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Results

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.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

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.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

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.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

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.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

Interaction of Schmallenberg virus with human and sheep cells 31 May 2018

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.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

The role of biofilm formation in colonic cell adherence by Streptococcus gallolyticus 31 May 2018

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.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

Investigating the Mechanisms Underlying Drug-Induced Retinotoxicity 27 Apr 2017

Summary: Quinoline-based compounds have been reported to cause forms of retinal dystrophy across a range of species (e.g. chloroquine-induced Bull’s Eye Maculopathy in humans, fluoroquinolone-induced retinal degeneration in cats, quinine-induced retinotoxicity in zebrafish). The precise mechanism underlying this form of retinal degeneration/toxicity is unknown. Here we will use a zebrafish drug-treated model to examine the precise effect of quinoline toxicity on retinal histology and retinal pathways. For this study we will examine quinine, fluoroquine, chloroquine and a novel quinoline compound. Aim: To use an induced zebrafish model to facilitate understanding of the cellular and molecular basis underpinning quinoline-induced retinotoxicity Goal 1. Determine drug dose which induces retinotoxicity Drug treat larval zebrafish and examine visual function using two visual behaviour assays: optokinetic response and semi-automated optomotor response (equipment available in the Zebrafish Facility). Goal 2. Investigate whether retinotoxicity affects retinal histology Drug-treat larval zebrafish and compare retinal histology to vehicle treated controls using fluorescent microscopy. Goal 3. Investigate whether retinotoxicity affects the expression of genes involved in visual function Compare the expression of genes involved in visual function in drug and vehicle treated zebrafish. This project will assist understanding of the cellular and molecular basis underpinning quinoline-induced retinotoxicity

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

Investigating a new model of neurodegenerative disease 27 Apr 2017

Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders characterised by degeneration of the longest motor neurons which leads to muscle weakness and spasticity in the lower limbs. There are currently no treatments to cure or even to slow the course of these diseases. In this project I will test a novel in vivo model of HSP generated by CRISPR/Cas9 gene editing in Drosophila. I will investigate gene and protein expression, locomotor behaviours and motor neuron endoplasmic reticulum (ER) organisation. My research will determine how HSP-causing mutations affect endoplasmic reticulum organisation and neuronal function. The results from this project will validate a novel model of HSP and will further our understanding of the molecular mechanisms underpinning this neurodegenerative disorder.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

Suicide and Stigma in an Indigenous Ethnic Minority: Engaging Irish Travellers with Lived Lives. 14 Jan 2015

Suicide is a significant public health concern, associated with stigma. Young men, mental illness sufferers, prisoners and indigenous ethnic minorities bear an increased suicide risk. Irish Travellers are an indigenous ethnic minority with social and cultural parallels with similar groups internationally (Inuits, Aboriginals, Maoris, etc). Travellers experience racism and discrimination, with elevated suicide rates (x7 national average for males) and associated stigma. Traditionally their nomadi c lifestyle and limited literacy made them hard-to-reach . Nowadays they are frequently under-served and excluded from research, impacting health research and intervention. Nevertheless, we recently described methods to document their health risks (including suicide) with 80% response rates (All Ireland Traveller Health Study). Using collaborative science/arts research methods (Lived Lives) we devised methods for studying suicide and its aftermath which safely engages bereaved at-risk communiti es, the public and suicide prevention policy-makers. The Lived Lives exhibition, with artist and scientist, co-curated by communities, has facilitated dialogue and response, described as transformative. Following collaborative pre-planning with Traveller leaders and youths, Lived Lives will be transposed into Pavee Point, the national Traveller resource centre, manifesting privately and publicly, and documented over 7 days (Autumn 2015). Outputs will include an interactive exhibition and learnin g materials about suicide and its aftermath among indigenous ethnic minorities such as Travellers. The project will be evaluated by feedback from participants and expert evaluators to assess how it relates to suicide in their community, how it has shaped their understanding of suicide and its impacts, and its relevance to other socio-cultural contexts, nationally and internationally.

Amount: £28,941
Funder: The Wellcome Trust
Recipient: University College Dublin

UCD, Computational Infection Biology. 22 Jun 2015

Not available

Amount: £154,017
Funder: The Wellcome Trust
Recipient: University College Dublin

Computational and experimental analysis of virulence characteristics in pathogenic Candida species 24 Jun 2013

The aim of this project is to identify virulence factor networks in the pathogenic fungus Candida parapsilosis using both computational and laboratorymethods. We will use RNA-seq, ChiP-seq and phenotypic knockout profiling data to assemble virulence factor networks. Data will be generated from C. parapsilosis cells growing in different environments, including during infection of the model host Galleria mellonella. Identifying these networks could be valuable in drug target discovery. In a second approach we will use newly generated transcriptional data in conjunction with the Candida Gene Order Browser (CGOB) to identify non-coding RNAs in C. parapsilosis. This project is an extension of rotation 2, where conserved regions in non-coding DNA were identified computationally. The computational approach will be complemented using RNA-seq data of total RNA compared to poly-selected RNA. RNA will be extracted from cells growing in conditions associated with virulence, such as different oxygen concentrations.Newly identified non-coding regions will be verified experimentally, and their

Amount: £155,242
Funder: The Wellcome Trust
Recipient: University College Dublin

Host tropism in the Mycobacterium tuberculosis complex: the role of the secreted protein MPB70 24 Jun 2013

Tuberculosis (TB) is the most deadly human bacterial disease in the world, killing over 1.5 million people annually and with a reservoir of 2 billion latently infected individuals. Allied to this, tuberculosis in animals is a global threat to public health and animal welfare. The human TB strain Mycobacterium tuberculosis shares 99.95% nucleotide sequence identity with thebovine strain Mycobacterium bovis, but the molecular bases for host preferenceare currently unknown. The aim for this project is to identify host tropic proteins from the Mycobacterium tuberculosis complex (MTBC). We will focus our study on MPB70, aprotein constitutively secreted at high levels by M.bovis, as we have preliminary data to show that this protein modulates cellular immune responses. We will build on these data using both conventional techniques and global transcriptome analyses via RNA-Seq. For the latter, we will develop novel approaches in data analysis in the area of longitudinal cluster analysisto define the mechanism of action of this protein in mixed cellular

Amount: £155,242
Funder: The Wellcome Trust
Recipient: University College Dublin

Ribo-regulation in Mycobacterium abscessus 24 Jun 2013

Characterization of regulatory RNAs (such as sRNAs) in mycobacteria is still developing, however demonstration of their differential expression under environmental stress and regulation of virulence by two-component systems suggest a role for such agents in pathogenesis. In order to characterize the regulome of M. abscessus, it is the intention of the project to generate and subsequently analyse a number of different data types including, RNA-seq, which characterizes the transcribed portion of the genome, and differential RNA-seq,which facilitates the identification of transcriptional start sites (TSS). In addition, in orderto identify the coding

Amount: £155,242
Funder: The Wellcome Trust
Recipient: University College Dublin

Non-coding RNAs and HIV-1 latency 31 Aug 2011

After decades of research, overcoming HIV-1 post-integration latency remains imperative. When HIV-1 genome integrates into the host, it behaves as a mammalian gene and it is subject to the same mechanisms controlling host gene expression. Gene silencing is a complex and multifactorial process that can beepigenetically mediated, involving steps such as chromatin remodelling, DNA methylation and histone modifications. Non-coding RNAs (ncRNAs) are well established players in this process at the host level, however, its role in HIV-1 proviral silencing is yet to be described. This project aims to address this gap and, combining in silico techniques with molecular virology based assays, explore ncRNA species role in HIV-1 post-integration latency. We will begin with in silico screening for ncRNAs that demonstrate sequence specific affinity to the HIV-1 promoter. After selection, the most promising candidates will go into function validation assays and their effect on HIV-1 transcription will be assessed. Following, wewill experimentally validate 5'LTR sequence targeting and carry out a

Amount: £153,367
Funder: The Wellcome Trust
Recipient: University College Dublin

The effect of mucus and mucin Pseudomonas aeruginosa phenotype and interaction with host cells 16 Jul 2012

Pseudomonas aeruginosa colonises mucus in the lungs of individuals with CF resulting in chronic respiratory infections. We will examine how the bacteria respond to the presence of mucin/mucus and whether or not this response has aneffect on expression of mucin binding proteins and on virulence. We will collect data on the differential expression of Pseudomonas Outer Membrane Proteins (OMPs) in response to both the presence of mucin and mucus and the interaction with host cells. Effect of co-culture of the organism with mucus secreting cells and with purified mucin on OMP expression will be examined using SDS PAGE and affinity blots. The role of these proteins in mediating interaction with mucin and glycans will be assessed using mucin affinity blotting, neoglycoconjugate arrays and a novel microarray platform. Bioinformatics techniques will be used to predict Pseudomonas OMPs that have lectin-like properties. This will aid us in identifying protein properties andmotifs that are responsible for facilitating the binding of proteins to glycans. We also propose to use global transcriptional analysis of selected strains of P. aeruginosa by RNA seq grown in the presence and absence of mucin. The biological relevance of bioinfromatic findings will be assessed in the lab.

Amount: £153,645
Funder: The Wellcome Trust
Recipient: University College Dublin

Genome-scale analysis of pathogenic Escherichia coli 16 Jul 2012

The aim of this project is to identify Escherichia coli gene signatures which can be used to classify pathogenic strains. Recent outbreaks have shown that there is a need for rapid identification and subtyping of pathogenic strains in real time. We will construct and leverage the power of the E. coli pan genome by grouping all genes across the available E. coli genomes (environmental, pathogenic and commensal strains) into core, accessory and distributed gene sets. This will define an E. coli species-wide gene pool which will facilitate the detection of gene combinations associated with pathogenic strains. The incorporation of genome data from other species that display similar modes of infection or inhabit similar environments will generate corss species correlog information and widen the scope of our findings. In addition to the pan genomic approach, the methylation profile of E. coli serotypes will be determined using SMRT sequencing to provide insights into the role methylation plays in virulence. The project will mostly consist of bioinformatics analysis with lab work including the preparation of samples and validation of bioinformatics findings.

Amount: £153,645
Funder: The Wellcome Trust
Recipient: University College Dublin

Madness, Migration and the Irish in Lancashire, c.1850-1921 11 Jun 2009

Through a close survey of the records of the Lancashire asylum system, the project will explore the relationship between Irish migrants and mental illness from c.1850 to 1921, a period marked by high levels of migration into Lancashire and Liverpool in particular. It will explore the linkage of mental disorder amongst the Irish to migration, trauma, isolation, poverty, and social and cultural dislocation, questioning whether underlying explanations of mental illness and its predisposing factors differed from those attributed to English patients, other migrant groups, and Irish patients in Ireland. The project will examine whether there were particular stereotypes concerning the Irish which influenced their admission to the asylum and experiences of care, and how concerns about the very visible rise in their numbers were linked to changing debates about insanity, including the impact of degeneracy, race and gender, at a time of massive growth in asylum numbers overall. Uniquely, this project will situate the experiences of Irish pauper asylum patients and those treating them within a broader canvass of efforts to manage perceived and real problems of disease, poverty, and intemperance amongst Irish migrants. The main outputs comprise a co-authored book, three articles, a workshop, conference and public engagement activities.

Amount: £73,342
Funder: The Wellcome Trust
Recipient: University College Dublin

MA in the Social and Cultural History of Medicine. 31 Aug 2007

The 1940s were a watershed in the development of the Irish health system. The fuel and food shortages caused by WWII and the compulsory medical inspections of Irish immigrants to Britain from 1943 drew attention to the continuing deficiencies in the health of the nation. There ensued a debate on the future of the Irish health system. Various alternatives to the system in place were proposed and resisted by interest groups, most notably the Catholic Church, the government and the medical profession. Central to this discourse was the question of how much power the state should have over the lives and health of families, whose primacy was enshrined in the constitution. This thesis will examine how this debate impacted on the health and welfare of Irish Travellers. In this period the perception and status of Irish Travellers was changing due to modernisation and the strains of post war Ireland. This process culminated in the perception of Travellers as an 'itinerant problem' that needed to be fixed. Hitherto Travellers operated on the margins of the state. This had serious health implications for Travellers who experienced with high birth rates, high infant mortality rates, high suicide rates and low life expectancy. The change in the perception of Travellers in the post war period culminated in the appointment of a Commission on Itinerancy in 1960 to investigate the rehabilitation, education and health of Travellers.

Amount: £20,258
Funder: The Wellcome Trust
Recipient: University College Dublin