- Total grants
- Total funders
- Total recipients
- Earliest award date
- 20 Nov 1998
- Latest award date
- 18 Jan 2019
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
LifeLines 20 Apr 2016
This is the expansion of a project supporting volunteers aged 50 plus to run activities for vulnerable older people to improve health and well-being. These have previously included art classes, creative writing, yoga and computer club. The group will expand across the city, recruiting more volunteers, supporting more than 800 new people and establishing a Menâ€™s Network to encourage older men to socialise regularly. It will also extend its HealthLink scheme to help older people get to medical appointments.
Kilkeel RBL - Saving Our Community Venue 22 Oct 2015
The group is a community and voluntary based organisation providing a range of services and activities to the local community. They received a grant of Â£10,000 to make improvements to their venue so that it can be used for more classes and activities.
Towards improving access and facilities for disabled people at the Forest Hall Ex-Servicemen's Institute.
Grant awarded to Community Service Volunteers (Training and Enterprise NE) (Tyne & Wear) 13 Jul 2004
To provide daycare services to older people living in high rise flats in Newcastle.
Combined topographical and high speed confocal imaging systems for interdisciplinary membrane and cell biology research. 15 Mar 2011
This proposal is for 2 cutting-edge imaging systems, which will be applied individually or in combination to enable (i) topographical scanning of surface membrane structure in living cells or artificial membrane bilayers (ii) focal dispensing of small molecules (e.g. channel agonists) at the cell surface or within specialized membrane invaginations (iii) ion channel recordings from regions of interest identified by topographical scanning (iv) confocal imaging of fluorescently tagged membrane proteins, which can be correlated with topographical information (v) high speed full-frame confocal fluorescence imaging of intracellular ions or other components of signaling cascades. The first of these imaging systems is the Ionscope scanning ion conductance microscope (SICM), which can resolve the surface structure of living cells at nanometer resolution, without making contact with the sample. The second imaging system is the Andor Revolution confocal microscope. This is a high perf ormance spinning disk confocal system, capable of collecting full x-y images at hundreds of frames per second from a user-defined confocal plane. These systems will enable a step change in ongoing interdisciplinary projects that address, for example, basic research on membrane structure and function, disease mechanisms (e.g. amyloid diseases, cardiac hypertrophy) and novel delivery methods for therapeutic agents.
We are seeking 1M in funding from the Wellcome Trust to provide essential infrastructure and facilities in structural biology. These will build on our existing strengths in the interdisciplinary Astbury Centre for Structural Molecular Biology (ASCMB). This money will be matched by a 1.161 investment by the University, reflecting the central roles structural and quantitative functional studies play in the emerging fields of systems and synthetic biology, and their potential contributions to wid er societal needs. The specific aims of this proposal are: 1. To provide advanced facilities for structural biology (macromolecular crystallography, negative stain electron microscopy and nuclear magnetic resonance spectroscopy) that will enable us to generate detailed structural information central to understanding the molecular basis of living processes 2. To underpin these facilities with iso-thermal calorimetry and circular dichroism spectroscopy, complementing our existing suite of bio physical techniques, to ensure that our systems of study are in a physiologically relevant and functional state for structural studies.
Despite the importance of amyloid disorders in today s population, attempts to inhibit the progress of amyloidosis have met with limited success. New therapeutic strategies require the structure, stability and dynamics of every species populated during assembly to be determined and the effects of individual species on cellular function deduced. Here we propose to combine biophysical, biochemical and cell biological approaches to address three questions that lie at the heart of our quest to u nderstand amyloidosis at a molecular level: (i) how does molecular self-recognition occur in the earliest stages of amyloid assembly; (ii) which species nucleate fibril formation and what is the structure of higher order oligomers and amyloid fibrils; and (iii) how do amyloid fibrils and fibril-associated species exert their toxic effects? Using beta2-microglobulin as a paradigm, and embracing other assembling proteins/peptides, our aim is characterise all species possible on an as sembly landscape in order to define the entire molecular assembly pathway from monomer to fibril. In parallel, by combining different strategies we aim to derive new understandings of the origins of amyloid-associated cytotoxicity. Together the programme will provide the much-needed structural, biophysical and cellular insights required for therapeutic intervention in the years ahead.
Regulatory Mechanisms in Myosins. 09 Mar 2011
The programme aims to investigate the structure and function of a subset of myosins to determine how these proteins are regulated in vivo and in vitro, and thereby seek the underlying principles of regulation of biological movement. For myosins 2, 5 and 7 that we have shown to fold up into a compact, switched-off form, we will determine where activating partners bind and the structural changes they cause. We do not yet know whether myosins 1e, 9 and 10 use a compact form to regulate activity so we shall examine them to explore the diversity of control mechanisms myosins use. In addition we aim to exploit the specific, compact structure of the inhibited states of some myosins to discover the structure of whole myosins for the first time and at the highest resolution possible. We will use 3D reconstruction from cryo-EM images initially of whole myosins 2, 5 and 7 that we already know have a compact conformation. This will be complemented by crystallography of their tail domains to allow docking within the EM density envelope and an atomic scale appreciation of the regulatory interactions.
Spinal cholinergic interneurones influencing sympathetic function: a wider role in integration? 07 Oct 2010
Cholinergic transmission is an important mechanism for control of neuronal circuitry throughout the CNS. At the spinal cord level, cholinergic interneurones are thought to play roles in motor, sensory and sympathetic processing, however information regarding those interneurones involved in sympathetic control is lacking. Based on our preliminary evidence indicating extensive axonal arborisation from these neurones, we propose a novel hypothesis for a role of cholinergic interneurones in the in tegration of sympathetic, motor and sensory activity from the spinal cord. We will identify interneurones using cholinergic reporter mice and use electrophysiological, anatomical and immunohistochemical means to fully characterise these interneurones. We will determine their electrophysiological properties, axonal projections and synaptic inputs that influence their activity in spinal cord slices. We will determine any subclassification of these neurones based on these properties. We will inv estigate, both functionally and morphologically, how descending and afferent pathways influence their activity. The full axonal arborisation patterns of these cholinergic interneurones may give an insight into possible co-ordination of sympathetic and other motor outflows. This study will provide the first characterization of spinal cholinergic interneurones that may co-ordinate spinal activity and will provide insight into their targets and innervation patterns throughout the spinal cord.
Elasticity in Myosin Motor Proteins. 29 Aug 2008
Myosins form a family of eukaryotic motor proteins that participate in important cellular functions including muscle contraction, intracellular cargo transport, cell migration and cell division. Identified by a conserved motor domain that binds actin and hydrolyses ATP, myosins share the ability to translocate or move cargo along actin filaments (F-actin). Mutations are associated with disease, including cardiomyopathies, neurological disorders, immunodeficiencies and hearing and vision loss. Myosin structure is characterised by three domains: motor, lever and tail. The mechanical properties of the lever are especially important in function. This domain. a single a-helix with a number of bound light chains, must be both rigid enough to rotate as a lever arm and generate force, whilst be flexible enough to accommodate functionally important strained conformations. Variety in lever structure across the myosin family suggests evolution of structure to match function. Despite its functional importance, an understanding of the relationship between internal structure and mechanical properties of myosin levers is lacking. In this research, it is proposed to study the mechanical properties of myosin levers in detail, using myosin 5 as a model system. The main aim is to characterise the elasticity and mechanical properties of the myosin 5 lever. Findings will be related to function and could be generalised to other. myosin classes. Using various experimental and analytical techniques, the following objectives will be tackled: (1) Determination of the source and nature of elasticity in the myosin 5 lever. (2) A study of deformation and strain in myosin and F-actin during myosin 5 Walking. (3) Pursuit of a high-resolution (-10 A) 3D structure of the myosin 5 motor and lever bound to F-actin by cryo-electron microscopy. (4) Development of a detailed mechanical description of myosin 5 lever and application in a stepping model.
Human respiratory syncytial virus (hRSV) is an enveloped, negative-sense, single-stranded RNA (ssRN virus responsible for severe paediatric respiratory disease worldwide. The virus infects epithelial cells both the upper and lower respiratory tract, and is a leading cause of severe bronchiolitis and pneumonia young childre. Most children will be infected by the virus by the age of two, and infection may require hospitalization a few months after birth. Additional groups at risk of infection include the elderly and immunocompromised. The high morbidity and mortality of hRSV-associated diseases, as well as the susceptibility of individuals to repeated infection has strongly motivated the development of a vaccination. Furthermore, hRSV represents an excellent model for understanding other negative-sense ssRNA virus including important human pathogens such as the Ebola, influenza, measles, mumps, parainfluenza, rabies and Rift valley fever viruses. The proposed research project will investigate the structural organization of hRSV at both extracellular and intracellular stages of the virus life-cycle. Electron cryo-microscopy (cryo-EM) will be used to achieve each of the following: 1. Virion morphogenesis of hRSV strains A and B w/11 be investigated by visualizing mature virus particles (virions) grown using different cell types. 2. The structure of the hRSV RNA-dependent-RNA-polymerase (RdRp) and related complexes will be determined by single-particle cryo-EM (SPEM). 3. Electron cryo-tomography (cryo-ET) will be developed to study the structure of hRSV extracellular and intracellular states. hRSV specimens will be visualized in a native and hydrated state for the first time. Three dimensional (30) reconstruction of the resultant data will provide novel insights into the organization of the virus, and interactions between virus and host factors. Such information will shed light on the structural basis for virus infection, replication and spread, informing strategies for rational antiviral and vaccine development against viruses of this class.
Amyloid-forming proteins chiefly recognised for their association with age-related neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, are also responsible for a host of debilitating systemic and localised amyloidoses, including Diabetes Mellitus Type 2 and Dialysis Related Amyloidosis (DRA). Despite the frequency of these disorders within human populations, no effective cures are currently available for these conditions. Decades of research have established two main hypotheses for amyloid-associated cytotoxicity which implicates either soluble oligomers or mature amyloid fibrils as the primary determinants of cell death. However, recent data suggest the two may be linked. Several experiments have shown that mature fibrils are dynamic entities, releasing soluble material with cytotoxic potential. Others have highlighted that increasing the surface hydrophobicity of soluble toxic oligomers while maintaining a high degree of intermolecular beta-sheet structure greatly enhances their cytotoxic potential. Surface hydrophobicity is also increased among shorter B2m amyloid fibrils (Fig. 1a), which are known to be more cytotoxic than their longer counterparts. This raises the possibility that toxic oligomers and mature amyloid fibrils share common structural and/or chemical/physical properties that endow their cytotoxic potential. In this proposal, we will investigate whether fibril hydrophobicity and dynamics are key mediators of amyloid-associated toxicity. By using four different amyloid-forming sequences including AB1-40/42, B2-microglobulin (B2m) and ccB-p, we will determine: 1. Accurate fibril length distributions of AB1-40/42 and ccB-p amyloid fibrils 2. The role of hydrophobicity in fibril-associated cytotoxicity 3. How 'molecular recycling' properties of fibrils affect cytotoxicity 4. Structural elucidation of fibril-cell interactions This project will take a multidisciplinary approach, combining biophysical and cell biological experiments under the leadership of Prof. S.E. Radford and Dr E.W. Hewitt. Cryo-tomography techniques will be developed with Prof. H. Saibil (Birkbeck College, London) and mass spectrometry will be performed in collaboration with Prof. A.E. Ashcroft.
Characterisation of the interactions between the KSHV ORF57 protein and the human TREX complex 14 Jun 2010
Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncovirus responsible for the formation of Kaposi's sarcoma (KS). Tumour formation is closely associated with immune suppression1 and shows an epidemic-like morbidity and high mortality in patients with AIDS. Concurrent with the HIV epidemic approximately 17% of the population in Sub-Saharan Africa develop KS. Presently, KS is the most common type of cancer in Africa. The KSHV ORF57 encodes a multifunctional protein essential for virus replication. It recruits the human transcription/export (hTREX) complex to form an export competent viral ribonucleoprotein particle (vRNP), in order to facilitate nuclear export of viral intronless mRNAs. We have recently shown for the first time that CIP29, a newly identified member of the hTREX complex, is also part of the ORF57-mediated vRNP. To date, the role of CIP29 within the hTREX complex remains to be elucidated, although speculations suggest that CIP29 functions as an accessory factor to the DEAD-box helicase UAP56. Understanding the role of CIP29 in both the hTREX complex and the vRNP may have important implications for viral pathogenesis and will aid the development of new treatments. Therefore, this project has the following objectives: 1) Characterisation of the functional significance of the ORF57/CIP29 interaction. 2) Determination if inhibition of ATP-dependent RNA helicase UAP56 using ring expanded nucleosides affects KSHV mRNA export and replication. 3) Elucidation of the role of other putative members in the hTREX complex and their role in ORF57-mediated nuclear export of viral intronless mRNAs.
In silico rational design of novel inhibitors to Hepatitis C virus (HCV) non-structural proteins 14 Jun 2010
Around 3% of the world population is currently infected with hepatitis C virus (HCV). Chronic infection will develop in 85% of cases and is a prerequisite to liver cirrhosis and hepatocellular carcinoma1-3. Response rates and toleration to current treatments vary between the viral genotypes, placing an emphasis on identifying novel ways to treat infection. Several viral polymerase and protease inhibitors are currently in clinical trials2,4, though the inaccuracy of the viral polymerase leads to rapid development of resistance mutations5, suggesting a combination therapy approach may be required. This project will utilise available structural information, virtual high-throughput screening (vHTS) and rational drug design to identify and optimise novel inhibitor compounds targeted to the viral protease NS2, and to other non-structural proteins involved in viral replication such as NS5A. Identified active compounds will be purchased or synthesised, analysed and optimised to produce new anti-virals against both existing and novel viral protein targets. This project will involve a combination of structural biology, virtual high-throughput screening, rational drug design and chemical synthesis, and as such will take advantage of the interdisciplinary nature of the Astbury Centre at Leeds University.
What is the role of syntaxin 11 in the exocytosis of secretory lysosomes by natural killer cells?. 01 Oct 2009
Natural killer (NK) cells eliminate aberrant cells, including pathogen infected and tumourigenic cells. The recognition of an aberrant cell triggers secretory lysosome exocytosis by a NK cell, resulting in the secretion of cytotoxic molecules that kill the target cell. Despite its central role in NK cell cytotoxicity, little is known about the mechanism of secretory lysosome exocytosis. The analysis of immunodeficiency disorders has, however, provided insights into this process. One such disord er familial haemophagocytic lymphohistiocytosis type 4 (FHL-4), is caused by mutations in syntaxin 11, and is characterised by defective NK cell secretory lysosome exocytosis and cytotoxicity. The function of syntaxin 11 is poorly understood, although it is predicted to be a member of the SNARE, a family of proteins that catalyse membrane fusion reactions. This project will test and develop the hypothesis that syntaxin 11 is part of a SNARE complex that catalyses a membrane fusion reaction requi red for secretory lysosome exocytosis by NK cells. These studies will provide new insights into the molecular basis for secretory lysosome exocytosis by NK cells. Furthermore, by determining why syntaxin 11 mutations impair NK cell cytotoxicity, this project will provide information that may ultimately be used to develop therapies for FHL-4.
This proposal aims to identify new genes and proteins involved in eye development by studying a cohort of consanguineous families with recessively inherited microcornea, cataract and iris coloboma. This combination of signs and inheritance pattern has not been reported before, though similar conditions have been described. Preliminary analysis showed that two of these families map to new genetic loci on chromosomes 10 and 20 while a third has a mutation in a gene only previously implicated in ca taract alone. I now propose to complete the genetic analysis of the remaining families, screen known genes where they are implicated by the genetics and look for mutations in new eye development genes at the new loci. Initially I will prioritise positional candidate genes then sequence them directly, but if necessary I will use Next Generation sequencing to generate a complete list of all sequence variants within one of the loci to ensure I find the gene involved. Once I have found such a gene I will use the techniques of molecular and cellular biology to characterise it further in order to better understand how the eye develops and how mutations in this gene cause an inherited developmental defect.
Investigation of the obligatory coupling of bunyavirus transcription to ribosome translocation. 07 Feb 2008
Bunyaviruses are unique among negative-strand RNA viruses in that their transcription is obligatorily coupled to translation. We recently showed this coupling was because ribosomes must translocate along nascent mRNAs as they are transcribed. When translation is prevented, the bunyavirus RNA-dependant RNA polymerase (RdRp) prematurely terminates transcription, causing a fatal-loss of gene expression. The aim of this proposal is to determine how ribosomes affect RdRp activity. Experimental eviden ce favors two models: The first proposes that ribosomes prevent termination by colliding with RdRps paused at termination sites. This model will be tested by preventing this collision, achieved by both slowing-down ribosome translocation, and also by increasing the distance between the point of ribosome assembly and the site of termination. The second model proposes that ribosomes prevent termination by disrupting RNA interactions specified by the termination signal that are required for its act ivity. We will test this possibility by performing a comprehensive functional analysis of the bunyavirus termination signal, to determine whether formation of RNA interactions determines termination signaling ability. In addition, host cell factors are known to promote the RdRp-ribosome interaction. We will attempt to identify these components to further reveal molecular details of how the ribosome affects RdRp activity.