- 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.
The project will investigate the socio-psychological consequences of pandemics from ancient civilizations to the present, challenging common assumptions that collective violence inevitably accompanied pandemics. By charting which pandemics tended to spark collective violence, this study will question common explanations usually based on a single pandemic or disease and often for a particular place and time--the Black Death, 1347-52, plague in the sixteenth and seventeenth centuries, cholera in 1832, AIDS in the 1970s and 1980s. It will be comparative over time, place, and disease in an effort to explain, for instance, why cholera continued to spark class hatred and riots from its first appearance to as late as 1912, while yellow fever did not, even though its symptoms were as horrific, its transmission and pathology took longer to discover, its victims centred more on the poor and recent immigrants and with mortality rates as high as 70 percent. By building databases of pandemics and hatred over two-and-a-half millennia, the project will chart the varied relations between disease and collective violence to discover the significant variables across time, space, and disease. Knowledge of these variables and their mix could prove critical for understanding the socio-psychological effects of future pandemics.
This project will explore how signal regulatory protein ? (SIRP?) regulates dendritic cell function in the intestine. Previous work has identified SIRP?+and SIRP?- subsets of dendritic cells (DC) in mouse and human intestine, and has suggested that these DC may play distinct roles in driving effector immuneresponses or tolerance. Mice with a non-signalling mutant form of SIRP have reduced numbers of CD103+CD11b+ DC in the intestine, as well as fewer IL-17 producing CD4+ T-cells, a population which plays important roles in controlling the intestinal microbiota and in inflammatory bowel diseases. Here we will characterise fully the functions and localisation of SIRP + and SIRP - subsets of intestinal DC, will identify the cells expressing CD47, the ligand for SIRP + and will determine how SIRP might influence other myeloid cells in different parts of the intestine. Using SIRP mutant DC and by ligating SIRP in vitro, we will examine directly how SIRP? modifies DC activation and will explore the signalling pathways involved. By comparing these parameters in steady state and after administration of adjuvants with
Investigating the downstream effectors of the cAMP signalling pathway in Trypanosoma brucei as potential drug targets 12 Jul 2011
Current drug treatment options in trypanosomiasis are old, toxic and highly ineffective. Signalling transduction pathways have been shown to have important cellular functions and are therefore good pharmacological targets. The metabolism of cyclic adenosine monophosphate (cAMP) has recently been validated as a drug target in T. brucei. The phosphodiesterase inhibitor CpdA,used in the validation, was fatal to bloodstream forms. However, the downstream effectors of cAMP activity in trypanosomes are unknown. We intend to use reverse genetics, genomics, proteomics and metabolomics to elucidate potential pathways targeted by changes in cellular cAMP levels. Several genes have already been validated as reducing CpdA-sensitivity when knocked down through RNAi and we will study the expression, phosphorylation and localisation of the encoded proteins to understand their role in cAMP-regulated processes. We will try to identify further cellular components of the cAMP pathways by co-immunoprecipitation with these proteins, by comparative proteomics at various cAMP concentrations and by genomic analysis
Macrophages (mφ) are abundant in the normal intestine and it is essential that their activation is regulated properly. Although they are partially activated and are crucial for maintaining homeostasis to commensal bacteria, they do this without causing inflammation. During inflammatory bowel disease, control of mφ activation is lost and they cause pathology, meaning they are attractive targets for therapy. However the mechanisms of this regulation are unclear and it is not known how th e mφ populations found in healthy and inflamed intestine are related to each other. Here we will exploit newly refined techniques for characterising colonic mφ in mice and powerful in vivo models to study two novel aspects of intestinal mφ biology. We will examine the relationships between two phenotypic subsets we have defined based on the expression of Ly6C and the CX3CR1 fractalkine receptor in intestinal inflammation caused by DSS, Helicobacter hepaticus and Toxoplasma gondii. The role of the inhibitory CD200R1 in regulating mφ function will be explored. By characterising these cells at the molecular level, our studies will help understand how the normal intestinal immune system adapts to commensals and will define the processes which determine how the mucosal mφ population changes during inflammation and infection.
Defining the role of kynurenine pathway metabolites in the inflammatory response to trypanosome invasion of the CNS. 07 Mar 2011
This project will define the role of the kynurenine pathway in generating the neuroinflammatory response in a mouse model of human African trypanosomiasis (HAT), also known as sleeping sickness. Recent findings in our laboratories using a kynurenine-3-monooxygenase (KMO) inhibitor have demonstrated the neuropathogenic importance of this metabolic pathway in generating the more severe form of CNS inflammatory response to trypanosomes. Our core hypothesis is that kynurenine pathway catabolites ar e key determinants of the CNS inflammatory response to trypanosome invasion. This is of importance for both a better understanding of HAT neuropathogenesis and a potential new mode of adjunctive treatment for late-stage disease. The proposal will address the following questions: 1. Does KMO inhibition alter the concentration of kynurenine metabolites or inflammatory mediators within the brain? 2. Do changes in the concentrations of kynurenine pathway metabolites and key inflammatory media tors correlate with BBB function as assessed by MRI? 3. Is the severity of CNS inflammation and BBB breakdown reduced or abrogated in KMO knockout mice? 4. Does treatment with a SP receptor antagonist enhance the reduction in CNS inflammation in KMO -/- mice compared with wild-type animals? 5. Are kynurenine pathway metabolites potential markers for disease staging?
Role of the fibroblast in pulmonary vascular remodelling: paracrine signalling and molecular mechanisms. 04 Dec 2008
Pulmonary hypertension (PH) is a life threatening condition, for which current therapies cannot offer a cure. This is because these treatments have little effect on the underlying structural pathological changes (referred to as pulmonary vascular remodelling). All three cell types of the pulmonary artery proliferate in the remodelling process. In vitro, fibroblasts proliferate in response to hypoxia. Likewise in vivo, in a chronic hypoxic rat model of PH, PAF adopt a pro-proliferative phenotype . Both processes are p38MAP Kinase dependent. In contrast, preliminary data from our lab has shown that under conditions where smooth muscle cells (SMC) did not proliferate in response to hypoxia, a co-culture with fibroblasts initiated proliferation which was dependent on p38MAPK in the fibroblasts. My hypothesis is that hypoxia stimulates a p38MAPK dependent release of mitogen(s) from the fibroblast which are responsible for SMC proliferation. We will identify the mitogens and characterise the signalling pathway involved in this process. Both in vitro cell work and in vivo animal models will be used to address these questions.
Systematic analysis of essential parasite genes linked to invasion of the host cell in Toxoplasma gondii. 06 Apr 2009
Apicomplexan parasites evolved unique organelles (micronemes, rhoptries and IMC) that enable invasion of the host cell. Interestingly, these organelles are linked to the secretory system. Therefore, systematic functional characterisation of factors believed to play a role in vesicular traffic, like Rab-GTPases, motor proteins, dynamins or SNAREs, will lead to novel insights as to how apicomplexans regulate biogenesis, maintenance and regulated secretion of these organelles. We previously demo nstrated that parasites deficient in these processes are unable to invade and we established image based approaches to automatically identify and characterise these mutants. We now want to expand our systematic, functional characterisation of genes of interest (GOIs) linked to these processes, using two complementary approaches: targeted mutagenesis and a random mutagenesis screen to identify novel factors that cannot be identified bioinformatically. The key goals are: I) Functional characte risation of GOIs 1) Determination of mechanisms of vesicular traffic and regulated secretion involving known GOIs 2) By screening of a new library of random parasite mutants, identification of novel mutants affected in host cell invasion 3) Functional, mechanistic characterisation of confirmed novel GOIs II) Long term goals 1) Establishment of an open access database for characterised mutants 2) Screening for chemical inhibitors for validated GOIs
Functional, biochemical and structural analyses of Plasmodium falciparum pyruvate dehydrogenase complex and glycine cleavage systems. 16 Jun 2008
To investigate the precise role of the giant multi-enzyme complex pyruvate dehydrogenase (PDH) in P. falciparum via genetic, molecular biology, biochemical and biophysical techniques. Specifically to answer the following questions: a. Is PDH required for Plasmodium growth during intra-erythrocytic development? b. What is the precise function of apicoplast-located PDH? c. How is the activity of PDH regulated in the absence of genes encoding PDH kinases and phosphatases? d. Are there biochemical and structural peculiarities in PDH that are exploitable for future drug development?
Migration versus scavenging: Opposing roles for the chemokine receptor CCR2 during inflammation. 16 Jun 2008
1. To define the full chemokine binding profile of CCR2 on primary cells; 2. To compare chemotactic activity of CCR2 ligands on distinct CCR2+ cell types; 3. To determine if CCR2 scavenges chemokines after desensitisation; 4. To examine scavenging of immobilised chemokines by CCR2.
African trypanosomas are important pathogens of humans and domestic animals in sub-Saharan Africa. In order to fully understand and manage the diseases caused by these parasites, we must develop an understanding of their population dynamics. Understanding how these parasites transmit and exchange their genetic material will allow predictions of their ability to spread into other geographical locations, hosts, or to develop and spread traits, such as drug resistance, that are important for the epidemiology of the disease. The objective of this project is to compare and contrast the population genetics of the main pathogenic African trypanosomas, T. vivax, T. congolense and T. brucei, which exist in different ecological environments. The specific questions to be addressed are: 1. What is the nature and extent of genetic exchange in each of the species and does this differ in different populations? 2. Are the species sub-structured due to geography, host specificity or transmission cycles? 3. Has selection been acting upon the trypanosome populations due to the widespread use of drugs?
African trypanosomes evade host specific immunity by undergoing antigenic variation, the differential expression of a family of ~1000 Variant Surface Glycoprotein (VSG) genes. Several VSG gene switching mechanisms operate in laboratory-adapted trypanosomes, which have a greatly reduced VSG switch rate, but in high-switching, non-adapted lines, we have now found there is one dominant mechanism, gene duplication, that preferentially uses telomeric genes. VSGs are first expressed in the metacyclic stage in the tsetse fly, where genes are activated by a mechanism of random selection of telomerically located promoters. Together, these findings lead to the proposal that VSG gene activation systems involve telomere silencing, which can be alleviated for individual switch events by specific, positive factors. I propose to dissect the gene duplication mechanism and its possible hierarchical nature in bloodstream trypanosomes, and the promoter activation mechanism in the tsetse fly phase. Simultaneously, basic characterization of telomere silencing has begun with a specialist laboratory, and the aim is to draw together all these strands. VSG expression is closely linked with other essential phenotypes, and I aim also to assess the nature and extent of diversity in these phenotypes in the critical metacyclic population. We specialize in study of trypanosomes in an organismal background, and the proposed studies would lead to an integrated understanding of how trypanosomes survive through programmed diversification.
Dissecting differences in joint, tendon sheath and systemic pathology between two murine models of synovial self-tolerance breach: what are the respective roles of T helper-1 and -17 cells? 20 Jul 2010
This project will utilize murine models of early events in rheumatoid arthritis (RA) pathogenesis, to determine any differences in pathology when T-helper type 1 (TH1) or type 17 cells (TH17) respectively, are used to initiate loss of synovial self-tolerance. Arthritis will be induced following transfer of TH1 or TH17 cells that recognize ovalbumin peptide i.e. a joint-irrelevant antigen. It will be determined if the severity and nature of histological lesions differs between the two groups in affected joints, associated tendons and draining lymph nodes. This will include identifying transferred T-helper cells. Other organs and tissues will be examined for inflammatory lesions, as in human RA patients they are not limited to diathrodial joints. Finally, it will be established whether the key products of TH1 and TH17 cells i.e. interferon-g (IFN-g) or interleukin-17 (IL-17) are present, and at what levels. This project, conducted as part of a larger immunological study and with the applicant embedded in a large collaborative team of biomedical researchers, will assist in elucidating different or overlapping roles of T-helper cell types during a self-tolerance loss event. Without this basic information, it will not be possible to develop preventative measures for this painful, common and distressing human disease.
Elucidating Intestinal Macrophage Biology. 02 Feb 2009
There are large numbers of macrophages in the normal large intestine, positioned immediately under the epithelium and the commensal microbiota. Although these resident macrophages are actively phagocytic and bactericidal, most do not express toll like receptors or produce inflammatory cytokines. Thus they may contribute to intestinal homeostasis by limiting penetration of commensal organisms without causing inflammation. Recognition of microbial products by macrophages also controls epithelial i ntegrity in the healthy intestine, while activated intestinal macrophages play a central role in protective immunity against pathogens. Macrophages are also important effector cells in inflammatory bowel diseases (IBD), with the appearance of a dominant subset of TLR-expressing, cytokine producing macrophages. Our recent work shows that a few TLR+ macrophages are also present in normal colon and it is unclear how all these apparently distinct properties are controlled, nor is it known if the re sident and inflammatory subsets represent distinct lineages of macrophage which are recruited differentially in health and disease, or if they reflect alternative differentiation of the same lineage. This sabbatical will allow Professor Mowat to acquire flow cytometric methods and skills available at the University of Lund which will allow these issues to be addressed in animal models used in Glasgow.
Exploiting ES-62 to dissect dendritic cell d signals regulating initiation and the phenotype of the inflammatory response. 08 Jun 2009
The core aim of the project is to dissect the signalling mechanisms underlying ES-62-mediated subversion of dendritic cell (DC) maturation to a phenotype that drives hyporesponsive/antiinflammatory T cell-mediated immune responses. Specifically, the major objectives of the project are 1. Define whether ES-62 subverts DC maturation by signalling via a TLR4/PAF-co-receptor complex 2. Identify key signals regulating the switch converting DCs from a pro- to anti-inflammatory phenotype 3. Define whether modulation of the DC signals targeted by ES-62 mimics the phenotype of immune responses associated with ES-62 in vivo By dissecting the molecular mechanisms underlying how ES-62 subverts DC maturation, we aim to identify candidate immunomodulatory targets to facilitate novel drug development for inflammatory disease. This project will be complemented by, and will achieve added value, in terms of reagents and training, by on-going projects identifying the molecular targets of the immunomodulatory actions of ES-62 in B cells and mast cells within our longstanding collaborative grouping (MM Harnett, AJ Melendez and W Harnett).
Bluetongue is one of the most important diseases of livestock. The disease is caused by an arbovirus, bluetongue virus (BTV), transmitted by the biting midges. BTV is probably one of the best understood viruses with respect to its structure and replication. However, we have an incomplete understanding of the genetic variability of these viruses. This hampers efforts to determine the origin of some BTV outbreaks making it very difficult to quantify and minimise the risk of future ones. The common thread of this programme is that bluetongue and bluetongue virus are in reality a group of diseases induced by a variety of distinct viruses. BTV can induce a completely asymptomatic infection or kill the infected host. This variability is due to factors related to the virus, the host and the environment. We don t know what differentiate a highly virulent from a less virulent BTV strain. We have a limited understanding of the basis of the wide range of susceptibility to bluetongue displayed by different species and breeds of ruminants. In this ambitious programme, we will provide a multifaceted and holistic approach to understanding key aspects of BTV biology, transmission dynamics and pathogenesis.