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The Wellcome Trust

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Inhibitors of Lysyl Oxidase for the Prevention and Treatment of Invasive and Metastatic Cancer 30 Jul 2010

Inhibitors of Lysyl Oxidase for the Prevention and Treatment of Invasive and Metastatic CancerThe enzyme lysyl oxidase (LOX) regulates cross-linking of structural proteins in the extracellular matrix.LOX also plays a role in stimulating the metastatic spread of cancer through the body. Its expression is increased in hypoxic cancers and is correlated with tumour metastasis and decreased patient survival. In model systems its inhibition significantly decreases cancer metastasis and increases survival. Since metastasis is responsible for over 90 per cent of cancer deaths these data validate LOX as an important therapeutic target in cancer. Professor Caroline Springer and Professor Richard Marais from the Institute of Cancer Research have been awarded Seeding Drug Discovery funding to develop drugs that target LOX. They are applying a medicinal chemistry drug discovery approach underpinned by a strong programme in LOX biology with the aim of producing orally available, small molecular weight drugs that inhibit LOX activity for cancer treatment.See our video: BRAF and cancer: collaborative drug discovery

Amount: £818,674
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Retinoic acid receptor a agonists for the treatment of Alzheimer's disease 31 Jan 2010

Retinoic acid receptor a agonists for the treatment of Alzheimer's disease. The current licensed treatments for Alzheimer's disease improve the symptoms that people experience but do not alter the progression of the underlying disease changes in the brain.Most of the attempts to develop new treatments have focused on altering deposits of the amyloid protein in the brain, but despite more than a decade of intensive research this has still not yielded any new therapies in the clinic. The studies of Dr Jonathan Corcoran of King's College London highlight a specific retinoic acid receptor (RAR)a agonist as a novel and exciting target for the development of new treatments. This agonist has two mechanisms of action - it regulates amyloid deposits in the brain and also plays a key role in the survival of neurons. In their project they will generate novel RARa agonists for the treatment of Alzheimer's disease.

Amount: £354,795
Funder: The Wellcome Trust
Recipient: King's College London

Selective glucocorticoid receptor agonists for the treatment of inflammatory conditions. 22 Feb 2010

Research by Professor David Ray and his team at University of Manchester has identified how to modulate the function of the glucocorticoid receptor.The glucocorticoid receptor responds to both natural hormones and synthetic glucocorticoids to inhibit the inflammatory response. Inflammation lies behind many important human diseases, including rheumatoid arthritis, and opening up novel approaches for therapy offers new hope for these chronic, disabling conditions. The award will allow development of new molecules capable of harnessing the glucocorticoid receptor for treatment of multiple inflammatory diseases, without the wide range of side effects that currently limit use of conventional drugs. If successful the research will lead to an orally active drug for use in inflammatory arthritis within five years.

Amount: £444,497
Funder: The Wellcome Trust
Recipient: University of Manchester

Development of a novel compound series to treat life-threatening, drug-resistant, Staphylococcal infections through the inhibition of the essential cell division protein, FtsZ. 21 Sep 2010

Drug-resistant Staphylococcal strains represent a growing threat to human health. The emergence of MRSA in particular has received considerable media attention and is attributed to > 1 ,400 of the deaths caused by infections and complicates the treatment of > 7000 patients in UK hospitals per year. With the aid of Trust funding, Prolysis will progress one of their novel antibacterial chemical series that specifically inhibits Staphylococcal cell division through a chemical optimisation programme, preclinical development and into Phase I clinical trials. The project aims to deliver a new targeted therapy for the treatment of Staphylococcal infections acquired in hospitals or the community and to offer a prophylactic treatment for MRSA carriers prior to invasive procedures.

Amount: £464,800
Funder: The Wellcome Trust
Recipient: Biota Europe Ltd

Control of noise in gene expression. 22 Mar 2010

Stability and precision in gene expression are necessary to generate and maintain structure and function in biology. To understand these fundamental problems requires novel technologies to detect and measure transcription from single genes in real time. We have therefore developed a novel technology to visualise the transcriptional behaviour of single genes in individual living cells. We demonstrated that transcription is stochastic, characterised by irregular pulses of gene activity. But how is stochastic behaviour compatible with spatiotemporal precision and stability of gene expression? To address how stochastic pulsing generates precise spatial patterns of gene expression, and to distinguish between direct and feedback models of cell response, we will study pulsing during formation of a precise embryonic gene expression boundary. To determine origins of temporally precise gene expression, we will measure and entrain transcriptional cycling in single cells. To address how st ability of gene expression is regulated, we will use long term imaging to determine the extent to which transcriptional firing is maintained in cell lineages. We will address the role of chromatin in transcriptional memory. To define the regulators of transcriptional stability with unbiased approaches we will use FACS to purify mutants with high noise and low gene expression memory.

Amount: £1,059,276
Funder: The Wellcome Trust
Recipient: University of Dundee

Functional circuits in visual cortex: multi-photon imaging and computer modelling. 19 Apr 2010

It has long been known that the retina adapts to the prevailing level of lightentering the eye. It is also now clear that the visual cortex can dramaticallychange its profiles of temporal and spatial integration depending on the pattern, the movement, and the contrast of the scene. A striking example is adaptive temporal integration (ATI), which Movshon and I discovered in complexdirection selective cells of the primary visual cortex (V1): the responses of these neurons speed up as they are challenged with faster moving stimuli. Findings of this type have far-reaching implications for mapping and modellingneuronal function, particularly for understanding how the visual cortex responds during natural viewing, when the statistics of the scene change frequently from moment to moment. The key goal is to integrate computational modelling and experimental electrophysiology into a unified research group to formulate a biologically plausible model that explains ATI and other fast-acting adaptive phenomena. Major cell classes in V1 will be tested with dynamic stimuli to find the origin of ATI. The spatial and temporal selectivity of ATI and its influence on synchronous firing will be probed in V1 and in the motion area V5/MT. The resulting model will adhere to four principles: (1) modular components will represent major cell classes at several levels from the retina to the perceptually relevant responses in V5/MT, (2) arbitrary time-varying stimuli will be accepted as input, (3) responses will be given as spike trains and membrane voltages, (4) the model will be publicly available online so that it can be utilized and refined by scientists anywhere in the world.

Amount: £199,872
Funder: The Wellcome Trust
Recipient: University of Oxford

Neurobiology of speech communication:cognition, plasticity and social interactions 19 Apr 2010

Functional imaging studies (PET and fMRI) have revealed that human speech is processed along distinct (though interacting) streams, in ways that are analogous to the functional and anatomical auditory streams seen in animal primate studies. I am proposing a series of studies in which aspects of human speech perception and production are investigated, to identify the neural basis of low level and higher-order control of speech perception, the neural basis of production and perception of speech in different masking contexts, and plasticity and individual differences in speech processing. I am particularly interested in how we can apply these results to the understanding of clinical issues (e.g. aphasic stroke and cochlear implantation), and will address the latter with studies of cochlear implant users and simulations. I also aim to extend this work to consider how the importance of social factors, such as how communicative intent affects the neural regions recruited in addition to those involved in the linguistic processing of speech. This is an attempt to integrate the neurobiology of speech perception and production with themes in social neuroscience, and important link to establish, given the central role of speech as a communication tool.

Amount: £1,184,506
Funder: The Wellcome Trust
Recipient: University College London

Studying neurogenesis through developmental time. 19 Apr 2010

In this proposal, we aim to understand two mechanisms of progenitor maintenance. The first mechanism is set up before neural induction and it inherently inhibits a population of apicobasally polarised progenitor cells from undergoing premature neurogenesis. The serine-threonine kinase aPKC is sufficient and necessary to maintain the progenitor state of these cells. In aim 1, we will identify phosphorylation targets of aPKC by a candidate and an unbiased proteomics approach and we will determine the transcriptome of these progenitors by microarray analysis. The second mechanism follows neural induction, and it operates within a second population of progenitors, which are apolar. This mechanism depends on the localised expression of transcription factors, such as Foxg1. Since FoxG1 is expressed in both progenitors and differentiated neurons in the forebrain, we reasoned that its activity may be distinguished by co-factors and post-translational modifications; these will be characteri sed in aim 2. To link the control of FoxG1 with its transcriptional output, we will identify the transcriptional targets of FoxG1 by ChIP-seq and microarray analysis. To link the two, in aim 3, we will undertake lineage-tracing experiments to understand whether different mechanisms of inhibiting differentiation early on, have a lasting impact on progenitor fate.

Amount: £2,072,642
Funder: The Wellcome Trust
Recipient: University of Manchester

Structural and functional studies of regulatory assemblies and macromolecular machines. 19 Apr 2010

Many macromolecules in the cell function through multi-component assemblies whose activities can affect complex processes. We propose to study representative assemblies that play central roles in the regulation of gene expression and the coupling of metabolic pathways, and that comprise the machinery of transmembrane transport: Gene expression. Orchestrated turnover of mRNA is a key determinant of gene regulation. A critical role in regulating the balance and composition of mRNA transcripts is played by the multi-component RNA degradosome in Escherichia coli, effecting the coordinated expression of many genes from diverse metabolic pathways. We have solved several structures of the degradosome components and are investigating their interactions. We will study the structure and function of the complete assembly and of the analogous exosome, to explore how the machinery has evolved to meet the requirements of an expanded genome. Metabolism. We are continuing to investigate multi-enzyme systems, such as 2-oxoacid dehydrogenase, building on our structure determination of a subassembly and identification of a new mechanism of intersubunit-communication. Transport. We are investigating the movement of drugs and proteins across biological membranes. We will continue studies of a variety of energy-driven transporters, their assembly and mechanism, based upon our crystal structures.

Amount: £342,635
Funder: The Wellcome Trust
Recipient: University of Cambridge

Mesenchymal Stromal Cells as Therapeutic Vectors for Metastatic Cancer. 02 Jun 2010

I have shown that activation of mesenchymal stromal cells (MSCs) engineered to deliver TNF-related apoptosis-inducing ligand (TRAIL) eliminates lung metastases when delivered systemically. During the following programme of work, I will improve my understanding of the basic mechanisms of MSC homing to tumours, in vivo tumour cell killing and confirm the most effective form of delivery. I will also delineate an imaging strategy for future translational studies in man. This proposal encompasses thr ee aims with the following specific goals. 1) The first aim will determine the efficacy of different forms of TRAIL expressed on syngeneic and allogeneic MSCs, and shed light on the role of the immune system in tumour cell killing in xenograft and endogenous cancer models closely resembling human disease. 2) The second aim will inform on the mechanism of MSC homing to tumours. The goal is to exploit this knowledge to engineer MSCs to home to tumours in an effective and specific manner. 3) The final aim will define the usefulness of magnetic resonance imaging for the detection and quantification of MSC tumour infiltration for future translational studies of this therapy in humans.

Amount: £1,658,140
Funder: The Wellcome Trust
Recipient: University College London

Lipodystrophy-A paradigm for elucidating pathogenic mechanisms in the metabolic syndrome. 02 Jun 2010

My project has four themes: 1) Characterising the phenotype and molecular properties of two novel forms of lipodystrophy due to mutations in two lipid droplet proteins, perilipin and CIDEC. Perilipin s biological role is well documented so I will define the human phenotype associated with the mutations and characterise the biological properties of the mutants. The biological function of CIDEC is poorly understood, so I will characterise the mutant and explore the protein s biology including d etermining its precise localisation, its structure and identifying interacting proteins. 2) To use patients with genetically defined forms of lipodystrophy to explore questions relating to more common diseases - a) To understand the mechanisms of adaptive thermogenesis in lipodystrophy using humans and animal models. b) To identify the major sources of fatty acids responsible for fatty liver and dyslipidaemia? c) To establish if mitochondrial dysfunction, a feature of T2DM, is a cause or conseq uence of insulin resistance? 3) To identify novel genetic causes of lipodystrophy using next generation sequencing platforms. 4) To establish protocols for adipocyte differentiation of induced pluripotent stem cells. These cells will be invaluable tools for characterising the consequences of novel and unidentified forms of lipodystrophy and, ultimately for therapeutic replacement strategies.

Amount: £1,200,001
Funder: The Wellcome Trust
Recipient: University of Cambridge

Inhibitory natural killer cell receptors: role and mechanism of action in hepatitis C virus infection. 02 Jun 2010

We have recently shown that specific combinations of inhibitory killer cell immunoglobulin-like receptors (KIR) and their HLA class I ligands determine the outcome of hepatitis C virus (HCV) infection. The goal of this project to is to understand how this protection works at a molecular level. There are three specific aims: To determine the role of KIR in the response of chronically infected individuals to interferon-a based therapies and whether the KIR:MHC class I interaction impacts on HCV diversity To determine how expression of the activating and inhibitory receptors on NK are "balanced"; and how specific KIR alleles affect this balance such that some KIR alleles protect against chronic infection with HCV. To investigate the peptide specificity of KIR as a mechanism that underlies their protective effect in HCV infection. This will test the hypothesis that different KIR have different peptide specificities and that diversity in peptide specificity is one reason why only specific KIR alleles are protective in HCV infection. These studies will give novel insights into NK cell receptor biology and can thus inform potential NK cell based therapies for chronic HCV infection.

Amount: £294,391
Funder: The Wellcome Trust
Recipient: Imperial College London

Characterisation of genetic variation regulating gene expression within the MHC class III region. 02 Jun 2010

Characterisation of genetic variation regulating gene expression within the MHC class III region This study aims to define DNA sequence variation that alters the way genes are regulated. The inability to identify regulatory DNA polymorphisms is a major roadblock to investigating the genetic basis of susceptibility to common multifactorial diseases. For variation resulting in a coding change in the translated protein, the consequences are amenable to functional prediction and testing. In contrast it is currently unclear how best to identify and analyse functionally important non-coding polymorphisms that modulate gene expression. I propose to define how allele-specific gene expression relates to sequence diversity in vivo across a 300kb region of the Major Histocompatibility Complex Class III region on chromosome 6. Until recently, it has been possible to analyse only a minority of genes for allele-specific expression due to the requirement for a transcribed marker polymorphism to distinguish between alleles. This study will be able to determine allele-specific expression among all combinations of variants at a given gene using a novel approach I have developed which quantifies the relative allelic loading of actively transcribing Pol II, the enzyme responsible for transcript synthesis. The endpoint of this research would be to resolve allelic differences in primary human cells in a disease state. However to attribute allelic differences to genetic variance on a given allele, heritability needs to be assessed. Therefore initial work will use a model system of lymphoblastoid B cell lines established from family pedigrees spanning three generations of individuals. Molecular mechanisms operating in vivo will be resolved by interrogating specific stages in the process of transcriptional regulation, epigenetic phenomena and protein-DNA binding. These molecular models of how genetic variants may modulate transcription will be tested by reporter gene analysis and by mutagenesis of large intact genomic regions transferred into cells. I will proceed to analyse candidate regulatory variants in other cellular contexts, notably primary human peripheral blood mononuclear cells.

Amount: £297,954
Funder: The Wellcome Trust
Recipient: University of Oxford

Impact of HLA class I alleles on immune control of adult and paediatric HIV infection. 27 Apr 2010

The overarching aim of the work undertaken in the applicant's research group is to better understand what are the CD8+ T cell responses mediating effective control of adult and paediatric HIV infection. In a population-based study in KwaZulu-Natal, South Africa, we showed that only Gag-specific CD8+ T cell responses are associated with low viraemia in chronic infection. Env- or Accessory/Regulatory-specific responses are associated with high viral loads. The first aim of the proposed work is therefore to determine whether Gag-specific responses are inherently more effective than non-Gag-specific responses, or whether these discordant associations with viral load are merely the consequence of chronic infection. The second aim is to determine whether HIV adaptation at an individual level is reflected by adaptation at a population level to these effective CD8+ T cell responses in Gag. The third aim is to extend studies initiated to examine whether CD8+ T cell response play an important role in control of paediatric HIV infection. Our preliminary data suggest that they do, both via the specificity of the responses generated in infancy by the child, and also via the impact maternal CD8+ T cell responses might have on the replicative capacity of transmitted virus.

Amount: £31,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Definition and Characterization of the Contribution of Neurocysticercosis to Seizure Burden in Endemic Areas. 25 Mar 2010

The larvae of Taenia solium commonly invades the human brain causing neurocysticercosis (NCC). Studies suggest that NCC is the most important factor associated with acquired epilepsy in developing countries and probably in the world, and thus an important public health problem. This project will assess the contribution of NCC to seizure burden both in field and hospital conditions, with particular emphasis in the study of symptomatic perilesional edema around calcified brain larvae. This phenome non is likely to be a significant contributor to neurological morbidity in endemic regions. The proposed fellowship program is composed of four studies: 1) A series of community-based surveys and active surveillance to monitor changes in seizure incidence following a massive control intervention in a previously endemic region. 2) Field-based study to compare the prevalence of peri-calcification brain edema in individuals with and without recent neurological symptoms; 3) Hospital-b ased cohort study to gather a population with symptomatic calcified NCC, to further characterize peri-calcification edema and frame a population for a treatment trial; and 4) A clinical trial in individuals with symptomatic peri-calcification edema, comparing acetazolamide or steroids to no treatment in terms of reducing the likelihood of symptomatic relapses without increased risks of drug side effects.

Amount: £916,623
Funder: The Wellcome Trust
Recipient: Universidad Peruana Cayetano Heredia

Identifying low frequency and rare genetic variation involved in type 2 diabetes using next generation sequencing data. 24 May 2010

To answer my research question, I will utilize the following datasets: Dataset 1: Whole genome sequence from 1500 Type 2 diabetes patients and 1500 characterised controls at 4 fold coverage. Dataset 2: Targeted sequencing of 50-200 selected genes from 480 young onset diabetes patients and 480 normo-glycaemic controls, at 50 fold coverage. Dataset 3: Variant data from the publicly available 1000 genomes project My project will then proceed in four stages. In Stage 1 I will use NGS data fr om datasets 1-3 to identify low frequency and rare variants in the coding regions of selected candidate genes. In Stage 2 I will annotate these variants including their likely functional effect and genomic context. In Stage 3 I will prioritise variants for follow up using a combination of criteria including nominal association (p<0.05). In Stage 4 I will follow up prioritised rare variants by genotyping in additional samples of up to 50,000 cases and equivalent numbers of controls. I will also t est the impact these variants have on beta-cell function and insulin resistance in well phenotyped non-diabetic cohorts. My fellowship will improve understanding of biological mechanisms involved in diabetes and may lead to stratification of individuals for treatment or preventative measures.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Exeter

The regulation of B cell responses during malaria infections. 24 May 2010

The literature provides strong evidence that germinal center B cell responses, and the subsequent generation of long-lived memory B cells and high affinity plasma cells, are impaired during malarial infections. We propose to examine the context in which antigen is presented in the follicle (whole parasites or just soluble protein antigen?), and to examine the cues that lead to an unusual positioning of plasma cells in the splenic T cell zone during P. chabaudi infection. The process of selection of high affinity germinal center B cells involves competition for antigen and for T cell help. We postulate that the release of large amounts of malarial antigens during periods of high parasitemia may lead to impaired selection of germinal center B cells. We aim to generate transgenic parasites expressing duck egg lysozyme, a low affinity antigen for the transgenic Hy10 B cells line, to enable us to follow the cognate response in vivo, and assess the efficiency of affinity maturation during ma laria infections. We will infect mice with different ratios of transgenic and WT parasites, to determine whether the availability of antigen plays a part in regulating the process of selection of high affinity B cells during malaria infection.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford

The Trypanosome flagellar pocket -functions and adaptations in differentiation, pathogenicity and immune evasion. 24 May 2010

Cell body architecture of unicellular organisms influences a variety of cellular functions. The goal of this research is to understand how a specialised invagination of the trypanosome cell surface membrane called the flagellar pocket (FP) functions in differentiation, pathogenicity and immune evasion. I will investigate the stumpy form FP to determine what structures distinguish it from other lifecycle stages. I will perform a highly detailed electron tomography study on the FP, correlat e this with specific functions of the FP and then determine the effects of temperature and lifecycle progression on FP structures. This will enable me to understand how trypanosomes use their FP to perceive and respond to changes in their environment as they move between the mammalian and insect hosts. I will then combine reverse genetics with live cell imaging and molecular and cellular biology techniques to investigate specific questions relating to how some proteins are retained within th e FP whereas other proteins traffick freely to the bulk surface membrane. I will dissect the mechanism of protein retention within the FP and determine what role proteins signals, motifs and facilitator proteins play. I will also investigate the specificity of FP protein release that is observed under some conditions.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford