and sufficient for subsequent clinical studies in patients with acute liver failure, advanced cirrhosis and in patients undergoing large liver surgery, opening the prospect of taking hgf/sf into the clinic.

Amount: £221,744
Funder: The Wellcome Trust
Recipient: University College London

Spike timing-based memory in the hippocampus. 06 Feb 2007

Hippocampal area CA3 is widely considered to function as an autoassociative memory, supporting key aspects of episodic storage and recall, in conjunction with other hippocampal and cortical areas. However, previous accounts of this function fail to address the rich dynamical behaviours exhibited in CA3. We have recently suggested, and experimentally validated, a normative account that predicts the relationship between the dynamical interactions among pyramidal neurons during oscillatory memory recall and the characteristics of the spike-timing dependent synaptic plasticity (STDP) rule governing storage. We now propose to investigate three significant theoretical and experimental extensions to this account. First, we will study a model incorporating spiking rates as well as spiking times. Second, we will consider how STDP rules should optimally match the statistics of input patterns. Third, we will consider how coordinated neural oscillations between hippocampal subregions, and between the hippocampus as a whole and the neocortex, may support aspects of memory consolidation.

Amount: £163,593
Funder: The Wellcome Trust
Recipient: University College London