- Total grants
- Total funders
- Total recipients
- Earliest award date
- 20 Nov 1998
- Latest award date
- 05 May 2020
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Vacation Scholarships 2018 - University College Dublin
Campylobacter jejuni is the leading cause of bacterial gastroenteritis and thus poses a significant health risk. The bacteria is part of the natural microbiome of the chicken caecum where it appears to function as a non-invasive commensal but in the human intestine the organism becomes invasive and pathogenic. The Ó Cróinín group have recently reported that DNA supercoiling plays a key role in inducing this invasive phenotype and that relaxation of DNA supercoiling is associated with an increase in invasion and the appearance of an invasion associated secretive. This group have also unpublished data which reveals that DNA supercoiling allows the bacteria to survive and grow under anaerobic conditions which normally do not support growth. Given the anaerobic nature of some areas of the human intestine this could indicate that relaxation of DNA supercoiling could be critical in allowing this bacteria to both secrete virulence factors as well as to survive and grow under anaerobic conditions. The aim of this study is thus to investigate and characterise the effect of DNA supercoiling on the ability of the bacteria to grow under anaerobic conditions as well as to compare the secretion of proteins by microorganisms grown under anaerobic and microaerophilic conditions
The development of an induced pluripotent stem cell derived organoid platform to inform regenerative therapies for chronic kidney disease. 31 May 2018
The establishment of a platform that recapitulates the developmental process of renal organogenesis will increase our understanding of human development, while serving as a model for renal disease and pharmacological and toxicological studies. Importantly, organoids contain all components of the kidney and can thus be utilised for the study of each distinct cell type present, providing an exciting opportunity when combined with the power of scRNA-Seq and gene; tools such as the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system have been successfully used to generate specific genetic mutations in iPSC lines and single cell approaches will be used to map phenotypic trajectories in response to pathogenically relevant stimuli. Current protocols for the derivation of organoids have their limitations, and are likely to benefit from further improvements most notably a better understanding of the chromatin landscape during specification of individual cell types which will aid efforts towards achieving functional maturation. Indeed our preliminary data has demonstrated for the first time a method that facilitates the production of ZO-1+ve, CDH1+ve cells from iPSCs through manipulation of a Smad3-EZH2 switch and the establishment of a permissive chromatin state. Using this approach in organoids will likely increase their ability to reach maturation.
This research seeks to investigate the effect of human T-cell leukemia virus type 1 (HTLV-1) Basic Leucine Zipper (HBZ) protein on the overall function of the endosomal sorting complex required for transport (ESCRT) multivesicular body (MVB) pathway. HTLV-1 is a retrovirus that establishes persistent infection in humans, which cause pathologies like adult T-cell leukemia (ATL) and HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP)[1,2]. Recently, studies have shown an association of HTLV-1 budding with MVBs whose biogenesis is regulated by the ESCRT[3,4] . The ESCRT machinery is an evolutionarily conserved cytosolic group of protein subcomplexes for scission of membrane necks from the interior. Hence, viruses like HTLV-1 usurp this pathway for their survival. This project hopes to establish the effect of HBZ on the ESCRT MVB pathway. Epidermal Growth Factor Receptor (EGFR): Epidermal Growth Factor (EGF) uptake and degradation is widely used as a model to study MVB functionality. This will be performed using an EGF/EGFR uptake and degradation assay in which the uptake and degradation of EGF-ALEXA 595 by HeLa cells will be monitored using a fluorescence microscope in GFP-HBZ positive cells compared to GFP only cells. This will give a measure of the effect of HBZ on the ESCRT MVB pathway.
Investigation into antisense gene silencing of the CYP17A1 gene locus in advanced prostate cancer 31 May 2018
Epigenetic lesions act collaboratively as master regulators of gene expression and thus oncogenesis. This project will address the relationship between two epigenetic aberrations, DNA methylation and non-coding RNA. Metastatic prostate cancer is fatal. Whilst tumours initially respond to endocrine therapy, resistance inevitable ensues in the form of castration-resistant disease. One of the most promising new therapeutic agents in recent years, is CYP17 inhibitor, abiraterone, which blocks adrenal production of androgens. Mechanisms of resistance to abiraterone are unknown. Previous research in our laboratory identified intragenic methylation of the CYP17A1 gene is associated with poorer overall survival. The aim of this project is to determine whether intragenic methylation of CYP17A1 serves to silence the CYP17A1 anti-sense gene, thus leading to elevated expression of the CYP17 enzyme and higher production of testosterone. This will be carried out through a series of cell culture experiments of prostate cancer cell lines to determine expression of both genes and the effect of overexpression of the antisense transcript on endogenous CYP17A1 expression. Pharmacological demethethylation will be employed to establish a relationship between CYP17A1 methylation and expression. Ultimately, this work could help personalize cancer medicine through development of a predictive biomarker for abiraterone.
The Microbiome of Triple Negative Breast Cancer (TNBC) and Its Role in Disease Progression. 31 May 2018
Breast cancer is the second most common cancer to affect women in Ireland. Approximately 15% of breast cancers are described as triple negative breast cancer (TNBC), a subtype of breast cancer which lacks the receptors for oestrogen and progesterone and do not overexpress HER2. This renders hormone treatment and the monoclonal antibody Herceptin/Trastuzumab ineffective. TNBC is a particularly aggressive and invasive form of breast cancer which has recently been shown to have its own unique microbiome. These microbiome may contribute in driving the pathogenic process. It is also suggested that cancer microbiomes may play a significant role in chemoresistance. Our objective is to determine the association of the breast cancer tumour microbiome with tumour proliferation and chemotherapeutic drug efficacy. Importantly for this study, bacteria have been shown to be potentially involved in the degradation of chemotherapeutic drugs. In summary, tumour microbiome is beginning to gain recognition as one of the hallmarks of cancer. If our research were to show a link between the microbiome and the cancer cells’ proliferation and innate resistance to treatment, it could pave the way for further investigation into possibilities of treating cancer patients with antibiotics in addition to chemotherapeutics to improve clinical outcome.
A comparision of 3D printed anatomical models against tissue equivalent models under x-ray conditions 31 May 2018
This project involves designing and production of human anatomical models by Fused Deposition Modelling which is a form of 3D printing.This technology has existed since the 1970's and in the past five years has become much more affordable allowing researchers to explore its usefulness in medical education and in patient-specific surgical planning. Once the 3D printed model is made, it will be imaged under X-ray at the diagnostic imaging department, in order to assess image quality and the human-tissue equivalency of the printed materials. Key goals include; - modelling & slicing of anatomical 3D meshes - production & optimisation of a 3D printed model - X-Ray imaging of this model - Utilisation of ImageJ software to assess the tissue equivalency of this model vs. human images & pre-existing tissue equivalent phantoms - presentation of findings at the UCD SSRA research event. This model will be anatomically correct, customisable and contain a range of tissue equivalent materials that can be X-rayed. The model will be useful in anatomy education as it will provide tutors with a customisable learning aid and accompnaying diagnostic images. Together, these will serve to enrich the learning experience for students.
The research laboratory of Dr. Gerald Barry is interested in understanding how viruses interact with their host on a protein level. An ongoing project in his group is examining the interaction of Schmallenberg virus (SBV), a virus of the Peribunyaviridae, with mammalian cells from different species. SBV causes congenital abnormalities in calves and lambs. The virus causes little problems in adult animals but can infect the foetus, causing malformations and abortions. Schmallenberg emerged in Europe in 2011 and is now endemic across most parts of western and central Europe, triggering small outbreaks on an annual basis. The Barry group has performed immunoprecipitation studies focusing on the NSs and the N protein of the virus and analysed interactions between them and cellular proteins. This work has led to the generation of 24 proteins of interest, that they now wish to interrogate using siRNA knockdown studies. I will focus on 5 proteins from this list, using siRNAs to knockdown their expression in mammalian cells to see if their loss impacts positively or negatively on the virus. Follow-on experiments and bioinformatic analysis will broaden our understanding of SBV interaction with cells, and help us to identify if the interactions are species specific.
Effects of the prolyl hydroxylase inhibitors, DMOG and JNJ42021935, on rat colon motility. 31 May 2018
Currently 15,000 people in Ireland are living with Inflammatory bowel disease including Crohn's disease. Such conditions are currently incurable, with consequences for patients varying from vomiting and diarrhoea, to more serious implications such as bleeding and a further progression of the disease. Current anti-inflammatory treatments have significant limitations due to lack of treatment response in some patients. Recent studies using a group of enzymes, (prolyl hydroxylase inhibitors) which can sense oxygen, may represent a new class of therapeutic targets. However, previous research with these enzymes including DMOG & JNJ42021935, has only focused on the inflammatory and hypoxia (low oxygen) effects during the disease. This project seeks to determine if these enzymes have any effects on the contractility of the intestine. By conducting this research, scientific knowledge of hypoxia mimetics and how they interfere with intestinal contractility will be advanced. Furthermore, this research will advance our insight into the usefulness of these agents in inflammatory bowel disease and thus may lead to a more successful therapeutic approach.
Streptococcus gallolyticus (S. gallolyticus) is commonly found in the gastrointestinal tract of ruminants. Interestingly it can cause endocarditis in humans by translocating through the GI tract at sites of colonic cancer lesions. Studies have indicated that S. gallolyticus is an excellent colonizer of the intestinal tract, forming strong biofilms via effective adherence properties (Abdulamir et al 2011). However little is known about what mechanisms these bacteria use to colonise the gut and invade the bloodstream. We have assembled a cohort of bloodstream isolates from patients across Europe and are sequencing their genomes. This project will characterise the biofilm forming capacity of the strains and compare the phenotypes of the strong and weak biofilm forming strains in growth conditions that mimic the environment of the colon (anaerobic and rich in bile salts). We will then test representative strains from the strong and weak biofilm forming groups to bind to and invade colonic epithelial cells in order to see whether biofilm forming capacity has an influence on colonic cell adherence and invasion. Finally we will test these strains for translocation across a colonic cell monolayer to see whether biofilm production by S. gallolyticus can facilitate invasion of the gut mucosa in humans.
Neuroblastoma (NB) is an embryonal tumour originating from the peripheral sympathetic nervous system. NB displays huge clinical heterogeneity, from spontaneous regression to highly aggressive behaviour. The long term survival is less than 50% for high risk disease. Interestingly, neurotrophin (Trk) signalling contributes to NB cell fate, TrkA expression induces differentiation while TrkB induces proliferation and aggressive behaviour of NB cells[6,7]. My supervisor's group showed that Trk receptors signal via the same pathways but the duration of the signal is different, and this can be the culprit in determining cell fate. A MAPK phosphatase, DUSP16 has been identified to be differentially activated in TrkA and TrkB expressing NB cells. The aim of my project is to elucidate the role of DUSP16 in Trk-mediated signalling and cell fate of TrkA/TrkB expressing NB cells. i) I will focus on MAPK signalling in NB, and investigate the role of DUSP16 on ERK1/2, p38 and MAPK signalling (by Western blotting) in TrkA/TrkB expressing NB cells. ii) Also, I will test the effect of down-regulation of DUSP16 (by siRNA) on the cell fate of TrkA/TrkB expressing NB cells (microscopic observation). The ultimate goal is to find a way to induce the aggressive TrkB cells to differentiate.
Verocytoxigenic Escherichia coli (VTEC) is defined by the elaboration of a potent cytotoxin. It is a highly pathogenic type of E.coli and causes a range of disorders including bloody diarrhoea, haemolytic uraemic syndrome, kidney disease and death. The project aims to investigate the genomic features associated with the unusually high incidence of this pathogen in Ireland. We will apply state-of-the-art bioinformatics approaches to determine which genes are most commonly found to co-occur outside the core genome. This will be carried out across three separate cohorts of strains. The modules created will be analysed for potential functions and subject to machine learning techniques to identify those associated with the Irish strains specifically and the clinical phenotype.
An exploratory study of community activism for change in ‘direct provision’ food facilities for asylum-seekers in Ireland 04 Dec 2017
Asylum-seekers in Ireland are provided basic needs of housing and food by the state in a system which is known as Direct Provision (DP). However, the food provided therein has been criticised due to residents’ lack of autonomy over what and when they eat, as well as the nature of the food provided, with implications for the health of this vulnerable group. Inadequate political responses to these criticisms has led to the emergence of Our Table, a community-led project seeking to counteract the negative outcomes for DP residents arising from being denied the right to cook for themselves. The proposed programme of activities will form a short-term exploratory study examining Our Table; given the unique nature of the Irish DP system, there is neither an Irish nor an international study to date on community-led responses to food provisioning for asylum-seekers. Using a community-based participatory research approach, this exploratory study will provide a familiarity with the basic details, settings and concerns; it will facilitate the development of tentative theories or hypotheses; and it will aid a determination of whether a future wider study of community activism to change the system of food provisioning in DP is feasible.
Lived Lives: From Tory Island to Swift’s Asylum 03 Oct 2017
Suicide is the leading cause of death of young adults in Ireland and the UK, cloaked in stigma and shame. The durational arts-science collaborative model, Lived Lives addresses the stigma of suicide in a safe space through restoring identity of the deceased and acknowledging loss in a non-judgmental and compassionate setting. The voices of marginalized rural communities and psychiatric communities’ are often discounted around suicide. This proposal aims to bring Lived Lives to the border communities of Donegal, Leitrim and Tory Island, on the western tip of Europe, at a time of social, economic, and political uncertainty impacting mental health. In a progressive step towards addressing stigma, Lived Lives will then be installed within St Patrick’s University Hospital Dublin, Ireland’s oldest psychiatric institution, established following a donation from Johnathan Swift (1746). This project will address stigma in apposite communities, through co-collaboration, engagement, dialogue and action. The interactive lectures, mediated exhibitions and an international interdisciplinary symposium of artists, scientists and communities will engage the public around suicide with transformative impacts within these communities. Dissemination will inspire arts-science collaborations around sensitive topics that deal with feelings of loss, and where identity and validation are overlooked or eclipsed by the silence of stigma.
Candida species are the leading cause of opportunistic mycoses and a common cause of nosocomial bloodstream infections (Wisplinghoff et al., 2004). Candida tropicalis is a significant cause of candidiasis, particularly in tropical regions (Pfaller and Diekema, 2007). However, much remains unknown about the origins and virulence mechanisms of this pathogen. Previous studies of pathogenic organisms have focused on detailed analyses of single isolates. However, recent work using multiple isolates of Candida albicans has shown that specific virulence phenotypes are associated with specific clades (Pujol et al., 2004; MacCallum et al., 2009; Hirakawa et al., 2015). Some previous studies using multilocus sequencing typing to investigate population structure and phenotypes of C. tropicalis have generated conflicting reports (Chou et al., 2007; Desnos-Ollivier et al., 2008; Magri et al., 2013; Tavanti et al., 2005a). In this study, we will use whole genome sequencing and detailed phenotype analysis to compare at least 50 isolates of C. tropicalis from environmental and clinical sources. We will assess the correlation between genotype and phenotypic profile, using both in vitro and in vivo virulence assays.
Defining mycobacterial host-pathogen interactions: the role of the secreted protein MPB70 31 Jan 2017
Tuberculosis is an infectious disease which in humans is caused by Mycobacterium tuberculosis and in cattle by Mycobacterium bovis. The genome sequences of these two bacterial species are 99.95% identical, with deletion of genetic information leading to a reduced genome size in M. bovis and no unique genes per se in M. bovis compared to M. tuberculosis. The high degree of genetic identity contrasts with the distinct host preference of the pathogens, and suggests that host preference is likely driven by differences in the expression of key genes between M. tuberculosis and M. bovis. We are particularly interested in two genes coding for secreted proteins, MPB70 and MPB83, which show significant differential regulation between the two species. Through combined in vitro infection assays with bacterial mutants, proteomics studies and in silico evolution studies of these genes and their regulon, we will investigate if MPB70 and MPB83 play a specific role in the host-pathogen interaction and the nature of this interaction. By elucidating the role of these proteins in host preference, we hope to increase our knowledge of host-pathogen interaction and to open new avenues for the development of disease control approaches in both human and bovine tuberculosis.
Genome evolution in the Candida clade 31 Jan 2017
The CUG-Serine clade, a group of yeasts including the common human pathogen Candida albicans, has been known to translate the codon CUG as serine instead of leucine for over 20 years. Recently, a sister species that translates CUG as alanine was discovered. In my bioinformatics rotation I discovered a second, independent CUG-Ser clade as well as a CUG-Ala clade and three separate CUG-Leu clades.In my PhD project I will examine tRNA gene evolution in these clades and test the hypothesis that they descended from a catastrophic event in their common ancestor in which the CUG- decoding tRNA was lost. I will perform experiments to artificially push a yeast species to change its CUG translation from Ser to Leu by replacing a tRNA gene, and monitor the effect on the proteome. In parallel, I will study centromere evolution in yeasts, which show an extraordinary diversity of centromere types, by using ChiP-seq to find centromeres across the Candida clade and beyond. This project will develop valuable new tools for manipulating Candida genomes, including transformation vectors that completely lack CUG codons and should work in any species, and potentially also new centromere-based plasmids for use in C. albicans.
Computational analysis of gene clusters from antimicrobial producing and pathogenic bacteria. 31 Jan 2017
This project will develop a novel method for the in silico prediction of the function of bacterial genes based on the analysis of their genomic neighbourhood, with a specific focus on genes of interest in infection biology. Indeed, bacterial genes involved in the same cellular "macro-function", such as a signalling or biosynthetic pathway, are often physically clustering together on the genome. The computational analysis of these gene clusters could help to uncover the role of currently uncharacterised genes in certain pathways. The prediction method will be developed and tested on a dataset of publicly available bacterial genomes. Then, it will be applied to the analysis of clusters putatively involved in the synthesis of peptide antimicrobials or in processes targeted by known antibiotics. Orthologous clusters will be compared to identify protein domains that tend to co-occur in similar clusters ("domain correlation"). However, sometimes two alternative domains may fulfil the same biochemical function. In such a case, these two domains may be present as alternatives within functionally related clusters. This results in an "anti-correlation" of these domains within that cluster. The final aim of this analysis will be the identification of new antimicrobial processing enzymes and possible novel drug targets.
Streptococcus gallolyticus is a gram positive gut commensal that can cause Infective endocarditis (IE) a heart valve infection. Unusually, in the case of S. gallolyticus, patients presenting with infective endocarditis are also found to have colonic abnormalities i.e. colorectal cancer. It is thought that the presence of colorectal cancer allows translocation of the pathogen from the gut lumen into the bloodstream. To date, there is limited information on the virulence factors of S. gallolyticus that contribute to the pathogenesis of IE. This study aims to (1) identify common virulence factors in clinical isolates of S. gallolyticus from bloodstream infections and IE. This will be achieved by sequencing and de novo assembly of the genomes of 50 clinical isolates from Ireland, France, Italy, Spain and the US. The relatedness of these strains will be analysed and virulence factors identified. (2) Genes encoding these virulence factors will be deleted and the ability of the mutant strains to adhere to platelets, trigger platelet aggregation and adhere to colonic epithelial cells will be tested. (3) These genes will also be cloned into expression vectors and expressed in a surrogate expression host to analyse any gain of function conferred.
Prisoners, Medical Care and Entitlement to Health in England and Ireland, 1850-2000: Provision for Public Engagement 30 Apr 2017