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Results

Understanding the Role of VPS35 in the Intracellular Movement of Alpha-Synuclein in Neuronal Cells 31 May 2018

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease affecting 10 million people worldwide. A key protein linked to the aetiology of the disorder is alpha-synuclein for which misfolding is linked to the pathogenesis. Importantly alpha-synuclein misfolding can be passed from cell-to-cell by mechanisms which are poorly understood. One proposed mode of transfer is via exosomes, small extracellular vesicles that are released from cells when multi-vesicular endosomes fuse with the plasma membrane. Trafficking in the endosome system therefore has potential to modulate exosome production and affect the transfer of misfolded alpha-synuclein. One gene implicated in late-onset familial PD is vacuolar protein sorting-35 (VPS35). VPS35 is a component of the retromer complex which is a coat protein involved in retrograde trafficking from endosome to the Golgi apparatus. It has the potential to modulate multi-vesicular body (MVB) formation/biogenesis and thereby influence the quantity of exosome-associated alpha-synuclein released from neuronal cells. Our hypothesis is that knockdown of VPS35 will modulate MVB/exosome biogenesis, augmenting the release of exosome-associated alpha-synuclein from cells. We suggest exosomes from VPS35 knockdown cells will be more potent in transfer of alpha-synuclein between cells. This will be observed by using immunoelectron microscopy, Nanocount technology, and immunofluorescence.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of St Andrews

Divide and conquer: disrupting bacterial biofilms with cyclic dipeptides 21 Feb 2018

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.

Amount: £1,016,218
Funder: The Wellcome Trust
Recipient: University of St Andrews

Open Access Award 2017/18 30 Sep 2018

Not available

Amount: £25,479
Funder: The Wellcome Trust
Recipient: University of St Andrews

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.

Amount: £147,354
Funder: The Wellcome Trust
Recipient: University of St Andrews

Unravelling structure and mechanism of adenine(22)-tRNA methyltransferase: towards novel antibiotics against MRSA 05 Sep 2017

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of hospital infections worldwide. Once restricted to healthcare facilities, this bacterium has now been found to cause infections in otherwise healthy communities. MRSA isolates have emerged that are resistant to most antibiotics in clinical use. It is imperative that new drugs be developed against MRSA. It is easier to develop specific antibiotics when the bacterial molecules they are meant to target are well understood. Enzymes accelerate chemical reactions in all living beings. If we produce a drug that inhibits an enzyme essential for MRSA growth, that drug will stop infections. If such enzyme is absent in humans, a specific drug can be developed to avoid side effects. The enzyme N1-adenine(22)-tRNA methyltransferase (TrmK) is essential in MRSA and absent in humans, fitting the aforementioned criteria. However, we know little about its structure and function. In this project, we will elucidate the mechanism of action of TrmK using enzyme kinetics and crystallography. Our results will pave the way for follow-up work aiming at rational design of specific inhibitors to be further developed into drugs against MRSA infection. Keywords: kinetics, enzyme mechanism, crystal structure, tRNA methyltransferase, antibiotics

Amount: £99,930
Funder: The Wellcome Trust
Recipient: University of St Andrews

Institutional Strategic Support Fund 07 Sep 2016

Not available

Amount: £750,000
Funder: The Wellcome Trust
Recipient: University of St Andrews

Open access block grant 2016/17 30 Sep 2016

Not available

Amount: £22,045
Funder: The Wellcome Trust
Recipient: University of St Andrews

Cell Block Science 13 Jan 2016

Funding is sought to facilitate the delivery of a programme of public engagement with science activities in the prison learning centres of HMP YOI Cornton Vale and HMP Shotts. Activities will be designed and delivered by scientists from the Biomedical Sciences Research Centre (BSRC), St Andrews University with assistance from their public engagement officer, Mhairi Stewart. The BSRC is uniquely placed to cover many STEM subjects including Biology, Chemistry, Physics and Medicine. The programme will launch with Univeristy of St Andrews researchers visiting the prison learning centres and the establishment of a science library in the centres. The project officer (to be appointed) along with the named applicants will use these visits to evaluate the areas of most interest and widen the programme to include a series of science based projects delivered at differing levels of challenge that prisoners can undertake in the prison environment. Our aims are to engage prisoners with STEM subjects and provide opportunities for skill development including problem solving, communication skills, independent learning, and teamwork. Researchers will receive communication skills training and practice through the programme. This project will also contribute to knowledge on best practice in informal science learning within prison environments.

Amount: £32,664
Funder: The Wellcome Trust
Recipient: University of St Andrews

Seed Award in HSS 30 Sep 2016

This project proposes to open a comparative understanding of mental illness in contemporary Namibia through in-depth, inter-disciplinary research that illuminates the present postcolonial moment in the light of the colonial past while it discloses breaks along with continuities in discourse and practice. Patients and families-centred accounts, largely neglected in the existing literature, will figure notably in this project. Focusing this illumination on Namibia,, the proposed research addresses two interrelated themes: the ‘content of madness’, that is, the patients’ subjective illness narratives and their subsequent medicalization; and ‘the emotional world’ of insanity which encompasses the pro-active engagement of families insofar as they re-direct, support and/or oppose the medical intervention among their kin. Central to this project is an interdisciplinary approach and the use of a varied methodology, including archival research, audio recordings and multi-media fine art practices. The award would enable me to assess available archives and lines of research, test out experimental methodology and establish an interdisciplinary network of Namibia based academics, mental health practitioners and artists, to further explore theoretical and methodological issues. Research outcomes include: an interdisciplinary project proposal for the Wellcome Trust Investigator Award, a photographic and art exhibition, collaborative publications, and an end of project workshop.

Amount: £49,843
Funder: The Wellcome Trust
Recipient: University of St Andrews

Towards contextual consent in social media health research 10 Mar 2016

This project investigates whether it is possible to predict when social media users consent to having their data used for health research. The popularity of social media means that they form an attractive data source, but growing unease about the use of such data for other purposes means that researchers must address many ethical challenges when considering their use. Building on our existing work in non-health contexts, we investigate whether it is possible to use Nissenbaum’s contextual integrity to detect informational norms for the use of social media data and predict consent for use, enabling more meaningful informed consent without the burden of alternative approaches such as asking users each time they post to a social network. The goals of the project are two pilot studies looking at users of health support networks, collecting a large corpus of social media data, determining informational norms from these data, and applying contextual integrity to predict which data can be shared with whom (e.g. researchers, support providers, patients). Focus groups and workshops with social media users and practitioners will help build on the algorithms developed in these pilot studies; a follow-up project will develop tools for use in real-world health research scenarios.

Amount: £65,094
Funder: The Wellcome Trust
Recipient: University of St Andrews

An Analysis of Health Behaviour Modifications in Alleviating Fear of Cancer Recurrence (FCR) 01 Apr 2016

Cancer afflicts a considerable number of people and may have significant impact on them, such as heart problems and infertility. Distressful emotions, including loneliness and Fear of Cancer Recurrence (FCR) might be experienced. FCR is extrememly common among cancer survivors to varying degrees. In addition, high levels have been associated with depression, hopelessness and other undesirable consequences . As a highly prevalent unmet need of cancer survivors, such implications on their quality of life reveal the importance of research into FCR to improve care for cancer survivors. This research project aims to further investigate the relationship between loneliness, distress and FCR. In particular, it also seeks to study whether modifications in health behaviours can alleviate FCR. Research suggests that diet and physical activity may be key factors in reducing cancer risk. Furthermore, it is thought that FCR might motivate health behavior modifications in cancer survivors. However, more research is needed to delineate this relationship. Moreover, a theoretical understanding of if and how changing health behaviours may help the survivors manage their fears is not available. Therefore, the project will explore the relations between health behaviour modifications and FCR through interviews and surveys to attain both qualitative and quantitative data.

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

Molecular viable count testing in Pseudomonas chronic bronchial infection 01 Apr 2016

In this project, a novel Molecular Bacterial Load (MBL) assay that is able to quantify viable Pseudomonas in samples will be developed. Primers will specifically target the 16SrRNA in Pseudomonas bacteria. This will allow the assay to determine the presence of Pseudomonas bacteria in samples, as well as quantify the number of organisms that are alive. Compared to current techniques for determining the presence and viability of organisms in acute and chronic Pseudomonas infections, the MBL assay will provide results significantly faster, and will be much more specific. This means that the technology could be applied clinically as a new tool to monitor the response of patient to antimicrobial therapy, and ensure that there is not resistance to the selected treatment. This is relevant particularly in patients with chronic respiratory disease such as Cystic Fibrosis, where a chronic (and inadequately treated) Pseudomonas infection can significantly increase morbidity and risk of mortality. Key objectives for this project include: developing a 16SrRNA primer for Pseudomonas to be used in the MBL assay; to determine the specificity of the assay by testing it against organisms that are taxonomically related to Pseudomonas; and to validate the assay with a pre-existing clinical sample set.

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

Rapid functional characterization of patient-derived neural stem cells 01 Apr 2016

Human stem cells bring a great promise for personalized regenerative medicine, in vitro studies of patient-specific human diseases and new generation of effective drug-screening methods. In the last years, patient-derived induced pluripotent stem cells (iPSC) have been increasingly used in clinical trials of novel therapies and more fundamental studies on the genetic neuronal disorders. However, the great variability and heterogeneous behaviour of patient-derived iPSC lines has been recognized as a major obstacle in their clinical applications and in conclusive interpretation of in vitro studies and drug screening assays. Their functional electrical properties responsible for the neural function are particularly important for the success of neuroregenerative stem cell treatment. However, they are extremely difficult to study using traditional electrode-based methods and the selection of functionally optimal transplant cell line is currently unfeasible. In this project, we will apply our recently developed experimental system capable of rapid functional analysis of living neural cells to human iPSC-derived neurons. Using our light-based optogenetics approach we will aim to demonstrate an efficient methodology for selection of the optimal transplant iPSC line for neuroregenerative therapy based on its electrophysiological characteristics. Our non-invasive approach will enable complete electrophysiological characterization of hundreds of cells within each sample.

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

Institutional Strategic Support Fund Phase2 FY2014/16 27 Oct 2014

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.

Amount: £1,000,000
Funder: The Wellcome Trust
Recipient: University of St Andrews

Open access award 2015/16. 21 Sep 2015

Not available

Amount: £23,044
Funder: The Wellcome Trust
Recipient: University of St Andrews

Archival Research into the Theatrical Component of Early Modern Spanish Medical Practice. 29 May 2015

Archival research in four different locations in Spain, one week each. In each case, the goal is to find information in legal and other documents regarding any theatrical component in any medical practice, including the sale of medicine. These components can range from simple street-hawking, to setting up shop in a public place, to oration and speech-making in a public place, including song-and-dance as a means to attract and convince patients. 1) Archivo Hist rico Nacional: The Consejos section is housed here, which contains legal documents related to the licensing and disputes involving medical practitioners in Madrid. 2) Archivo General de Simancas: This archive contains legal documents related to the licensing and disputes involving medical practitioners, especially salary disputes, that are not contained in the Archivo Hist rico Nacional. 3) Archivo de la Real Chanciller a de Valladolid: This archive contains the documentation of many lawsuits involving medical pract itioners. 4) Archivo del Reino de Valencia: This archive a source of documentation on what Mar a Luz L pez Terrada calls extra-academic medical practices , evidence of which may not be covered by documents in other archives, or has been lost, or destroyed elsewhere.

Amount: £2,943
Funder: The Wellcome Trust
Recipient: University of St Andrews

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.

Amount: £500,000
Funder: The Wellcome Trust
Recipient: University of St Andrews

Open access publising costs 2014/15. 15 Sep 2014

Not available

Amount: £23,044
Funder: The Wellcome Trust
Recipient: University of St Andrews

Use of medieval recipes by a sixteenth-century reader. 14 Apr 2014

This grant application requests funding to support a one-week archival visit to Oxford. I wish to make a detailed study of a single fifteenth-century manuscript, Oxford, Bodleian Library, MS Rawlinson c. 299. This manuscript contains a collection of medieval medical recipes written in English. The hand-written collection comprises about 150 recipes in total, including some charms and a uroscopy. A unique point of interest is that the manuscript had a known owner and location in the sixteenth-cen tury. My investigation will consider this later owner's use of this medieval medical material by charting the exact nature of his annotations and interractions in the manuscript.

Amount: £653
Funder: The Wellcome Trust
Recipient: University of St Andrews