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Results

Leeds - Molecular Basis of Biological Mechanisms 30 Sep 2016

Leeds - Molecular Basis of Biological Mechanisms.

Amount: £119,875
Funder: The Wellcome Trust
Recipient: University of Leeds

Leeds - Molecular Basis of Biological Mechanisms 30 Sep 2016

Leeds - Molecular Basis of Biological Mechanisms.

Amount: £119,875
Funder: The Wellcome Trust
Recipient: University of Leeds

Leeds - Molecular Basis of Biological Mechanisms 30 Sep 2016

Leeds - Molecular Basis of Biological Mechanisms.

Amount: £119,875
Funder: The Wellcome Trust
Recipient: University of Leeds

Leeds - Molecular Basis of Biological Mechanisms 30 Sep 2016

Leeds - Molecular Basis of Biological Mechanisms.

Amount: £119,875
Funder: The Wellcome Trust
Recipient: University of Leeds

Leeds - Molecular Basis of Biological Mechanisms 30 Sep 2016

Leeds - Molecular Basis of Biological Mechanisms

Amount: £119,875
Funder: The Wellcome Trust
Recipient: University of Leeds

Provision for Public Engagement 31 Dec 2015

We will exploit our discovery of fundamental mechanisms regulating assembly in important single-stranded RNA viruses based on multiple, dispersed RNA-protein interactions (packaging signals, PSs) to: 1. Determine how genomic RNAs play regulatory roles in the mechanisms of virus assembly, maturation and host cell invasion. 2. Determine which viral and host components are needed to develop a quantitative systems understanding of assembly in vivo. 3. Analyse how viruses may evade anti-viral strategies targeting PS functions, triggering the occurrence of mutant strains. This paves the way for novel forms of anti-viral intervention.

Amount: £4,937
Funder: The Wellcome Trust
Recipient: University of Leeds

Investigating the potential of the microbiome to improve the accuracy of the NHS Bowel Cancer Screening Programme (NHSBCSP) 29 Jun 2016

This PhD will analyse the microbiomes of a cohort of the NHSBCSP directly from stool on guaiac Faecal Occult Blood Test (gFOBT) cards using 16SrRNA Next Generation Sequencing (NGS). Goals: 1) Characterise microbiome signatures of participants with a positive gFOBT result but normal colonoscopies. These microbiome signatures will identify false positive results, improve specificity and reduce unnecessary colonoscopies. 2) Characterise microbiome signatures of participants with a positive gFOBT result who have pathology at colonoscopy. Subsequently search for these signatures within a gFOBT negative cohort to identify false negatives and improve sensitivity. 3) Interrogate microbiome signatures to identify panels of biomarker bacteria which could be detected by qPCR rather than NGS. 4) Design a protocol to extract bacterial DNA directly from FIT (Faecal Immunochemical Test), enabling the research to transition as FIT replaces gFOBT. 5) Compare microbiome signatures from consecutive biennial screens to demonstrate the stability of microbiome signatures over time. These goals will demonstrate that incorporating microbiome analysis into the NHSBCSP: is feasible will improve sensitivity/specificity adds value, by detecting both bleeding and non-bleeding cancers could be used: to collect longitudinal population-based microbiome data; to screen for microbiome-associated diseases other than colorectal cancer; to perform national monitoring of antibiotic resistance.

Amount: £196,056
Funder: The Wellcome Trust
Recipient: University of Leeds

Identity and Governance of Bodily Extensions: The Case of Prosthetics and Avatars 10 Mar 2016

Prosthetics and avatars can both be defined as forms of bodily extension - one mechanical, the other digital. Both are used widely in everyday life, yet research into their impact upon users’ lived experiences has been approached with different emphases. Medical research into prosthetic limbs has tended to focus on functionality, while research into avatar usage has embraced embodiment, social identity and interaction, legal ownership and rights. This project brings together researchers from rehabilitation medicine, law, digital performance and media to apply multiple perspectives to prosthetic and avatar bodily extensions. How do different forms of bodily extension impact on experiences of embodiment and being in the world? How do body image and social identity relate to the design and function of bodily extensions? How far are bodily extensions defined and acknowledged in medical, information technology and human rights law? The project has three major goals: To establish a new interdisciplinary research network in bodily extension, specifically in relation to prosthetics and avatars. To produce three interdisciplinary peer-reviewed articles for readerships in digital media and culture, rehabilitation medicine and innovation law. To develop a funding application for a Wellcome Trust Collaborative Award to further this research.

Amount: £49,995
Funder: The Wellcome Trust
Recipient: University of Leeds

Structural studies on CEP290, the ciliary gatekeeper 15 Aug 2016

Cilia are the antennae of eukaryotic cells. They are microtubule-based organelles that project from the apical surface of most eukaryotic cells, which are able to sense and transduce environmental signals from a wide variety of sources (e.g light, molecules, proteins, and fluid flow). The cilium possesses a distinct protein and lipid composition relative to the rest of the cell. This compartmentalization is maintained by a structure of the base of the cilium called the transition zone (TZ; Figure 1A), which acts as a selectively permeable barrier to control the exchange of material between the cilium and the rest of the cell1. The TZ comprises over 20 polypeptide species. Mutations in TZ genes result in a number of inherited disorders characterized by retinal, renal and cerebral pathologies. However, the molecular mechanisms underlying these diseases are elusive, because we lack a basic understanding of the structure and function of the TZ and most of its constituent proteins. CEP290 is a major structural component of the TZ3 and is reported to bind to number of other TZ components4. However, a basic understanding of the structure and function of this molecule is absent. This proposal will perform a structural and biochemical investigation into CEP290.

Amount: £100,000
Funder: The Wellcome Trust
Recipient: University of Leeds

Proteomic and structural profiling of PXXP-SH3 interactions as key regulators of membrane receptor activity 08 Apr 2016

Membrane receptor signalling occurs upon growth factor stimulation. Interestingly, I have recently shown that fibroblast growth factor receptor 2 signalling can also be triggered under non-stimulated conditions. This occurs when proteins with Src homology 3 (SH3) domain bind its C-terminal proline-rich-motif (PXXP) and modulate its activity to induce a homeostatic or oncogenic response. Whether this occurs in other receptors remains unclear. .Notably, the genome encodes for >50 PXXP-containing receptors and >300 SH3 domain-containing proteins. Thus, I will test the hypothesis that SH3-PXXP interactions are abundant and critical for functional regulation of receptors which dictates cellular response. I will use 2 model receptors to: Generate short biotinylated PXXP-peptides immobilized on streptavidin-coated-beads to "fish-out" bound proteins from cell lysates. I will then employ mass-spectrometry to determine the identity of the SH3 domain-containing hits (to be validated by CRISPR/Cas9 pull-downs and fluorescent-lifetime-imaging). Run pilot biophysical experiments like microscale thermophoresis to reduce confounding elements such us complex formation rather than direct SH3-PXXP binding events. Evaluate functional modulation of receptors by running Reverse-Phase-Protein-Array and functional assays. This project will set the foundation for characterizing novel interactions to enhance our understanding of signalling mechanisms; with impact on structural modelling of receptors and cancer therapeutics.

Amount: £100,000
Funder: The Wellcome Trust
Recipient: University of Leeds

R-loop Dysregulation in Myeloid Neoplasms 14 Dec 2015

Insights gleaned from pre-neoplastic disorders have reinvigorated interest in the cancer-specific properties that trigger and respond to DNA damage. Myeloproliferative neoplasms (MPNs) are pre-leukaemic disorders that reflect an early-stage malignancy with the potential to progress to acute leukaemia. We have previously demonstrated that MPN-derived tumour cells exhibit perturbations in DNA replication that lead to DNA damage. We now have exciting preliminary data implicating nucleic acid structures called "R-loops" as the primary cause of MPN-associated genomic instability. R-loops are essential for multiple normal cellular processes but can also promote DNA damage if inappropriately regulated. This seed award application is focused on a central question: why do R-loops promote DNA damage in MPN cells but not normal cells? To address this issue, we will undertake two thematically-related but non-overlapping streams of investigations. For Aim 1, we will use an unbiased proteomics-based approach to characterise any differences in protein composition of R-loops between normal and MPN cells. For Aim 2, we will perform a pooled CRISPR/Cas9-based genetic screen to identify genes that modulate how MPN cells regulate R-loop-induced recombination. Cumulatively, we hope to generate preliminary data that starts to deconvolute the structural and functional complexity of R-loops in leukaemia development.

Amount: £97,612
Funder: The Wellcome Trust
Recipient: University of Leeds

Are innate immune genes regulators of organismal proteostasis and transcellular chaperone signalling? 14 Dec 2015

In recent years, it has become clear that in the context of multicellular organisms, protein quality control mechanisms are regulated in a cell non-autonomous manner. Using C. elegans I have shown that the regulation of chaperone expression is controlled cell non-autonomously by transcellular chaperone signalling (TCS)1. This inter-tissue signalling in response to a local imbalance of proteostasis adjusts chaperone expression between tissues and has the capability to restore proteostasis in tissues affected by protein misfolding disease. The mechanism of this response is however not understood and the identity of transcellular signalling molecules that mediate TCS are unknown. Using a systems-wide approach I have identified the GATA transcription factor PQM-1 and a set of 27 innate immune genes targeted by PQM-1 as potential mediators of TCS. Therefore, the aims of this proposal are to 1) determine which of the 27 identified innate immune genes are potential mediators of TCS; 2) define a functional basis of how PQM-1 and innate immune genes are involved in the regulation proteostasis, and 3) elucidate the PQM-1 binding profile in stressed animals. This Seed award will establish a strong foundation towards a mechanism of TCS and how it can be used for the treatment of proteinopathies.

Amount: £89,900
Funder: The Wellcome Trust
Recipient: University of Leeds

Lead identification of a novel anticoagulant agent targeted against activated factor XII for the prevention of thrombosis without the risk of bleeding associated with current antithrombotics 22 Oct 2015

At the University of Leeds, Dr Helen Philippou (PI) and Prof Robert Ariens (Faculty of Medicine and Health), with colleagues (Faculty of Mathematics and Physical Sciences) Dr Richard Foster and Prof Colin Fishwick with Prof Gregory Lip (University of Birmingham) have secured a £3,021,002 Wellcome Trust Seeding Drug Discovery award to develop new safer anticoagulants with minimal risk of bleeding. The medicines available to treat patients who suffer from an increased risk of blood clotting are effective but carry a significant risk of causing bleeding. Current treatments therefore involve a balance between reducing blood clots with inducing bleeding. The objective of this proposal is to discover highly specific compounds which block a protein, Factor XIIa, which is involved in clot formation, and for which there is good evidence to suggest inhibition will not cause bleeding. This will allow patients to be treated more safely with minimal risk of bleeding without needing therapeutic monitoring. The aim is to produce an agent which will be given by mouth daily.

Amount: £1,445,413
Funder: The Wellcome Trust
Recipient: University of Leeds

Assembly, activation and function of JAMM/MPN deubiquitylating complexes 24 Feb 2016

Ubiquitin is attached as a post-translational modification to protein substrates either as mono- or poly-ubiquitylation by ubiquitin ligases. This serves to regulate cellular signalling events and virtually all aspects of cellular life. Malfunctioning of signalling networks controlled by protein ubiquitylation can lead to diseases such as cancer, neurodegeneration and inflammation. Deubiquitylating enzymes (DUBs) remove ubiquitin from substrates and counteract the roles of ubiquitin ligases. There are approximately 100 DUBs, which belong to five families. The JAMM/MPN DUB family is unique in using Zn2+ for catalysis. Seven out of 14 family members are predicted to be catalytically active (denoted MPN+) while the others, which bear substitutions to essential catalytic residues, are predicted to be catalytically dead (denoted MPN–). MPN DUBs typically function within larger multi-subunit complexes, which imparts great potential for multi-layer regulation. BRCC36 is an MPN+ DUB that forms two multimeric complexes: a cytoplasmic BRISC-SHMT2 complex that regulates intereferon signaling, and a nuclear ARISC-RAP80 complex that is required for DNA damage response. I seek to uncover the structural and functional basis by which BRCC36 containing complexes select their specific substrates, are regulated by physiological means, and are modulated by small molecules that have the potential to serve as therapeutics.

Amount: £1,093,823
Funder: The Wellcome Trust
Recipient: University of Leeds

The Compassionate Imagination: Things that bring emotional intelligence to life 30 Jun 2016

This grant will fund inaugural workshops for six core members of the Compassionate Imagination network. The network builds upon established professional connections, including collaborations with theatre makers. Progressing current thinking about critical medical humanities (Viney, Callard, and Woods, 2015) it addresses an Arts and Health remit, working in conjunction with the Compassionate Mind Foundation’s leading practitioners of compassion-based approaches to education. The network’s pilot activities will involve school students as participant-researchers in a project to bring emotional intelligence (Mayer and Salovey, 1990; Goleman, 1995) to life, using material objects to invoke the flow of compassion. The inaugural network workshops, scheduled for 23rd-24th June 2016, centre upon knowledge exchange towards honing a Wellcome Seed Award application (deadline: 5 August 2016). Our discussions will address three key questions: How are compassion and imagination related in: a) contemporary clinical psychology, b) contemporary performance and live art, c) recent findings from the archaeology of human origins. From these perspectives, what is understood about material engagement (of humans with objects) and its relation to compassion? Inspired and informed by knowledge exchange amongst the core network, what research and development strategies are best suited to experiential learning in this field?

Amount: £4,779
Funder: The Wellcome Trust
Recipient: University of Leeds

Investiagtion of protein-lipid interactions 01 Apr 2016

Until recently the lipid membrane was thought to be a passive or neutral environment in which the transmembrane proteins are located, but this has now been supplanted by a model in which lipid-protein interactions are important to the functioning of the cell. Proteins can locally deform membranes, modify and reorganise lipids, and regulate membrane charge, diffusion and lateral organisation. One method for investigating protein-lipid interaction is to measure the effect of proteins on the elusive "lipid rafts", which are hypothesised to exist in membranes possessing two co-existing liquid phases, as micro-domains of liquid ordered (Lo) phase in a sea of liquid disordered (Ld) phase. However, our recent work using a Wellcome Trust funded high speed Atomic Force Microscopy indicates that a more subtle mechanism fully explains the known properties of lipid rafts in cell membranes; that rafts are actually a highly dynamic fluctuation of a single liquid phase near a critical point of the lipid bilayer phase diagram, and that this fluctuation is then stabilised by the presence of a transmembrane protein, creating a stable nano-scale raft of

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

Exploring DNA origami nanotiles using atomic force microscopy as potential therapeutic delivery vehicles 01 Apr 2016

Production of DNA origami nanostructures is a promising approach for creating biocompatible nanomaterials to be used as drug delivery vehicles. The size and shape of these DNA nanostructures can be controlled by rationale design of the sequence of the DNA staple strands relative to the long template strand. We use atomic force microscopy (AFM) of two-dimensional nanotiles to investigate their self-assembly and final structure. Typically, nanotiles are not completely flat due to the helical nature of the DNA, which introduces supercoiling distributed across the nanotile. Certain drugs bind naturally to the DNA double helix, often either in the minor groove or as intercalators, inserting in between the base-pairs. The binding of drugs will affect the helical pitch of the DNA and change the curvature of the nanotiles. We can assess the curvature of the nanotiles by seeing which way up they bind to a model mica surface using the AFM. This project will investigate how binding of drugs into the DNA helix affects the DNA origami structure and shape. This is critical knowledge for rational design of nanotiles as drug delivery vehicles. Recent published studies show that nanotiles readily cross the cell membrane and are ideal candidates as therapeutic carriers.

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

Accelerating motor learning using robotic devices 01 Apr 2016

Motor learning can be conceptualised as an iterative process where a parameter-space (an internal representation of a task) is built from a collection of inverse models via trial-and-error learning. This raises the question of whether parameter-space manipulations (e.g. those that artificially increase the amount of motor noise) can accelerate the creation of robust inverse models. In this experiment, we will test whether error augmentation via working point force fields can optimise this learning process. To this end, we will run a multi-session experiment where participants will control a robotic end-effector and follow a target moving in 2D space within a visuohaptic environment. Following baseline measurement of motor ability, we will compare the learning rate on this task after three 45 minute training sessions with: (i) haptic guidance (error minimization); (ii) haptic disruption (error augmentation) and (iii) no haptic guidance or disruption (control).

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

Manual Control During Exercise: Implications for Strategies to Increase Physical Activity in the Workplace 01 Apr 2016

Emerging evidence supports the feasibility of raising daily energy expenditure (EE) by replacing office work-related sedentary behaviour with low-intensity non-exercise physical activity (PA) via workstation alternatives such as under desk cycles. Using an under desk cycle while interacting with a computer requires the user to divide their attentional resources between the two tasks. Given this, it surprising that little research has examined whether under desk cycles compromises productivity. In this study, we examine the impact of using an under desk cycle on 3 upper limb motor tasks over a number of practice trials. Participants will cycle at 20 watts while completing (1) a tracking task (2) an aiming task (3) a tracing task repeating this 6 times over a 14 days period. We will sample and analyse 2D kinematics of the cursor while completing these tasks and Root Mean Squared Error (RMSE), movement time and path accuracy, respectively, will be used to quantify the effect that cycling has on manual control. Furthermore, this sudy will investigate if and how continued use and practice of the desk cycle affects these measures as week to understand if and how people adapt their control of manual tasks over a period of time.

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

Development of a microfluidic device to study single cells in controllable microenvironments 01 Apr 2016

The project is coming together of two exciting areas of sciences, which we think will make a significant contribution to our understanding for the nature of basic unit of life, the cells. The first aspect is the use of microfluidic technology as a quantitative and reproducible method for monitoring individual cells. The second aspect is the research of Embryonic Stem (ES) cells representing an excellent system to study the interaction between intrinsic and extrinsic factors in cell fate decisions. The primary goal of this research is the development of a microfluidic methodology that enables study of the gene expression occurring in a single cell, and controlling the microenvironments enclosing cells. The microfluidic technology will open the possibility of exploring problems in eukaryotic cells as much of our ability to harness the potential of ES cells will depend on our ability to control interactions between the cell and the signals that determine its behaviour.

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