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Results

Translational Medicine and Therapeutics Programme at the University of Cambridge: 'The apelin-ACE-2 axis in cardiopulmonary disease'. 31 Aug 2011

The objective of the project is to test the hypothesis that apelin signalling is altered in PAH and that apelin may be a new mediator and potential new drug target for this condition. Basic and translational research into the pharmacological actions of apelin has been hampered by a lack of selective agonists and antagonists. Two novel molecules have recently been discovered by the group: MM07 an agonist and MM54, a competitive antagonist at the apelin receptor (APJ). This project will focus on identifying the cellular expression of apelin and APJ and measuring APJ densities and pharmacological characteristics in lung and right ventricle from patients with PAH to determine changes in the apelin/APJ system in this disease. Parallel studies will be carried out in heart and lung of the monocrotaline-treated rat to discover if this model reflects the changes in the apelin system in human tissues. I will determine the effects of MM07 and MM54 on progression of PAH in this animal model to identify whether pathway stimulation or blockade improve outcome. In collaboration with Dr I Wilkinson, I plan to perform forearm plethysmography in healthy subjects. If successful, it would be possible, subject to ethics approval, to perform limited studies in PAH patients.

Amount: £268,427
Funder: The Wellcome Trust
Recipient: University of Cambridge

Training Programme in Translational Medicine and Therapeutics at the University of Cambridge: 'Comprehensive analysis of structural rearrangements in the progression from Barrett's oesophagus to oesophageal adenocarcinoma.' 30 Nov 2010

Oesophageal adenocarcinoma has a dismal prognosis; median survival is <1 year. It is thought that chromosomal rearrangements (including inversions, translocations, deletions and insertions) may play as much of a role in the development of cancer as the more thoroughly studied point mutations. Paired-end Sequencing allows rapid analysis of virtually all breakpoints in a tumour to a resolution of 500bp. Simultaneously it provides highly accurate copy number data comparable to that from arrayCGH. The Barrett's-?Dysplasia-?OAC is a well recognised paradigm. Ease of accessibility and longitudinal sampling as part of standard clinical practice provides a unique opportunity to study the biology of progression in epithelial carcinoma. Key Goals 1. Investigate structural rearrangements and copy number abnormalities involved in the genesis of oesophageal carcinoma in a small group of carefully selected patients with samples representing Barrett's oesophagus, Oesophageal adenocarcinoma and normal tissue from the same patient. 2. Confirm the importance of individual structural rearrangements by screening a large collection of primary tissue samples and comparison with clinical outcome 3. Functional assessment of potential therapeutic targets 4. Investigate the potential of personalised assays, based on unique structural rearrangements, for tumour cell-free DNA in patient serum as markers of disease status

Amount: £97,095
Funder: The Wellcome Trust
Recipient: University of Cambridge

Genetic and functional mapping of gene deserts in complex disease. 09 Mar 2011

It is suggested that as much as 93% of the human genome is transcribed although only 1.5% encodes proteins. The remaining transcriptional activity is presumably due to non-coding RNAs that regulate the expression of distal genes. Transcriptionally active DNA is discernible by the presence of certain histone modifications and transcription factor binding. There are some well-characterised examples of intergenic, transcriptionally active regions which are tissue specific and show limited sequence conservation but are affected by DNA polymorphisms. Some large intergenic regions, ( gene deserts ) have been identified as susceptibility loci in common diseases by genome-wide association studies. This further advocates that non-coding DNA has an important functional role. At least 12 of the 71 loci involved in Crohn's disease (CD) are gene deserts . We will use chromatin immuno-precipitation (ChIP) and RNA profiling to interrogate chromatin architecture and transcriptional activity at thes e loci in intestinal tissues from CD patients. New-generation sequencing (NGS) of recovered DNA and RNA will allow the identification of regulatory regions that co-localise with CD risk SNPs and potentially disease causing. We will then examine regulatory SNPs for association with changes in distal gene expression in primary tissues from CD patients by NGS of mRNA from colonic biopsies.

Amount: £471,730
Funder: The Wellcome Trust
Recipient: King's College London

Age-dependent beneficial effects of PI3-Kinase pathway inactivation on glucose and lipid homeostasis: Mechanisms and therapeutic potential in metabolic disease. 12 Oct 2010

Preliminary data demonstrate that inactivation of PI 3-Kinase p110alpha exerts a beneficial effect on glucose and lipid homeostasis in aged mice. We will dissect the mechanism underlying this effect. We will use constitutive or conditionally p110alpha gene-targeted mice. Muscle and adipose tissue are peripheral tissues with key roles in the regulation of glucose and lipid homeostasis. We will therefore specifically inactivate p110alpha in these tissues to assess their contribution to the phenoty pe of global p110alpha inactivation. To achieve this, we will challenge young and aged p110alpha gene-targeted mice with high-fat feeding followed by comprehensive metabolic phenotyping. In order to elucidate the molecular mechanisms underlying these effects, we will characterise signalling pathway activation and perform transcriptome analysis in insulin-sensitive tissues of these mice. We will also assess the effect of p110alpha inactivation on cellular bioenergetic capacity by studying mitoch ondrial biogenesis and function. The genetic experiments will be complemented by pharmacological inhibition and RNA interference of p110alpha expression in primary cells or established cell lines representative of insulin target cells. Our ultimate aim is to provide proof-of-principle that the p110alpha signalling pathway can be therapeutically targeted in the prevention/treatment of age-dependent obesity and type-2 diabetes and promote healthier ageing.

Amount: £567,855
Funder: The Wellcome Trust
Recipient: University College London

Biomedical Vacation Scholarship. 20 May 2011

Not available

Amount: £5,760
Funder: The Wellcome Trust
Recipient: University of Liverpool

Biomedical Vacation Scholarship. 20 May 2011

Not available

Amount: £1,520
Funder: The Wellcome Trust
Recipient: University of London

Biomedical Vacation Scholarships 20 May 2011

Not available

Amount: £7,200
Funder: The Wellcome Trust
Recipient: University of Leeds

Biomedical Vacation Scholarships 20 May 2011

Not available

Amount: £7,200
Funder: The Wellcome Trust
Recipient: University of East Anglia

Biomedical Vacation Scholarship. 20 May 2011

Not available

Amount: £4,560
Funder: The Wellcome Trust
Recipient: University of Westminster

Biomedical Vacation Scholarship. 20 May 2011

Not available

Amount: £35,530
Funder: The Wellcome Trust
Recipient: University College London

Biomedical Vacation Scholarship. 20 May 2011

Not available

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

Biomedical Vacation Scholarship. 20 May 2011

Not available

Amount: £1,520
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Biomedical Vacation Scholarship. 20 May 2011

Not available

Amount: £1,520
Funder: The Wellcome Trust
Recipient: Roehampton University

Biomedical Vacation Scholarship. 20 May 2011

Not available

Amount: £7,200
Funder: The Wellcome Trust
Recipient: University of Southampton

A Versatile, Minimally-Invasive Treatment for Cancer: Applying Temporal Focusing to Photodynamic Therapy. 06 Dec 2010

The goal of this research is to demonstrate that temporal focusing combined with two-photon absorption and photodynamic therapy can treat a tumour that is located within a mass of tissue. In year one, the goal will be to construct the optical setup, characterise it, demonstrate automated control of the illumination parameters, and demonstrate the ability to selectively illuminate regions of a test mass such as a dye-doped gel block. In year two, the goal will be to optimise the optical se tup, and selectively generate singlet oxygen at a defined site with high spatial resolution. Diagnostic imaging methods such as stimulated Raman scattering or optical coherence tomography will be investigated for incorporation. In year three, the effectiveness of the system will be tested on cell-lines in order to demonstrate that the cells can be selectively targeted. Diagnostic imaging will be finalised and incorporated, allowing a mixture of healthy and cancerous cells (taken from cell-lin es) to be differentiated, and the cancerous cells killed. The final year will be back in the UK; the system will be reconstructed (with any modifications deemed necessary). Subject to a successful outcome, applications will be made to test the system in animal models and possibly clinical trials.

Amount: £97,476
Funder: The Wellcome Trust
Recipient: Massachusetts Institute of Technology

Development of novel meta-machine learning algorithms for the integration of genomic and neuroimaging data for genetic pathway discovery: application to Parkinson's disease and schizophrenia. 27 Jan 2011

My proposed study is focused on computational approaches to identify genetic risk factors via the fusion of genomic and neuroimaging data on Parkinson's Disease and schizophrenia in order to discover pathways of genetic changes that are associated with increased risk for these diseases and that act directly on neuroimaging intermediate phenotypes associated with each disease. In order to do so, I will develop a novel meta-machine learning algorithm for the integration of these two disparate sources of data to increase the ability to detect pathways impacting on disease and imaging phenotypes.

Amount: £70,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Development of Smart Cane, an affordable above-knee obstacle detection and warning system for the visually impaired Watch (1 min) 04 Jun 2010

The Indian Institute of Technology (IIT) Delhi has developed the Smart Cane, a navigation and mobility aid for visually challenged people. The Smart Cane is an innovative device that can be mounted on a traditional white cane to enhance its functionality, resulting in improved mobility and safety, while reducing dependence on sighted assistance.White canes are currently the most commonly used visual mobility aid; however, a white cane can only detect certain types of obstacles within a limited range and cannot detect obstacles that are above the knee (e.g. a steel bar on the road) or protruding (e.g. a tree branch or an open window).The Smart Cane device uses ultrasonic sensors to detect obstacles up to 3m away, and the range of the detected obstacles is conveyed using vibratory signals with different vibration characteristics. It is designed as a user-detachable unit and is powered by rechargeable Li-ion battery. The design emphasis has been on making an affordable device, and it is currently expected to cost less than Rs 2000 (£30) to the end user.This project targets the design of a manufacturable device, optimising it based on user feedback from field trials and making it ready for regulatory approvals and certification. It has been proposed that extensive user trials should be carried out at multiple locations in the next 18 months. The project is being jointly undertaken by IIT Delhi with an industrial partner, Phoenix Medical Systems (P) Ltd, Chennai. The third partner in the project is Saksham Trust, New Delhi, who have domain expertise and links to the network of organisations working for the visually impaired.

Amount: £254,162
Funder: The Wellcome Trust
Recipient: Indian Institute of Technology Delhi

The establishment of a large case collection of childhood atopic dermatitis: a resource for genetic research 13 Oct 2009

Atopic dermatitis (AD; eczema) is the commonest inflammatory disease of childhood and causes a very significant burden of disease. AD leads to a markedly increased risk of associated food allergy, asthma and allergic rhinitis. While mutations in the skin barrier protein filaggrin are the strongest genetic risks identified to date, the genetic basis of AD remains poorly understood and there is a pressing need for additional large scale genome wide association studies (GWAS) on well-phenotyped, et hnically homogeneous populations to identify further genetic factors. This Biomedical Resources Grant has the key objective of generating a large collection of well-phenotyped paediatric AD cases suitable for GWAS and other studies investigating the genetic susceptibility of atopic dermatitis. In order to maximise efficiency, standardise clinical governance and quality of data and sample collection, the application will utilise established Clinical Research Centres including the Wellcome Trus t Clinical Research Facility in Manchester. To ensure the collection is processed rapidly, the collaboration will be performed in 9 clinical centres where large numbers of children with atopic dermatitis regularly attend for secondary and tertiary care. To ensure sustainability and compatibility with other collections, we will regularly collaborate with the two other leading groups in the field.

Amount: £223,031
Funder: The Wellcome Trust
Recipient: Trinity College Dublin
Amount: £1,267,815
Funder: The Wellcome Trust
Recipient: University of Exeter