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Results

Volunteering Matters 06 Nov 2014

Piloting Engage and Transform, a scheme to break down cultural barriers and develop a long-term partnership of mutual benefit between public and social sector organisations.

Free Will and Neural Activity in Consequential Action 31 May 2018

Neuroscientific and psychological studies have found that neural activity precedes the intention to act by several seconds, indicating that our actions are predetermined by unconscious neural computation. A major shortcoming of these studies is that the acts tested are trivial (e.g. move a finger at a time of your choosing), having no real-world implications. In a series of EEG experiments, we will assess complex choices that participants make. First, participants will be asked to choose to press one of two buttons. Then, they will be asked to a) ‘reward’ or ‘punish’ a person arbitrarily, b) reward or punish a person in response to a moral act, c) choose how much to reward or punish the individual based on their action, and finally, d) choose reward and punishment allocations within social or economic constraints, to reflect real-world decision-making. This will allow us to test if there is neural activity prior to the intention to act and also to compare between consequential and inconsequential choices. The investigation of neural activity in consequential action, examined in the light of philosophical analyses, addresses an essential unanswered question of past studies, and promises to shed new light on the nature and existence of free will.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Aberdeen

The role of protein tyrosine phosphatase 1B ( PTP1B ) in generation of tolergenic dendritic cells 31 May 2018

In homeostatic conditions dendritic cells are tolerogenic (Tol DC) and therefore, supress immune reactions, making them a key element in the maintenance of peripheral tolerance. Upon challenge, these Tol DC convert into mature, pro-inflammatory DC capable of initiating immune responses, this conversion is key in the induction of uveitis. It has been demonstrated that Tol DCs exhibit hyperphosphorylation of STAT3, a component of JAK/STAT signalling pathway, which is critical in controlling DC function. Previously, the lab has demonstrated that protein tyrosine phosphatase 1B is a key regulator of DC function via a STAT3 dependent mechanism. This project will investigate the role of PTP1B in intrinsic STAT3 regulation in DC by utilising a novel DC specific PTP1B knock out model (Zbtb46-PTP1B). I hypothesis that deletion of PTP1B in DC will result in hyperphosphorylation of STAT3, and preservation of Tol DC phenotype upon inflammatory challenge. Firstly, maturation status will be assessed through surface and intracellular flow cytometry for key DC activation markers (CD40, CD68, CD40, MHC class II) and cytokines (IL-12 and IL-10). Secondly, through assessment of key signalling pathways (JAK-STAT, PI3K-AKT, ERK1/2) involved in DC function, through western blotting, to allow mechanistic insight into the signalling pathways controlling Tol DC phenotype.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Aberdeen

Open Access Awards 2017/18 30 Sep 2018

Not available

Amount: £44,813
Funder: The Wellcome Trust
Recipient: University of Aberdeen

Combinatorial pursuit to spinal cord injury rehabilitation using an Epac agonist and hydrogel, promoting axonal regeneration in an inhibitory environment. 31 May 2018

Spinal cord injury imposes a daunting challenge on available regenerative procedures as its complexity lies in the considerable severity of symptoms, which are contingent on location and impact of injury to the spinal cord. Accordingly, it would require equally as drastic and diverse yet cohesive methods to combat such loss to motor and sensory physiological capabilities. Growth inhibition factors are activated after trauma below level of injury and the presence of the glial scar formation prevents any further axonal rejuvenation in the central nervous system. The aim of this research project is to systematically provide a supportive environment for axonal growth using a hydrogel scaffold biomaterial to circumvent the glial scar formation whilst simultaneously using an Epac (direct cAMP signaling effector) agonist to induce neuronal regeneration in the CNS inhibitory "hostile" environment. Using these two innovative methods reflects the difficulties in treating spinal cord injury, as using a singular strategy is ultimately insufficient to curing spinal cord injury all together.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Aberdeen

Orientation perception in aging 31 May 2018

Changes in visual perception are often assumed to be the result of age-related decline. This hypothesis is supported by previous studies on orientation specificity which found that neurons in older monkeys are less sensitive to orientation. However, a similar decline has not been confirmed behaviourally in human aging. Behavioural studies assessed only cardinal orientations whereas neurophysiological ones assess a spectrum of different orientations. Here, we will test the discrepancy between neurophysiological and behavioural studies on the basis of the oblique effect, which describes the phenomenon that younger participants perform better for cardinal than for diagonal orientations in a variety of perceptual tasks. Since cardinal contours are more dominant in our man-made visual environment than diagonal ones, the oblique effect has been suggested to be a result of environmental adaptation rather than decline in aging. In this study, we are testing younger and older adults for orientation discrimination abilities around cardinal and horizontal orientations. We expect to find better performance for cardinal orientations among all participants. More importantly, we expect the oblique effect to be larger in older adults, supporting the hypothesis that changes in orientation discrimination in ageing are based on visual experience rather than general decline.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Aberdeen

Are Phenotypic Variability and Drug Resistance in the Emerging Fungal Pathogen Candida auris Generated by Genetic Recombination? 21 May 2018

I aim to elucidate how genetic diversity is achieved in the emerging multi-resistant fungal pathogen Candida auris and how this influences its drug resistance phenotype. Using genetic, genomic, and imaging approaches this project will determine why the strains of this fungus causing different outbreaks are highly variable, and how this diversity underpins its multi-drug resistance and other phenotypic characteristics. This project is based on hypotheses framed by pilot data that suggest that this fungus is sexually recombining with non-human host strains to generate novel pathogenic phenotypes. In Objective 1 I will determine whether (para)sexual reproduction generates genetic diversity in C. auris thus driving its evolution and dissemination. In Objective 2 I will establish how chromosomal variability maps onto the global population structure of this yeast and how this correlates with its drug resistance profile. In Objective 3 I will establish which genetic factors underlie the multi-drug resistance of clinical C. auris isolates. This project will provide crucially important mechanistic insight into the genetics of an emerging and dangerous human pathogen, C. auris; and has major implications for our understanding of its epidemiology, and significant potential to elucidate the origin of differences in drug resistance between clinical isolates of C. auris.

Amount: £99,674
Funder: The Wellcome Trust
Recipient: University of Aberdeen

IVerbal Autopsy with Participatory Action Research (VAPAR): expanding the knowledge base through partnerships for action on health equity 26 Oct 2016

Health systems are increasingly considered in terms beyond 'building blocks' models, as complex, adaptive, human and relational. Despite the conceptual advances, people-centered health systems research methods remain underdeveloped. The proposed work will connect two issues: the lack of information on the health of people excluded from access to health systems, and the low utilisation of research evidence by health systems stakeholders. The proposal is to institutionalise a process to strengthen data on mortality registration, combine with local knowledge, and interpret, plan and act on this basis in the health system at different levels. The method combines Verbal Autopsy (VA) with Participatory Action Research (PAR). VA is a method to determine levels, causes and circumstances of deaths. In PAR, communities organise evidence for action. 3 phases are proposed. In Phase 1, a series of 3 reflection and action cycles will be conducted to generate evidence, analyse, plan and act. Data will be generated on levels, causes and circumstances of deaths (using VA) and on health needs and priorities for action (using PAR) with communities. Data will be analysed with provincial level policy makers, action plans will be developed and implemented by district-level practitioners, and progress will be re-assessed in subsequent cycles. In Phase 2, participants and researchers will evaluate the process using realist and political economy methods to understand changes in care, outcomes and progress towards health equity. In Phase 3, sustainability and transferability will be developed with authorities, research and technical groups, health systems stakeholders and communities in the study site, and to the public. The output will be a process based on international standards, that is contextually relevant in health systems at different levels, and capable of translating local priorities into actionable agendas for health systems strengthening as a means towards health equity.

Amount: £235,156
Funder: The Wellcome Trust
Recipient: University of Aberdeen

Zeiss LSM 880 confocal microscope with Airyscan detector for super-resolution imaging at the University of Aberdeen 06 Jul 2017

We seek funds for a Zeiss LSM 880 confocal microscope with Airyscan detector and Airyscan Fast Acquisition Module to advance a diverse range of interdisciplinary Wellcome Trust funded projects with a focus on medical microbiology and immunology that are central to the University’s strategic plan. Compared to conventional confocal microscopes, the LSM 880 with Airyscan provides greatly improved image quality and super-resolution imaging by simultaneously increasing signal to noise (4-8x) and resolution (1.7x) while enabling faster scanning (4x). Notably, laser power can be reduced substantially, thereby enabling long-term imaging of live cells expressing multiple fluorophores. This allows rapid, dynamic and complex processes to be acquired in super-resolution. The supplied ZEN2 software enables automation of many tasks. The equipment will be housed in our well-established Microscopy Core Facility in the College of Life Sciences and Medicine. The equipment will be maintained by core-funded staff with extensive expertise in state-of-the-art microscopy and decades of experience serving our research community, locally and further afield, using sustainable cost-recovery mechanisms. The equipment will primarily support our Welcome Trust funded researchers, but also other researchers working in the biomedical sciences, bringing considerable added value and new insights into these research programmes.

Amount: £332,338
Funder: The Wellcome Trust
Recipient: University of Aberdeen

Uncovering the Pharmacology of GPR75: Role in Pulmonary Arterial Hypertension 29 Nov 2016

Pulmonary arterial hypertension (PAH) is a devastating condition that if left untreated has an average life expectancy of less than three years from diagnosis. PAH is associated with proliferation of pulmonary artery smooth muscle cells (PASMC), which contributes to increased vascular resistance. The maintenance of the low vascular tone in the pulmonary circulation is dependent on the interaction of circulating and locally produced mediators, many of which act via G protein-coupled receptors (GPCRs). The accessibility of GPCRs on the plasma membrane, their tissue-selective distribution and role in regulating physiological functions make them excellent pharmacological targets. We used an "unbiased" approach (GPCR real-time-PCR arrays) to profile GPCR expression in PASMC isolated from control and PAH patients. Our data revealed that PAH-PASMC uniquely express an orphan GPCR (whose endogenous ligand has not yet been identified) compared to control-PASMC, namely GPR75. We aim to validate GPR75 as a novel target for PAH by uncovering its pharmacology and the functional significance and expression of receptor variants in PAH and by elucidating its physiological role in-vivo. Our hypothesis is that GPR75 is a key regulator of PASMC proliferation that characterizes PAH and is an exciting new target or genetic risk factor for the disease.

Amount: £99,881
Funder: The Wellcome Trust
Recipient: University of Aberdeen

Navigation and steering systems in fungal pathogens - the route to fatal infection 05 Apr 2017

Invasive candidiasis is the most common fungal disease among hospitalised patients in the developed world, affecting over 250,000 and killing 50,000 people a year. My research will discover how the microscopic filaments (hyphae) of Candida albicans disseminate from the bloodstream into solid organs, including the lung, liver, spleen, kidneys and bone, by addressing the hypothesis that hyphal guidance regulation is highly adapted to host microenvironments. My first aim is to determine the molecular mechanisms that regulate hyphal guidance. My second aim is to examine how physical properties of the microenvironment affect hyphal interactions with relevant host cells in vitro using biomaterials and the fluorescence live-cell imaging methods I have developed. With these, I showed that hyphal behaviour is determined by environmental factors, including adhesion, surface topography, substrate stiffness, calcium influx and carbon source, and can affect tissue distribution and interactions with macrophages. My third aim is to apply the understanding gained from my in vitro studies to an in vivo model of immune-cell activation and tissue invasion using see-through zebra-fish to image hyphal behaviour. This study will reveal how fungus-host interactions are influenced by the microenvironment and identify the regulatory pathways required for fungal dissemination during invasive candidiasis.

Amount: £1,258,447
Funder: The Wellcome Trust
Recipient: University of Aberdeen

Vacation Scholarships 2017 - University of Aberdeen 16 Jun 2017

Vacation Scholarships Institutional Award

Amount: £4,000
Funder: The Wellcome Trust
Recipient: University of Aberdeen

In vitro characterisation of neurons and glia derived from mouse ES cells having Y chromosome gene deficiencies 27 Apr 2017

The brain is a sexually dimorphic organ, which can explain why many psychiatric disorders are gender-biased. While it has been thought that fetal sex hormones play a crutial role in brain sexual differentiation, emerging evidence indicates that genetic and/or epigenetic factors encoded by sex chromosome genes are also involved. Here, we focus on several Y-linked genes expressed in the male brain, which may act in a dominant manner. Sry, Uty and Smcy genes, whose products can participate in histone modification, are of particular interest. However, their functions in the brain remain unknown mainly because of difficulties in conventional gene-targeting of Y loci in embryonic stem cells (ESCs). In this project, we will take advantage of Crispr/Cas genome-editing technology that allows us to modify Y-linked genes. Mutant alleles of these three genes in ESCs were created and then differentiation will be induced of neurons and glia from the mutant ES cells. Differential gene expression between wild-type and mutant cells will be analysed by RT-RCR and bisulfite PCR, and subsequently epigenetic status of these differential genes will be elucidated. The project will reveal influences of Y-linked genes on sex-specific epigenetic modification and lead to better understanding of gender-biased psychiatric disorders.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Aberdeen

CRISPR/Cas9 enabled study of cis-regulatory regions of the NPY gene 27 Apr 2017

NPY is a neuropeptide, expressed in the hypothalmus, which known to be involved in appetite regulation. Although little is known about the regulation of the NPY gene preliminary studies in the MacKenzie lab have identified highly conserved enhancers around the NPY locus many of which drive reporter gene expression in mouse hypothalamus. Dr Mackenzie's lab has recently carried out CRISPR based knockouts of regions of the NPY locus in mice and wish to study the affect on mouse feeding patterns and NPY gene expression in order to further characterise the enhancers controlling NPY. This will initially involve the use of in situ hybridisation and Qrt-PCR on tissues derived from genome edited mice from which candidate NPY enhancer regions have been ablated. Understanding the regulation of this gene will bring us significantly closer to understanding the factors affecting appetite, increased food intake and obesity.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Aberdeen

Institutional Strategic Support Fund 07 Sep 2016

Not available

Amount: £900,000
Funder: The Wellcome Trust
Recipient: University of Aberdeen

Genetic and chemical validation of sugar nucleotide biosynthesis as a target against Candida albicans 08 Dec 2015

The fungal pathogen Candida albicans is one of the leading causes of invasive fungal disease. The incidence of invasive Candidiasis has remained high due to a combination of a rising population of immunocompromised patients and the emerge of resistance against a small arsenal of only partially effective antifungal drugs. There is thus an urgent need for novel, properly genetically and chemically validated, drug targets. The Candida cell wall consists of chitin, glucan and mannan. Despite an emerging understanding of the complex membrane proteins involved in synthesis of these polymers, targeting them has proven difficult. Instead, in this proposal we aim to target the "Achilles heel" of cell wall synthesis – the production of the sugar nucleotides UDP-Glc, UDP-GlcNAc and GDP-Man that will cut deep into the essential wall biosynthetic machinery. Using state-of-the-art techniques we will genetically, structurally and chemically validate C. albicans enzymes from these sugar nucleotide biosynthetic pathways as antifungal targets. The output will be: 1) A significant increase in our molecular understanding of these enzymes, 2) A collection of novel chemical tools for use by the fungal scientific community, and 3) A portfolio of targets (and associated tools) that serve as a springboard for novel antifungal drug discovery.

Amount: £391,471
Funder: The Wellcome Trust
Recipient: University of Aberdeen

Open access block grant 2016/17 30 Sep 2016

Not available

Amount: £31,254
Funder: The Wellcome Trust
Recipient: University of Aberdeen

Combination therapy for obesity and type 2 diabetes treatment 08 Apr 2015

Drugs augmenting serotonin bioavailability are among the most clinically effective compounds for weight loss and represent the gold-standard for obesity treatment research. Due to sibutramine's withdrawal from the clinic and the recent failure of the serotonin2C receptor agonist lorcaserin to achieve FDA approval, a major unmet clinical need has emerged. Here we propose a refined strategy to dissociate and manipulate a critical serotonin energy balance pathway in an effort to circumvent off-tar get effects produced by global serotonergic compounds and selective serotonin receptor agonists. Building on work generated in the previous funding period where we characterised a downstream pathway required for serotonin to regulate energy homeostasis, here we propose cutting-edge techniques coupled with recently developed tools to delineate and manipulate in real-time serotonin efferents providing these critical inputs to coordinate energy balance. Furthermore, we will interrogate the effect of dietary choice and adiposity on serotonin neuron sensitivity to these inputs and nutritional signals. Finally, we will delineate nutrients and nutritional cues that directly influence the sertotonin neuron activity, with the aim of revealing new system-specific targets for obesity pharmacotherapy.

Amount: £199,253
Funder: The Wellcome Trust
Recipient: University of Aberdeen

Institutional Strategic Support Fund Phase2 FY2014/16 27 Oct 2014

The Wellcome Trust has recently awarded the University of Aberdeen £600,000 in funding to support a range of strategic research activities that fall within the Wellcome Trust's remit. Projects must fall within the remit of the Wellcome Trust and be within the strategic remit of the Aberdeen ISSF including; Infection, Immunity and Inflammation, particularly Medical Mycology Understanding the molecular basis of obesity for the development of interventions Applied Health Sciences, particularly through our Chief Scientist Office-funded Health Economics Research Unit and Health Services Research Unit. The support strategy for the fund is to: Facilitate more interdisciplinary research across the schools and institutes Enhance research impact through its translation into practice and dissemination through public engagement Enhance our Career Development Support in biomedical research The ISSF Seed Corn Fund will invite proposals from researchers working in a priority area with the aim of supporting new interdisciplinary collaborations by: Providing access to core facilities for proof of concept, feasibility or other pilot work needed to strengthen full scale applications to the Wellcome Trust or other similarly prestigious funders; Applications are particularly encouraged utilising the Centre for Genome Enabled Genomics and Medicine to strengthen pilot data and informatics; Developing new commercialisation or knowledge exchange opportunities, especially for Wellcome Trust funded projects (e.g. through support to develop and implement drug development roadmaps, appointment of external consultants, access to clinical trial design/expertise/health economic advice). As part of our commitment to recruiting and retaining the highest calibre ECRs, we want to enhance our support for the preparation of fellowship applications within the Wellcome Trust’s remit within the context of our highly successful fellowship management scheme. The ISSF will provide up to 6 months of salary support for around 5-6 recipients who meet our criteria and who participate in the College of Life Sciences and Medicine (CLSM) fellowship traffic light scheme. We are launching a programme aimed at female academic staff returning from maternity leave or a career break, which enables them to apply for a period of protected research time. This support will position individuals for subsequent success in attainment of research grant or fellowship funding, or the publication of findings which support career development. You may apply for teaching and administrative replacement costs, but in addition you may also request costs for an RA for a limited period, and/ or some consumables. We wish to expand clinical scientist numbers through the Aberdeen Clinical Academic Training (ACAT) scheme. This is intended to allow clinical applicants to develop a research interest within one of our priority areas. As well as increasing the number of clinical scientists this approach creates new opportunities for translational and interdisciplinary research.

Amount: £600,000
Funder: The Wellcome Trust
Recipient: University of Aberdeen