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The Wellcome Trust

Results

UK human iPS cell consortium: genotype to phenotype. 17 Apr 2012

We will exploit the opportunities of the UK National Health Service to generate a national resource of human iPS cells and associated data. We will generate and bank lines from 700 healthy and 800 disease-associated individuals, optimising techniques for iPS cell production and quality control. Cells will be subjected to extensive analysis of genome, epigenome, gene expression and proteome. For cells from healthy individuals, in-depth analysis of inter-individual variability will provide an open access platform for association studies of cellular function, and for distinguishing pathological from physiological variation. Patient collections will be selected via an open call, focusing initially on well-characterised conditions, where a single genetic lesion underlies a pleiotropic clinical phenotype. To characterise cellular phenotype we will construct high throughput artificial microenvironments. We will evaluate cell death, differentiation, morphology and division and specific signall ing pathways. We will collaborate to produce protocols to differentiate iPS cells into disease-relevant cell types. These approaches will provide in vitro readouts of inter-individual variation and disease and a platform for gene correction and engineering specific mutations into different genetic backgrounds. Our proposal will give researchers in the UK and beyond access to iPS cells and technology linked to extensive genetic, cellular and clinical information.

Amount: £1,550,170
Funder: The Wellcome Trust
Recipient: King's College London

UK human iPS cell consortium: genotype to phenotype. 17 Apr 2012

We will exploit the opportunities of the UK National Health Service to generate a national resource of human iPS cells and associated data. We will generate and bank lines from 700 healthy and 800 disease-associated individuals, optimising techniques for iPS cell production and quality control. Cells will be subjected to extensive analysis of genome, epigenome, gene expression and proteome. For cells from healthy individuals, in-depth analysis of inter-individual variability will provide an open access platform for association studies of cellular function, and for distinguishing pathological from physiological variation. Patient collections will be selected via an open call, focusing initially on well-characterised conditions, where a single genetic lesion underlies a pleiotropic clinical phenotype. To characterise cellular phenotype we will construct high throughput artificial microenvironments. We will evaluate cell death, differentiation, morphology and division and specific signall ing pathways. We will collaborate to produce protocols to differentiate iPS cells into disease-relevant cell types. These approaches will provide in vitro readouts of inter-individual variation and disease and a platform for gene correction and engineering specific mutations into different genetic backgrounds. Our proposal will give researchers in the UK and beyond access to iPS cells and technology linked to extensive genetic, cellular and clinical information.

Amount: £305,682
Funder: The Wellcome Trust
Recipient: Embl At Hinxton

Sleep and Circadian Neuroscience Institute (SCNi) 17 Apr 2012

Sleep and circadian rhythm disruption (SCRD) is a clinically important feature of severe neuropsychiatric disorders, but it is rarely viewed as pathophysiologically significant, nor are its consequences appreciated or its treatment prioritised. However, emerging data challenge these assumptions, with increasing evidence that SCRD is important in illness onset, overall physical health and as a therapeutic target. Developments in circadian neuroscience now permit a meaningful scientific investigat ion of these important but neglected issues. Building upon our recent findings, and a unique breadth of expertise and shared interest, we propose to bring together molecular and systems neuroscientists, psychiatrists, psychologists, and bioengineers, to form a virtual Sleep and Circadian Neuroscience Institute (SCNi). We aim to: 1) Understand the causal relationships between SCRD and the psychoses, testing the hypothesis that pathways common to both account for the comorbidity, using preclin ical and clinical approaches. 2) Develop evidence-based interventions that correct SCRD and improve health. 3) Provide training and teaching materials in sleep/circadian neuroscience for psychiatry. 4) Disseminate research knowledge and treatment packages using web-based platforms. 5) Develop novel telemetric devices for home-based measurements of sleep and circadian physiology. SCNi will be truly multidisciplinary and translational, and will achieve these goals through five i nterlinked themes, described in Q10.

Amount: £4,434,125
Funder: The Wellcome Trust
Recipient: University of Oxford

Dermatology and Genetic Medicine: A multidisciplinary research initiative aimed at translating basic science discoveries in genetic skin disease into clinical application. 17 Apr 2012

Dermatology is an under-resourced area of research, however, the University of Dundee has established a critical mass of internationally competitive researchers in genetic skin disease and cutaneous therapy development. This award will strengthen this multidisciplinary research centre and catalyze further clinically applicable research at the interface of genetics, dermatology and drug discovery. Specifically, a large collection of diverse monogenic disorders accumulated through a UK genoderma tology network will be analysed using whole exome sequencing approaches, informed by transcriptome analysis. Targeted sequence capture and next-generation sequencing of loci identified by genomewide association studies will discover new causative variants in eczema, in addition to streamlining analysis of the large, repetitive filaggrin gene. Our previous genetics work has identified a number of new therapy targets tractable by small molecule approaches, which will extended here. A profession ally-managed biotech-style cutaneous drug discovery portfolio will be developed (3 projects already initiated) and extended to run 15 high-throughput screens, supported by hit validation and early hit-to-lead chemistry, with the aim of taking at least 2 dermatology targets through to pharmaceutical partnering. Animal and cell-culture platforms for assessing cutaneous drug/siRNA delivery/efficacy will be established. This award will also strengthen our capacity for patient outreach and training of new investigators.

Amount: £5,869,875
Funder: The Wellcome Trust
Recipient: University of Dundee

Karonga Prevention Study (KPS) : whole genome sequencing in a whole population: supplementary proposal for tuberculosis whole genome sequencing. 30 Nov 2011

HIV, tuberculosis and pneumococcal disease are leading causes of mortality and morbidity in Africa. They interact, and undermine development. Control measures exist but are inadequate (HIV, tuberculosis) or unproven (pneumococcus). By combining the established large-scale Karonga epidemiological studies and knowledge of long-term disease trends with detailed laboratory and genomic analysis we will: 1. measure pneumococcal carriage, transmission and serotype change at a household level fo llowing pneumococcal conjugate vaccine (PCV) introduction into the EPI schedule, trial alternate PCV schedules, and determine options to maximise vaccine benefits using modelling methods. 2. identify where M.tuberculosis is being transmitted by screening patients at antiretroviral clinics, by tuberculin testing and by defining transmission chains using whole genome sequencing, to target control efforts. 3. establish genomic determinants of virulence in M.tuberculosis by comparing s trains that have transmitted and caused disease with those that have not, and investigate long term non-progression of latent infection to better understand the host and pathogen determinants of M.tuberculosis natural history 4. assess the long-term direct and indirect benefits and limitations of antiretroviral therapy on adults and children. We will continue to develop the capacity of the site as a centre of excellence for research and training, relevant to Malawi.

Multicentre Clinical evaluation of a neonatal seizure detection algorithm. 13 Apr 2012

Multicentre clinical evaluation of a neonatal seizure detection algorithmSeizures are difficult to detect in new-born babies and can be a marker of brain injury, resulting in lifelong disability. Treating seizures early is more successful than treating them at a later point, and there is evidence to show that controlling seizures can reduce brain damage. Seizures cannot be treated unless clinicians have an accurate way of measuring them – recognising seizures by observing the baby alone is not reliable.The only way to accurately detect these events is to monitor electrical brain patterns using wires attached to the scalp (EEG). However, EEG signals are very difficult to interpret and full-time monitoring of EEG outputs by trained clinicians is not practical. Using funding from a Translation Award, Liam Marnane and colleagues at the University College Cork have developed an automated intelligent EEG computer program that can detect seizure accurately. They will now test the system in neo-natal intensive units around the world to show its benefits for new-borns. The goal is to make the software reliable and compliant with international regulatory requirements so that it is suitable for inclusion in multiple medical monitors.

Amount: £2,619,942
Funder: The Wellcome Trust
Recipient: University College Cork

Chemokine-based microbicides: Bridging from a first-in-human study to a pathway to licence 16 Jul 2012

HIV/AIDS is still a catastrophic public health problem. Recent estimates show 2.3 million new infections per year and 1.6 million deaths among the 35 million people living with the disease. The problem is 95%+ in the developing world: young people, especially women and girls, are particularly vulnerable. The highest risk in rich countries is from receptive anal intercourse, with both women and men involved. Although HIV/AIDS has become a largely treatable condition in rich countries, serious long-term complications are now emerging: cardiac, metabolic, mental health, cancer-related, accelerated ageing. Prevention is therefore key. A working vaccine still seems years away but another strategy is the use of ‘microbicides’, anti-HIV compounds applied to the genital areas to prevent infection during sex. One such substance is called 5P12-RANTES. It is among the most potent anti-HIV substances known, potentially safer than many alternatives, and much better at avoiding drug resistance. Thanks to previous support from the Trust, a means of manufacture has been found opening the way to cheap manufacture even in some developing countries. The proposed project by Professor Robin Offord and colleagues at the Mintaka Foundation will allow a potential major backer to trial it in rectal use; permit development of long-acting formulations for vaginal and rectal use; and further reduce production costs with a view to transferring manufacture to developing countries.

Amount: £110,000
Funder: The Wellcome Trust
Recipient: Mintaka Foundation for Medical Research

Development of effective rift valley fever vaccines for use in sheep and humans. 21 Jun 2012

Rift Valley fever (RVF) is a mosquito-borne viral zoonosis that invariably causes death of newborn lambs and abortion in pregnant ewes. Human disease follows close contact with infected animal tissue and body fluids and is characterized by a mild febrile illness that occasionally progresses to a life-threatening haemorrhagic syndrome. No licensed vaccine is available for human use and that used in livestock is not safe for use in pregnant animals. Thus, the proposed research aims to develop a re combinant viral-vectored vaccine for use in sheep and humans. The RVF viral glycoproteins, Gn and Gc, that are targets of neutralizing antibodies, will be inserted into modified vaccinia virus Ankara (MVA) and a simian adenovirus (ChAdOx1) vector. These MVA-GnGc and ChAdOx1-GnGc vaccine constructs will then be assessed for immunogenicity in mice and the regimen yielding the highest neutralizing antibody titre identified. Finally, this regimen will be tested for efficacy against RVF in immunized sheep challenged intravenously with a virulent RVFV isolate. If protective, the immunization regimen will form the basis of a future sheep vaccine and provide proof-of-concept for human clinical trials.

Development of a cytotopically-modified antithrombotic agent for prevention of acute intra-graft thrombosis in transplantation 01 Mar 2012

"Dr Richard Smith and Professor Anthony Darling of the MRC Centre for Transplantation at King's College London have received a Translation Award to develop a peptide-based anti-thrombin agent that is capable of rendering a transplanted organ resistant to thrombosis without using systemic anticoagulation . This is achieved by perfusing the organ with a membraneinteractive ("cytotopic") agent (which sticks to the organ vasculature) and then flushing out excess agent prior to transplantation. At least 25% of patients currently on the waiting list for renal transplantation are there because they have pre-existing antibodies against potential donor tissue. Attempts to transplant organs into such patients result in thrombosis within the organ which is difficult to treat with conventional anticoagulants and can lead to severe graft damage. The translation programme will refine processes for the manufacture of the lead cytotopic agent ("Thrombalexin') and will include safety studies to enable a firstin- man study in patients at high risk of intra-graft thrombosis following renal transplantation."

Amount: £1,580,495
Funder: The Wellcome Trust
Recipient: King's College London

The development of a human growth hormone nasal spray to treat paediatric growth hormone deficiency. 16 Jul 2012

Human growth hormone (hGH) therapy is used to treat growth hormone deficiency (GHD) and other paediatric conditions e.g. Turners syndrome, idiopathic short stature and low gestational weight. The market for hGH replacement therapy was $2.8billion in 2007. hGH replacement therapy requires daily injection of hGH. Studies show that 36-49% of paediatric patients do not adhere to prescribed regimens, 70% are unhappy with injecting themselves daily, and 30% are considering stopping their treatment. This reduces efficacy and increases healthcare costs. There is a significant unmet clinical need for treatment options that can increase patient adherence. Critical Pharmaceuticals has developed CriticalSorb an efficient novel nasal hGH delivery system that allows replacement of a daily injection with a daily nasal spray of hGH. This nasal spray will increase patient adherence by avoiding painful and complex administration procedures. A technology transfer award will allow a clinical assessment of the effectiveness of the hGH nasal spray in a Phase 1 clinical trial. The key goals of the proposed research are to: " Optimise the current prototype nasal formulation " Obtain human pharmacokinetic, pharmacodynamic and nasal tolerability data on lead formulations " Obtain long term non-clinical nasal tolerability data on the lead formulation

Amount: £50,000
Funder: The Wellcome Trust
Recipient: Critical Pharmaceuticals Limited

Translational Medicine and Therapeutics Programme at the University of Cambridge: 'Molecular imaging of glycosylation changes in Barrett's oesophagus to detect dysplasia: endoscopic and radiological applications.' 31 Aug 2012

To determine whether glycans can be used as molecular imaging targets. We hypothesise that labelled glycan can be detected endoscopically and thereby guide biopsies to macroscopically normal areas of dysplasia within Barrett’s oesophagus as prior to more generalized application in the aerodigestive tract.An in vivo endoscopic molecular imaging study using lectin-guided biopsies in the surveillance of BE will be completed as well as adapting a bioorthogonal chemistry approach from an animal model to label the human oesophageal glycome in human organ culture as a step towards to imaging of the human glycome without the application of lectins for imaging.

Amount: £182,345
Funder: The Wellcome Trust
Recipient: University of Cambridge

Translational Medicine and Therapeutics Programme at the University of Cambridge: 'Activating Akt mutations and metabolism: translational and therapeutic opportunities.' 21 May 2012

To elucidate the mechanisms by which the AKT2-E17K mutation affects the regulation of the downstream substrates involved in glucose and lipid metabolism in vitro approaches including western blotting, immunoprecipitation, quantitative PCR and confocal microscopy will be used. Complementary studies with AKT inhibitors will be performed and their effects on the above outcomes will be assessed. Transgenic mouse models of the Akt2-E17K and Akt1-E17K mutations have been obtained and detailed phenotyping of these mice will provide in vivo insights into the consequences of the E17K mutation as well as reveal important insights into the isoform specific functions of these enzymes. In addition, these mice will be used for pre-clinical studies investigating the clinical efficacy of compounds that impact upon AKT signalling. Collectively, the data collected from these studies will inform future clinical studies investigating the efficacy of AKT inhibitors in disease states characterised by hyperinsulinism.

Amount: £144,918
Funder: The Wellcome Trust
Recipient: University of Cambridge

Interdisciplinary Training Programme for Clinicians in Translational Medicine and Therapeutics at the University of Cambridge: Support for the 2012 MPhil Appointments. 31 Aug 2012

We propose an innovative training scheme for Translational Medicine and Therapeutics (TMAT) which builds on the exceptional conjunction on the Cambridge campus of leading scientists and clinical specialists, with an industrial research environment embraced both by international pharmaceutical and local biotech companies. Much of this is found under the same roof, the Addenbrookes Centre for Clinical Investigation (ACCI), with a track record of integrated training: academic with industrial, clinical with scientific, pharmacology & therapeutics with patient-based specialties. The novel TMAT programme will attract the brightest candidates at several levels of seniority, ranging from MB PhD students to clinical lecturers, some wishing translational skills in their chosen specialty, others not yet differentiated who may become future leaders and teachers of TMAT. Each trainee will have a customised programme. Part of this will be a bespoke, modular MSc modelled on the well-known small-group lectures and supervisions of the Cambridge final year undergraduate courses. However the centrepiece for most candidates will be a PhD including formal teaching in a wide range of translational and pharmacological skills, and a project which takes proof-of-concept studies in cell or animal systems forward to proof-of-concept studies in humans. We have assembled an outstanding faculty of PhD supervisors spanning a wide choice of skills and experience in basic and clinical science. All trainees will have the opportunity for hands-on exposure to the design and conduct of experimental medicine studies investigating the therapeutic potential of new drugs, in collaboration with our industrial partner, GlaxoSmithKline (GSK). Our product will be a new generation of clinician scientists with 360-degree vision of the complex landscape of modern therapeutic medicine, who can rise to the challenges and opportunities of 21st century drug development.

Amount: £18,531
Funder: The Wellcome Trust
Recipient: University of Cambridge

Training Programme in Translational Medicine and Therapeutics at the University of Cambridge: 'Novel therapeutics in multiple sclerosis and regulation of the immune system'. 17 Sep 2012

This project has two key goals: to investigate the role of IL7 and IL7R in the pathogenesis of multiple sclerosis and, in so doing, to educate a young physician about translational medicine. It is built upon the observations that IL7R is genetically associated with multiple sclerosis and that an antibody which antagonises IL7R ameliorated the animal model of multiple sclerosis by downregulating TH17 cells. The research question is: does antagonism of the IL7/IL7receptor pathway reduce disease activity in multiple sclerosis?The applicant will first investigate the in vitro consequences to lymphocyte biology of IL7R genotype; then explore the effect of this genotype on reconstitution of the lymphocyte repertoire therapeutic depletion. Then he will take part in a first-in-human anti-IL7R antibody trial in healthy individuals and people with multiple sclerosis. He will be involved in the design and execution of the clinical trial and the parallel laboratory studies.

Amount: £247,313
Funder: The Wellcome Trust
Recipient: University of Cambridge

Translational Medicine and Therapeutics Programme at Imperial College London: 'The genetic determinants of right ventricular dysfunction'. 31 Aug 2012

Right ventricular failure is a major determinant of survival in pulmonary hypertension (PH). Some patients tolerate pressure overload for a considerable period, while other deteriorate more rapidly. Right ventricular (RV) hypertrophy is the typical response of the compensated myocardium. Patients who deteriorate exhibit dilatation. The factors underlying this differential response are poorly understood. 3D cardiac magnetic resonance (CMR) provides high spatial definition and, coupled with atlasing techniques, provides improved power in detecting regional changes in anatomy and physiology. I propose to employ this approach in a detailed study of the RV response to PH to better understand the transition from a compensated to a decompensated myocardium. I will: 1. Develop an atlas for the right heart in healthy volunteers using 3D CMR to examine the population variation in anatomy and physiology. 2. Correlate this with anthropometric and cardiac data (e.g. ECG, blood pressure) to understand the variables that influence mass, shape and ejection fraction. 3. Explore for association between RV phenotype and genomic variants. 4. Use CMR data to compare and describe the RV in a cohort of patients with PH. 5. Relate changes in RV anatomy and function during a 1 year period of follow up to (i) survival in the PH cohort and (ii) genomic variants associated with RV phenotype.

Amount: £337,483
Funder: The Wellcome Trust
Recipient: Imperial College London

Scottish Consortium TMaT Programme: 'Characterising the development of chemotherapy induced peripheral neuropathy (CIPN) and assessing a novel TRPM8 agonist treatment, using functional magnetic imaging resonance (fMRI)'. 21 May 2012

We propose a first-class training programme to create a cadre of clinical academics withoutstanding TMT capabilities [Glossary:Annex-A], building on an established collaboration among internationally competitive scientists within four Scottish clinical academic institutions and a leading global pharmaceutical company, Wyeth (TMRC, value ~£50million). STMTI will focus initially on translational approaches to disorders of high priority in which considerable unmet clinical need remains, and where there is compelling opportunity for ‘pathogenesis-to-clinic’ transition. Thus, cardiovascular/metabolic, inflammation, musculoskeletal, neuroscience and reproductive health themes are proposed [Annex-B]. STMTI builds on a well-established collaboration among academia, industry, NHS and government, combining complementary strengths in drug discovery and the various stages of drug development. Critically, all relevant enabling tools – bioinformatics, genetics, proteomics, imaging, biomarker development and high- quality phenotyping – are available. STMTI employs established, well-developed and nationally networked clinical research facilities, and an associated Scottish-wide research education programme. STMTI thereby creates an innovative interdisciplinary TMT training programme that will allow seamless academic career progression for outstanding clinicians: from MSc certification to clinical PhD training, and onwards to academically-protected clinical lectureships. STMTI will place its fellows in an enviable and highly competitive position for a career in TMT and ultimate appointment to senior academic positions.

Amount: £215,422
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Jewish mothers and Jewish babies: Childbearing and childrearing amongst Jewish women in England and Israel c. 1948-1990. 13 Jun 2012

Combining archival research with oral history, this research will contrast the experience of three groups: (i) women from Jewish communities in England, (ii) Jewish women of European (Ashkenazi) heritage in Israel and (iii) Jewish women of North African and West Asian (Mizrahi) heritage in Israel, in order to examine the relationship between scientific and religious discourses in the fields of maternal and child health. The project seeks to question existing historical interpretations which hav e viewed the approbation of medical technologies that intervene in maternity and reproduction as a facet of modernity and secularization. The project will examine the national and cultural differences that led to the divergence in responses towards the medicalization of birth in the two countries and will ask whether the Israeli state imposed one model of maternity care specifically in order to deal with the diversity of its population and establish national unity. It will interrogate how diff erent traditions of collective childcare in England and Israel shaped mothers' experiences, and the flow of ideas on child development between the two nations. Finally it will explore the effects of the different patterns of migration and settlement upon the three groups' experiences of childbearing and childrearing.

Amount: £229,613
Funder: The Wellcome Trust
Recipient: University of Warwick

Biomedical Vacation Scholarship 25 Jun 2012

Not available

Amount: £1,440
Funder: The Wellcome Trust
Recipient: Quadram Institute Bioscience

Biomedical Vacation Scholarship. 25 Jun 2012

Not available

Amount: £1,440
Funder: The Wellcome Trust
Recipient: University of Portsmouth