- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
By 2050 10 million lives could be claimed a year by drug resistant infections. We must develop new strategies for antimicrobial drugs. Often in infections bacteria form biofilms, requiring concentrations of antibiotics up to 1000 fold higher to be treated. Cyclic dipeptides are molecules produced by organisms in all domains of life, and their function is unknown. They can inhibit bacterial growth and/or biofilm formation, albeit by undetermined mechanisms. The majority of the biological effects caused by cyclic dipeptides are inter-species and in some instances inter-kingdom, mediating host pathogen interactions. I will study enzymes from gram-positive and gram-negative bacteria involved in the production of different cyclic dipeptides. I will characterise each enzyme biochemically and structurally and determine their substrate scope. I will produce novel molecules, which will be used to disrupt growth and biofilm formation in Pseudomonas aeruginosa and Staphylococcus aureus growing alone and in bacterial co-cultures. I will combine genetic and chemoproteomic approaches to determine the molecular targets of cyclic dipeptides in P. aeruginosa and S. aureus. I will validate targets using bacterial mutants and biochemical assays. The identification of molecular targets of cyclic dipeptides will unveil crucial pathways for inter-species interactions and identify novel antimicrobial targets and molecules.
Institutional Strategic Support Fund FY2013/14 17 Oct 2013
a) Seedcorn Our rationale will be to direct resources where, based on individual cases, we can see the most impact. We will be flexible in what can be requested; we will consider funding for personnel with support for consumables or multiuser small equipment. Our priorities will be new investigators, projects with a clear demonstration that the funding will lead to grant application, projects where critical data is required to translate an important discovery or where we can see significant leverage by securing external funding for strategic priority areas. b) Enhancing and developing core multi-user facilities We have identified two such key core facilities in this period, bioinformatics and biophysics. Bioinformatics builds upon our success from the last round (vide supra) and biophysics will be a core facility for entire BSRC. Bioinformatics (http://bioinformatics.st-andrews.ac.uk/ [http://bioinformatics.st-andrews.ac.uk/]) is a joint Biology and Medicine initiative. The biophysics facility coupled to investment in protein production facilities and crystallization ensure we remain competitive. ci) People: bridging We have an excellent track record of bridging researchers into their own independent careers or between positions This flexible pot of money allows us to fund people not projects cii) People: Key technologists For the biophysics centre we will fund a person for two years to set up and establish the facility and continue support for Dr Miguel Pinheiro. Other key core technologists are currently self-sustaining we have reserved some funding in case we need to invest over the two year period. d) Public engagement We will use ISSF funds to create a coordinated effort for public engagement across life sciences. We will recruit a person and provide dedicated administrative support.
Cell Block Science & Beyond the Walls 07 Sep 2017
Cell Block Science will build on our successful programme of delivering informal science learning in HMPs Shotts and Low Moss. By expanding the programme into HMP Perth and HMPYOI Polmont we will include women prisoners and young offenders in the programme as well as piloting integrated delivery for family learning through HMP Perth’s established family programme. To enhance this family delivery we will create a virtual school with the Childrens’ University to encourage the uptake of informal learning opportunities beyond this project. For researchers this will provide an opportunity for developing interactive, accessible activities linked to their research and, through training and delivery, to gain confidence in delivery and insight into their research. We will open this programme to researchers from all Scottish universities as well as participants from community organisations such as science centres and Zoos. The programme will be evaluated for best practice and disseminated through all possible stakeholders and interested parties, including a wider European network of prison learning providers who have already expressed an interest. In addition we aim to highlight the value of science learning in the prison curriculum to present to policy makers as evidence for including formal science learning.
Living Links to Human Biology and Medicine 13 Oct 2010
We have recently established the 'Living Links to Human Evolution' Research Centre in the heart of Edinburgh Zoo. 'Living Links' was designed to facilitate multiple Science Engagement activities with visitors from the 600,000+ who roam the Zoo annually. A Science Engagement Grant from the Scottish Government supported a first phase exploiting this potential, beginning to furnish a Science Exploration Zone and last year attracting an estimated 400,000 visitors to directly witness and engage with ongoing research and related activities. Our data show that visitors now spend longer in Living Links than normal zoo exhibits. To build on this success, we here apply for support of a second phase to enhance the scope and depth of Engagement, in ways of direct interest to the Wellcome Trust.
The Bunyaviridae family are a diverse group of over 350 RNA viruses classified into five genera, namely Hantavirus, Orthobunyavirus, Phlebovirus, Nairovirus and Tospovirus. Many bunyaviruses are important pathogens of humans, animals and plants for which preventative or therapeutic treatments are unavailable. Bunyavirus pathogenesis depends on formation of the ribonucleoprotein (RNP) complex, in which the bunyavirus genome is entirely encapsidated by the virus-encoded nucleocapsid protein (N). O nly in the form of the RNP is the genome replicated, transcribed and packaged into new progeny particles. Using Bunyamwera orthobunyavirus and Rift Valley fever phlebovirus, we propose to perform a detailed quantitative analysis of the role of individual N protein amino acids in both gene expression and virus assembly. Critical to these analyses, we have generated the first high-resolution crystal structure of a complete bunyavirus N protein. We will pair this information with findings of our fu nctional analyses to reveal the structure-function relationship of the entire RNP complex for both viruses. Also critically, we will generate infectious viruses incorporating N protein mutations, which will allow us to validate our findings in the context of a live-virus infection, and relate how perturbation of molecular interactions between individual viral components affects the overall viral life-cycle
Institutional Strategic Support Fund 2011/12. 20 Dec 2011
a) Seedcorn Our rationale will be to direct resources where, based on individual cases, we can see the most impact. We will be flexible in what can be requested; we will consider funding for personnel with support for consumables or multiuser small equipment. Our priorities will be new investigators, projects with a clear demonstration that the funding will lead to grant application, projects where critical data is required to translate an important discovery or where we can see significant leverage by securing external funding for strategic priority areas. b) Enhancing and developing core multi-user facilities We have identified two such key core facilities in this period, bioinformatics and biophysics. Bioinformatics builds upon our success from the last round (vide supra) and biophysics will be a core facility for entire BSRC. Bioinformatics (http://bioinformatics.st-andrews.ac.uk/) is a joint Biology and Medicine initiative. The biophysics facility coupled to investment in protein production facilities and crystallization ensure we remain competitive. ci) People: bridging We have an excellent track record of bridging researchers into their own independent careers or between positions This flexible pot of money allows us to fund people not projects cii) People: Key technologists For the biophysics centre we will fund a person for two years to set up and establish the facility and continue support for Dr Miguel Pinheiro. Other key core technologists are currently self-sustaining we have reserved some funding in case we need to invest over the two year period. d) Public engagement We will use ISSF funds to create a coordinated effort for public engagement across life sciences. We will recruit a person and provide dedicated administrative support.
The Bunyaviridae is a family of mainly arthropod transmitted viruses that contain a tripartite single-stranded RNA genome. Some members of the family are of medical importance causing encephalitis or haemorrhagic fever in man. My laboratory has used Bunyamwera virus, the prototype of the family, as the representative on which to perform molecular biological studies such as functional analyses of recombinant expressed viral proteins, and the development of a reverse genetic system to recover infe ctious virus entirely from cDNAs. This proposal exploits the materials and reagents we have developed to continue and expand our work analysing the replication processes of bunyaviruses at the molecular level, with the overall goal of understanding how the virus interacts with host cells of mammalian and insect origin. Our underlying hypothesis is that differences in virus:cell protein:protein interactions between these cell types determine the outcome of infection. Specifically, using a combina tion of molecular, biochemical and cell biological approaches we will address the following interrelated areas: (i) interactions of viral proteins with cellular proteins during bunyavirus replication; (ii) real-time microscopic analysis of bunyavirus infection using fluorescently tagged viruses; and (iii) functional analysis of the bunyavirus NSs protein in mammalian and insect cells.
Whilst much has been learnt over recent years about how viruses interact with the interferon (IFN) system, there are still significant gaps in our knowledge. By building upon our extensive experience on the interaction of paramyxoviruses with the IFN system we propose to address some of these questions. More specifically, we will continue to characterise the nature of (paramyxo)virus inducers of IFN and how the IFN-induction cascade is activated and controlled, with particular reference to obser ved heterocellular nature of IFN induction. We will also identify the IFN-induced genes that affect the replication of paramyxoviruses (in particular PIV5), and detail how these viruses deal with cells in a pre-exisitng IFN-induced anti-viral state. In this regards, the importance of virus cytoplasmic bodies to the life-sytle of these viruses and their ability to establish prolonged/persistent infections will be examined. In addition, we will develop generalised methods for the rapid selection o f viruses that are either good inducers of IFN or cannot block IFN signalling, both for our fundamental studies and because such viruses may be developed as potential attenuated vaccine candidates. Such procedures may be particularly valuable for newly emerging viruses that pose an immediate threat to human and animal welfare.
We have established that bacterial cells require cellular homeostasis for growth and survival in diverse niches. Ion channels play major roles in cellular homeostasis, as exemplified by our previous work on mechanogated (MscS & MscK) and electrophile-activated (KefC) channels. We have made considerable progress in understanding the gating of these two channel types and the future programme will concentrate specifically on the gating transitions in the channels. Additionally, we will pursue high resolution structures for the closed state of both MscS and MscK and assess important regions of the KefC structure in order to link them to function. The team members have become expert in electrophysiology, molecular genetics and protein biochemistry and they have made significant contributions to understanding the mechanisms and physiological roles of bacterial ion channels. The programme builds on these core skills, which will be augmented by strategic structural and biophysical collaborations (Naismith & Perozo). The key objectives will be: Detailed understanding of the gating transition of the MscS and MscK channels. Closed structures for MscS and MscK. Structural analysis of KefC - definition of the ion translocation pathway and the gating transition.
Lipid biosynthesis and its influence on the glycosylphosphatidylinositol pathway in protozoan parasistes. 19 Sep 2007
Advances in the understanding of general cell-surface architecture of trypanosomatid parasites, particularly human pathogens like Trypanosoma brucei, Trypanosoma cruzi and Leishmania has come about by the identification and structural characterisation of the most abundant cell-surface molecules. The majority of these are glycosylphosphatidylinositol (GPI) anchored glycoproteins and/or GPI-related molecules. Significant differences between the GPI biosynthetic pathways of protozoa and humans has lead to the suggestion that it might be a viable therapeutic target. In T. brucei, the causative agent of African Sleeping Sickness, this has been validated by the lethal disruption of the GPI biosynthetic pathway in the bloodstream form of the parasite by knocking out the TbGPI10 gene. Thus, it follows that the formation of the acceptor and donors required for GPI biosynthesis must also be essential. These incude the biosynthesis pathways of phosphatidylinositol (PI) acceptor, phosphatidylethanolamine (PE) and dolichol-phosphate-mannose (Dol-P-Man) donors. In yeast, several null and conditional (temperature sensitive) mutants of the genes involved in these lipid biosynthetic pathways have been created. These have been invaluable in studying lipid biosynthesis and several of these have been shown to affect GPI biosynthesis. Current knowledge of the biology and biochemistry of these biosynthetic enzymes in trypanosomatids is inadequate in many respects, but advances in molecular and biochemical techniques and the advances in the T. brucei genome project has made available exiting new possibilities for investigations of these biosynthetic enzymes and pathways. Thus, the primary theme of this proposal is to study the enzymology, mechanisms, structure, protein-protein interaction and influence that these biosynthetic enzymes have on the the GPI pathway. Unique pathways and/or enzymes involved in lipid biosynthesis in trypanosomatids may be identified, highlighting potential exploitable differences between mammalian and parasite lipid biosynthesis and providing novel therapeutic targets. Finally, part of the project is to capitalise on pre-existing inhibitors of general lipid biosynthesis having anti-protozoan activity and ascertain whether these inhibitors can be modified so that they can permeate the cell-membrane of living trypanosomes. The proposed project will continue my research interests in GPI biosynthesis, but from a wider perspective, using a multi-disciplinary approach to study parasite lipid biosynthesis and its direct effect on the essential GPI pathway.
Making associations: is the pedunculopontine tegmental nucleus involved in learning about the outcomes of actions? 12 Oct 2006
We will test the hypothesis that the pedunculopontine tegmental nucleus (PPTg)is critically involved in establishing associations between actions and their consequences. A series of experiments from this laboratory strongly suggests that the PPTg is involved in this. We will (i) examine whether the PPTg is critically required when associations are being made (when an action has low outcome predictability) but not once associations are established (when an action has a predictable outcome). (ii) Define the nature of PPTg involvement with associative learning: is it involved with action-outcome associations (subject, for example, to reinforcer devaluation), habit formation (a stimulus-response process insensitive to reward changes) or the effort required to respond? (iii) Test the hypothesis that separate parts of the PPTgare differentially involved in this. (iv) Examine the involvement of the PPTg with these processes using immediate early gene expression, and to examine theimpact PPTg lesions has on other neural systems engaged with them. The hypothesis that PPTg processes incoming data to enable selection of