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Recipients:
University of Cambridge

Results

Investigating the phenotype, function and interactions of tissue-resident B cells 30 Sep 2016

Tissue-specific immunity is shaped by the local milieu. In organ systems that interface with the environment (e.g. skin, gastrointestinal tract), exogenous signals generated by commensals or diet can profoundly influence resident immune cells. In non-interfacing tissues (e.g. kidney), endogenous signals such as interstitial osmolality may also influence the immune landscape. Tissue epithelial cells play an important role as environmental sensors and may instruct local immune responses. In addition, environmental cues may be directly detected by resident immune cells. To date, studies of tissue sentinels have focused on innate immune cells and on T cells with limited data on B cells. We have preliminary data from human and murine kidneys, and from human liver tissue and murine bladder tissue demonstrating the presence of tissue-resident B cells. In humans, they are predominantly of a memory phenotype. We hypothesize that tissue-resident B cells make an important contribution to local immune responses and that their localization and function will be determined by tissue-specific environmental cues. This project aims to investigate the phenotype of these tissue resident B cells (both in mouse and human), their antigenic specificity, origin, function and interaction with other cells.

Amount: £235,304
Funder: The Wellcome Trust
Recipient: University of Cambridge

Infectious disease engagement activities in Sierra Leone during the post-Ebola recovery period 24 Feb 2016

We aim to understand the mechanistic basis for why GII.4 noroviruses have dominated for the past 15 years as well as identifying new mechanisms of controlling and preventing norovirus infection. One goal of the project will determine the contribution of the viral RNA polymerase fidelity and activity to norovirus pathogenesis as the enzyme from pandemic noroviruses is more error prone and has higher activity than non-pandemic noroviruses. We will use cutting edge sequencing methods to characteris e norovirus evolution in the human population, identifying possible pandemic signature mutations in the viral RNA polymerase. We will then characterise the effects of these mutations on RNA polymerase activity, virus replication and virus pathogenesis, identifying new vaccine strategies. State of the art quantitative proteomics will be used to determine the effect of the norovirus replication on the host cell and the role of these pathways examined in more detail. We will then identify small mol ecule inhibitors of these pathways and examine if they have anti-norovirus activity. We will also consider the role of the host cell RNA quality control pathway in the norovirus life cycle as our preliminary data indicates that this pathway provides an attractive therapeutic target

Amount: £59,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Receptor tyrosine phosphatases in physiology and disease. 21 Oct 2015

The reversible phosphorylation of tyrosine residues on proteins serves as a critical switch in the regulation of fundamental cellular processes and is controlled by the antagonistic actions of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Dysregulation of this balance is associated with numerous diseases as well as developmental abnormalities. Located at the cell surface, the receptor subfamily of PTPs (RPTPs) have the potential to function as key environmental sensors by me diating important processes such as cell-cell adhesion and intercellular signalling. Moreover, several RPTPs have recently been implicated in physiological functions important for human health, yet the physiological roles, substrates and regulation of many receptors remain elusive. The receptor PTPRK was identified as a candidate tumour suppressor in the mouse intestine by a forward genetics screen. In humans it is mutated in ~10% of colorectal cancers, and is a recurrent gene fusion partner, re sulting in heterozygosity. My goal is to use a multidisciplinary approach to reveal the physiological role of PTPRK, initially in gastrointestinal homeostasis, and to identify regulators and substrates that are key to its function. These advances will reveal new modes of cell signalling through tyrosine dephosphorylation and novel cellular mechanisms that serve to restrain oncogenic kinase signalling.

Amount: £1,074,941
Funder: The Wellcome Trust
Recipient: University of Cambridge

Ischia Summer School on the History of the Life Sciences 31 Aug 2016

The Ischia Summer School on the History of the Life Sciences provides advanced training in history of biology and medicine in a historically rich and naturally beautiful setting for 26 PhD students and postdoctoral fellows, with strong UK representation. Lectures and seminars at the Ischia branch of the Naples Zoological Station by nine distinguished international faculty, with student presentations and discussions, encourage exchange of ideas across academic cultures. The 15th school, scheduled for 24 June – 1 July 2017, is on ‘Cycles of Life’, which we understand to range from ancient cycles of generation and corruption, the seasons and the weather cycle to modern reproductive, metabolic and ‘biogeochemical’ cycles, as well as contraceptive interventions in menstrual cycles and strategies to disrupt pest and pathogen life cycles. We will trace connections and identify patterns of continuity and change, explore shared properties of cycles and the differences and relations between disciplines and research programmes. The Naples Station will grant use of facilities, NSF will cover the costs of American participation and students will each pay €300. We are very grateful to Dan O'Connor for inviting an application and would be thrilled if the Trust could provide the balance of the funds.

Amount: £19,960
Funder: The Wellcome Trust
Recipient: University of Cambridge

MetaboFlow - the development of standardised workflows for processing metabolomics data to aid reproducible data sharing and big data initiatives 16 Jun 2016

The processing and analysis of mass spectrometry and nuclear magnetic resonance spectroscopy data in metabolomics is largely performed on an individual basis following local laboratory methodologies. Metabolomics lacks reproducible computational workflows based on internationally accepted standard operating procedures and this is impacting on the field in terms of reproducibility of studies and subsequent sharing of data. Furthermore, with improvements in reproducibility in analytical equipment, individual laboratories are acquiring larger, more complex datasets, which are a significant challenge to process. We propose to build, test and deliver the cloud-based Galaxy workflow, MetaboFlow, which will have computational capacity to process datasets with 1000s of samples and simultaneously capture all metadata associated with the users’ data processing workflow to allow rigorous reproducibility. We will formulate the workflow using several popular processing, feature extraction and compound identification tools and provide functionality to readily use on-line databases including our international repository, MetaboLights. The tools will be selected based on our current survey of the international metabolomics community. This proposal is a re-submission following consultation with the Trust. Specifically we have developed and implemented a plan to capture the communities’ needs, and have made significant cost savings by integrating our work with other initiatives using Galaxy.

Amount: £124,821
Funder: The Wellcome Trust
Recipient: University of Cambridge

Evaluation of feasibility of assessing liver function during ex situ liver perfusion using microdialysis 01 Apr 2016

Each year 15% of patients on the UK liver transplant waiting list die awaiting a donor liver, while a significant proportion of livers go unused because clinicians are unsure that the liver would provide life sustaining function. We are now able to perfuse a liver ex situ with oxygenated blood while evaluating markers of damage and function, enabling better assessment of organ viability. Microdialysis is a method in routine use in neurosurgery to evaluate brain metabolism following trauma, and involves passing a fine dialysis catheter into the brain parenchyma and perfusing it with an isotonic perfusate and examining the dialysate for metabolic markers such as glucose, lactate, and pyruvate. It can also be used to interrogate metabolism by introducing labeled substrates. Microdialysis has been used to study liver transplants post transplant, but has not been used to evaluate function ex situ where its relatively rapid readout may facilitate early and accurate decision making.This project will examine the feasibility of using microdialysis in perfused livers. Human livers that have been declined for transplantation will be studied and the optimal technique developed. Microdialysis results will be correlated with perfusate chemistry (lactate fall, maintenance of pH, ALT, AST) and metabolomic profile.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

The effect of music upon cognition: behavioural, neural and modelling studies. 19 Nov 2014

My long-term aim in this project is to understand how music can impact upon cognitive task performance in Alzheimer's patients. A key element of my work will be to select a range of musical pieces that are most likely to elicit changes in cognition. The key goals of the proposal are: 1. Assess how different music conditions affect performance of basic cognitive tasks. 2. Provide a quantitative physiological description (e.g. heart rate, blood pressure and respiration) of consequences for t he above. Are these good indicators of a subject's arousal levels, and cognitive performance? 3. Use neuroimaging to elicit activation of the brain regions that are recruited during listening to these musical pieces. Perform structural equation modelling to assess the different networks active when listening to the different types of music? Does music act directly upon cognitive function, or indirectly by activating mood/arousal pathways? 4. Build a computational model that takes the struc tural networks from goal 3 above to assess how network performance is modulated by perturbing these networks. This model can then be used to predict network activation in clinical populations where the alterations in network structure have already been characterised (e.g. alter hippocampal activation representing atrophy in Alzheimer's patients).

Amount: £295,429
Funder: The Wellcome Trust
Recipient: University of Cambridge
Amount: £164,360
Funder: The Wellcome Trust
Recipient: University of Cambridge
Amount: £163,052
Funder: The Wellcome Trust
Recipient: University of Cambridge
Amount: £163,052
Funder: The Wellcome Trust
Recipient: University of Cambridge
Amount: £163,052
Funder: The Wellcome Trust
Recipient: University of Cambridge

The mechanisms by which animal allergens affect Toll-Like Receptor signalling 30 Jan 2015

The mechanisms by which allergens are detected by the host has yet to be established. This project will focus on animal allergens. The key goals are listed below: 1. Assess the effect of animal allergens on Toll-like receptor (TLR) signalingin cell lines (mouse and human). The inflammatory effects of Fel d 1, Can f 6 and Equ c 1 will be tested. TLR-4 complex stoichiometry will be investigated for changes upon allergen stimulation. 2. Test the response of different cell types to allergen stimulation. We will test different cell populations to pin-point which cell types are sensitized by allergen exposure.3. Determine whether cells from allergic and non-allergic patients behave differently to allergen stimulation. A preliminary study will be conducted where we will stimulate cells from patients with and without specific allergies. This will indicate whether sensitization by the allergen is specific to allergic patients, or whether this is a more general response. 4. WT and TLR-4 knock-out mice will be used to assess TLR-4 dependency of different allergens tested in vitro.

Amount: £10,456
Funder: The Wellcome Trust
Recipient: University of Cambridge

Support for a Wellcome Trust/Academy of Medical Sciences Internship 22 Jun 2015

In light of growing evidence for a transgenerational component in the current human obesity epidemic, it is important to understand how maternal environment affects the long-term health of the developing foetus. In animal models, maternal over-nutrition has been shown to programme a metabolic syndrome-like phenotype and hyperphagia in the offspring. In this project, we propose to use anestablished maternal diet-induced obesity (DIO) mouse model to investigate (i)whether exposure to a high fat, high palatable diet after weaning exacerbates the hyperphagia and increased adiposity previously seen in chow-fed offspring and (ii) how maternal DIO programmes hyperphagia in the offspring with a particular focus on the mesolimbic dopamine pathway involved in palatable feeding. For this, our key goals are to (a) characterise the behavioural phenotype of these offspring in terms of food preferences and motivated behaviours; (b) define the structural development of neural projections within the mesolimbic dopamine pathway; (c) to establish the effect of maternal DIO on gene and protein expression levels in this pathway to explore underlying biochemical mechanisms. Thes three levels of investigation will provide us with novel insight into the mechanistic and functional aspects of the developmental programming of the central control of feeding.

Amount: £5,825
Funder: The Wellcome Trust
Recipient: University of Cambridge

Support for a Wellcome Trust/Academy of Medical Sciences Internship. 27 Oct 2014

Aim 1: To examine preference for, and rewarding properties, of dietary fat. Aim 2: To examine preference for, and rewarding properties of, sucrose. Aim 3: To determine whether preference for dietary sucrose and fat is mediated melanocortin signalling. Aim 4: To examine the brain activation response to manipulation of single/multiple diet macronutrients. 1. Increased dietary fat content in food will increase the preference for and rewarding properties of the food. Increasing fat content in food will be positively correlated with brain activation of areas involved in reward. 2. Increased sucrose content in food will increase the preference for and rewarding properties of the food. Rewarding properties and preference for food containing artificial sweetener in place of sucrose will be reduced compared to matched sucrose formed contents. Increasing sucrose content in food will be positively correlated with brain activation of areas involved in reward. 3. MC4R deficient subjects will display an increased preference for high-fat food (but not high sucrose food) in comparison to equally obese subjects matched for age.

Amount: £5,655
Funder: The Wellcome Trust
Recipient: University of Cambridge

Public Engagement Provision. 14 Jan 2015

Environmental cues can prompt diet-related behaviours, however, responses to these cues may be moderated by motivation towards different foods and by inhibitory control. In addition, both food motivation and inhibitory control may be socially patterned, thereby contributing to health inequalities. The proposed research aims to examine responses to healthier vs. less healthy environmental cues by socioeconomic status (SES), through: 1. A systematic literature review summarising existing evi dence; 2. Laboratory studies examining the impact of the relative availability of healthier or less healthy foods on food choice by SES, and the extent to which food motivation and inhibitory control mediate the relationship between SES and food choice; 3. A field study pilot exploring the extent to which displays of healthier or less healthy foods influence sales in more vs. less deprived areas. Together, the proposed programme of work will examine: (i) the extent to which investigated hea lthier vs. less healthy environmental cues are effective at changing behaviour; (ii) potential pathways linking SES and dietary behaviour via food motivation and inhibitory control, and (iii) whether interventions targeting the investigated healthier and/or less healthy environmental cues would be likely to lead to reductions in socioeconomic differences in food choices.

Amount: £4,250
Funder: The Wellcome Trust
Recipient: University of Cambridge

Environmental cues for healthier vs. less healthy options: Effectiveness at changing diet-related behaviour and reducing socioeconomic inequalities. 14 Jan 2015

Environmental cues can prompt diet-related behaviours, however, responses to these cues may be moderated by motivation towards different foods and by inhibitory control. In addition, both food motivation and inhibitory control may be socially patterned, thereby contributing to health inequalities. The proposed research aims to examine responses to healthier vs. less healthy environmental cues by socioeconomic status (SES), through: 1. A systematic literature review summarising existing evi dence; 2. Laboratory studies examining the impact of the relative availability of healthier or less healthy foods on food choice by SES, and the extent to which food motivation and inhibitory control mediate the relationship between SES and food choice; 3. A field study pilot exploring the extent to which displays of healthier or less healthy foods influence sales in more vs. less deprived areas. Together, the proposed programme of work will examine: (i) the extent to which investigated hea lthier vs. less healthy environmental cues are effective at changing behaviour; (ii) potential pathways linking SES and dietary behaviour via food motivation and inhibitory control, and (iii) whether interventions targeting the investigated healthier and/or less healthy environmental cues would be likely to lead to reductions in socioeconomic differences in food choices.

Amount: £229,325
Funder: The Wellcome Trust
Recipient: University of Cambridge

Characterisation of novel obesity-associated mutations in G protein coupled receptor 10 (GPR10). 26 Feb 2015

Targeted deletion of G-protein-coupled receptor 10 (GPR10) causes severe obesity in mice. We have recently identified novel heterozygous mutations in GPR10 using exome sequencing of 1000 UK individuals with severe, early-onset obesity recruited to the Genetics Of Obesity Study (GOOS) cohort. In this project, I propose to undertake the detailed functional and clinical characterisation of GPR10 mutations. These studies will provide novel insights into the role of GPR10 mediated signalling in the regulation of energy balance in humans. Of particular interest, GPR10 has been identified as a potential drug target for obesity.

Amount: £188,864
Funder: The Wellcome Trust
Recipient: University of Cambridge

Fragment-based lead discovery against the protein-protein interaction between Aurora A and TPX2 for the treatment of cancer 01 Mar 2015

The Wellcome Trust has awarded over £2.3 million to Chris Abell, John Skidmore and co-workers at the University of Cambridge to use fragment-based approaches for the generation of molecules which disrupt the interaction between the kinase Aurora A and the regulatory protein TPX2. Such compounds are expected to have utility in the treatment of a number of solid and haematological cancers, with one particular focus being reversal of taxane resistance in solid tumours. The project will generate lead compounds suitable for screening in cancer cell-lines and animal models to further validate the target and will also provide leads for future optimisation towards a drug. This funding follows on directly from an ongoing Strategic Award pioneering the use of fragment-based approaches against protein-protein interactions, which used biophysical screening and X-ray crystallography to generate the fragment leads for the planned project.

Amount: £1,101,333
Funder: The Wellcome Trust
Recipient: University of Cambridge