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Biomaterial-based delivery of neurotrophic factors to the Parkinsonian brain 31 May 2018

The concept of cellular brain repair for Parkinson's disease is relatively simple - if brain cells die in this condition, then it should be possible to replace these cells through transplantation of healthy cells back into the brain. Over the past three decades, numerous animal studies and several clinical trials in human patients have shown that this concept has significant potential for repairing the brain affected by Parkinson's disease. However, poor survival of the healthy cells has limited the widespread roll-out of this cellular reparative approach to patients. Biomaterials, that is, materials that have been engineered to interact safety with living tissue for therapeutic purposes, have the potential to improve such cellular reparative therapies for Parkinson's disease. Specifically, injectable biomaterials gels have the potential to significantly improve cell survival by providing a physical scaffold and pro-survival environment for the implanted cells. Thus the aim of this proposal is to determine if biomaterial hydrogels can be used to improve cellular reparative therapies for Parkinson’s disease using animal models of the condition. We will specifically investigate the beneficial effect of biomaterials on stem cell-derived neuron cell transplantation approaches.

Depression, anxiety and quality of life in a palliative population: a comparative study across different settings – home, hospice and hospital 31 May 2018

Palliative medicine deal with a fragile population- both in terms of the patient themselves and their families. Psychological health is often an extremely delicate topic to approach. By conducting a comparative study across different settings – home, hospice and hospital I intend to begin bridging that gap between physical and psychological care. I will conduct a cohort study to gather qualitative data on the mental wellbeing of palliative care patients, specifically measures of depression, anxiety and quality of life. Examining the relationship between symptoms depression, anxiety and adjustment disorder in a palliative population will allow terminally ill patients the opportunity to be heard. Publishing my data and statical findings introduces the possibility that end-of-life patients could improve their peers treatment and quality of life. Furthermore, by uncovering an intricate connection between a palliative patient's environment and their overall wellbeing, my research could help to produce local and national guidelines for a more tailored healthcare plan.

Investigate the role of forced expression of Programmed Death-Ligand1 on mesenchymal stem cells on immunomodulatory properties in vitro. 31 May 2018

Despite success in in-vitro and in pre-clinical models, the therapeutic efficacy of mesenchymal stem or stromal cells (MSCs) is somewhat limited. In this project, we will investigate two different strategies to enhance their therapeutic efficacy by forced expression of Programmed Death-Ligand1. PD-L1 expression has been shown to protect cells and tissues from T-Cell mediated cell death. Recent work carried out by Prof.Ritter’s lab showed that overexpression of PD-L1 on corneal tissue before transplantation significantly prolongs corneal allograft survival upon transplantation in allogeneic recipients. This indicates a pivotal role for PD-L1 in immunomodulation. Additionally and as of interest, preliminary data indicate that expression of PD-L1 is highly up-regulated on licensed MSCs or on MSC treated with tumor conditioned medium (TCM) indicating a role in immune evasion of tumors. We aim to understand if forced expression of PD-L1 enhances the immunoregulatory properties of these MSCs in vitro. We will attempt to achieve this using either lentiviral gene transfer of PD-L1 or licensing with tumor-conditioned medium. This research will contribute significant data to the development of novel treatment protocols for patients suffering from inflammatory conditions such as impaired wound healing in diabetes and ocular surface injuries.

An investigation of how saliva and salivary proteins may interact with polyphenol-rich beverages to alter their available antioxidant capacity 31 May 2018

Polyphenols are a diverse group of phytochemicals found in plant-derived foods and beverages. A plethora of studies have demonstrated potential health benefits of polyphenols and of polyphenol-rich foods and beverages, and there are indications that they may have potential for use as medicinal agents and as dietary supplements. However, many of the studies have been performed in animals and in vitro cell systems, and although there is some evidence for their beneficial effects in humans, more studies in human systems are necessary. The bioavailability of these agents is currently under scrutiny, and it is crucial to develop understanding of how these polyphenols can function within physiological systems. In this study, saliva will be used as a physiological medium in which to study the antioxidant capacity of some polyphenol-rich beverages. Previous studies have shown that saliva may modulate antioxidant capacity of polyphenol-rich dietary agents, possibly due to interactions of polyphenols with salivary proteins. This study aims to further investigate the interactions between polyphenols and saliva by measuring the antioxidant capacity of hawthorn juice, cranberry juice, blueberry juice, pomegranate juice and green tea in saliva under varying experimental conditions. The interactions between these beverages and specific salivary proteins will also be investigated.

Biomedical Vacation Scholarship 22 Jun 2015

Not available

Amount: £48,000
Funder: The Wellcome Trust
Recipient: National University of Ireland Galway

Use of ɣ-H2AX as an indicator of DNA repair capacity in breast cancer cell lines 31 May 2018

H2AX is an abundant histone variant and a key component of the DNA damage response. H2AX is phosphorylated at Ser-139 in response to DNA damage and this protein, known as gamma-H2AX, is involved in the recruitment and retention of repair factors to ensure that DNA damage is efficiently repaired. Over recent years there has been an increase in the use of gamma-H2AX, as a marker of the activation of the DNA damage response, in tumour samples to try to understand more about the treatment and progression of the disease The abundance and distribution of H2AX is expected to impact on genome stability and we are therefore interested to investigate this protein in cancer cells. In particular, the potential role of this protein in breast cancer progression and the impact of varying expression levels on treatment options are being investigated. The aims of this project are twofold; firstly to investigate the use of gamma-H2AX in clinical tumour samples which will be done primarily by literature searching and also through discussions with pathologists working at University College Hospital Galway, and secondly to investigate the levels of DNA damage as measured by gamma-H2AX in several breast cancer cell lines.

Primary cilia and cellular senescence 05 Sep 2017

Somatic cells undergo senescence after a finite number of divisions, indefinitely arresting their proliferation. The mechanisms of cellular senescence are not well understood, although DNA damage signalling is one major cause. We have found that senescent human fibroblasts have increased frequency and length of primary cilia, antenna-like structures that sense and transduce various extracellular signals, notably Hedgehog. Here we propose to test the hypothesis that primary ciliation contributes to cellular senescence. We will use genome editing in primary cells to ablate CEP164, which is required for primary ciliogenesis, and then follow the kinetics of cellular senescence in the knockout population. We also propose to examine cilium-controlled signalling pathways to determine how they are affected during the initiation of senescence programmes. We will perform competitive co-culture experiments between ciliated and non-ciliated populations to define how ciliation capacity directs senescence in mixed populations. Together, the proposed experiments will test a novel cellular mechanism of senescence, a process of great significance in human health and the normal aging process.

Amount: £51,168
Funder: The Wellcome Trust
Recipient: National University of Ireland Galway

Biomaterial-based delivery of neurotrophic factors to the Parkinsonian brain. 01 Apr 2016

A disease-modifying neuroprotective therapy remains a vital but unmet clinical need in the treatment of Parkinson's disease. One potential neuroprotective agent is the neurotrophic factor, GDNF, but its progress through clinical trials has been hampered due to issues with delivery. One novel delivery system that has the potential to overcome some of the issues associated with current GDNF delivery methods is the use of biomaterials as protein delivery vectors. This, in this project, we aim to determine the safety (biocompatibility and biodegradablity) and preliminary efficacy (kinetics of GDNF release) of GDNF-loaded collagen microspheres in the rat brain. If we can show that this novel therapy is safe in the rat brain, and can provide sustained delivery of GDNF, then this will indicate its potential as a treatment for the human condition.

'Problem Patients': Experience of and attitudes towards patients with substance misuse problems' 01 Apr 2016

My research intends to examine levels of empathy and compassion shown by undergraduate medical students in NUIG, with a particular regard on problem drug users, and to assess need for supplementary skills training in these areas. This will be accomplised by establishing patterns of empathy among undergraduate years in medicine and identifiying factors associated with either higher or lower levels of empathy, exploring perceptions and attitudes towards problem drug users and how they change during medical training, and also analysing the desire of students to have more educational opportunities to practice communication skills showing empathy and compassion. Specific objectives include establishing: Current understanding of empathy and its importance in clinical practice among medical students Current patterns of empathy fluctuation in undergraduate medicine Attitudes of students towards substance misuse and problem drug users, and the factors influencing these attitudes If additional education in empathy and compassion be welcomed by students or considered unnecessary Frequency of interactions with patients

Functional characterisation of excitatory neurons 27 Apr 2017

Autism spectrum disorder (ASD) is a complex, neurodevelopmental disorder characterised by deficits in social and communication skills, language delay and repetitive or stereotypical behaviour. A variety of copy number variations have been identified that play a role in ASD, including the Neurexin1 gene (NRXN1) which encodes a family of presynaptic cell adhesion transmembrane proteins, vital for neurotransmission and synapse differentiation. It is widely accepted that neurexin and mutations disturb the balance between excitatory (alpha- and beta-nrxn) and inhibitory (mainly alpha-isoform) synaptic activity that is thought to be critical in the pathology in ASD. The seminal discovery that somatic cells can be reprogrammed to produce induced pluripotent stem cells (IPSCs) has revolutionised biological research and medicine. The ability to differentiate these IPSCs into neural cells offers a tremendous opportunity to study disease modelling associated with impaired neuronal cell biology. In this study we will characterise the functional firing properties of IPSc derived glutaminergic neurons differentiated from normal controls and patients carrying a NRXN1 mutation. Functional properties will be assessed by patch clamp examining voltage gated sodium and potassium channels and action potential firing properties under current clamp conditions. This work will be essential to aiding our understanding of ASD.

Investigation of COX2 Regulation of HERV-K in Triple Negative Breast Cancer 27 Apr 2017

HERV-K is the youngest family of human endogenous retroviruses which constitute 8% of our genome. HERV-K is capable of transcribing gag and env proteins, and the spliced accessory proteins Rec and Np9. My supervisor Dr. Sharon Glynn has previously demonstrated the HERV-K env protein is expressed in breast and prostate cancer, and is associated with lymph node metastasis and poor outcome in breast cancer patients. However the molecular mechanisms by which HERV-K is induced and impacts breast cancer progression are unknown. Currently research has established a role for estrogen and progesterone as inducers of HERV-K in breast cancer. However HERV-K is also expressed in hormone receptor negative-triple negative breast cancer. We hypothesise that inflammatory mediators including COX2 may play a role in HERV-K expression in triple negative breast cancer. Objectives: Determine if pro-inflammatory cytokines and prostaglandins are inducers of HERV-K mRNA in triple negative breast cancer. Determine if NSAIDs (e.g. ibuprofen and aspirins) inhibit HERV-K mRNA expression in triple negative breast cancer through inhibition of cyclooxygenase enzymatic activity. Examine the association of COX2 and HERV-K env expression in 20 cases of invasive ductal carcinoma of the triple negative breast cancer subtype, and correlation with pathological features and disease free survival.

Assessing Redundancy in DNA Replication Initiation 27 Apr 2017

CDC7 kinase is a key molecular switch for DNA replication. CDC7 kinase is a protein kinase which phosphorylates and activates the mini-chromosome maintenance (MCM) helicase thus triggering DNA replication origin firing. However, recent research has shown that CDC7 kinase inhibition with some ATP competitive inhibitors does not entirely inhibit DNA replication and cell cycle can still proceed, thus have marginal effects on cell proliferation. Importantly the FANCI protein, that is normally involved in DNA repair, has been shown to be involved for the firing of DNA replication origins during replication stress and to regulate CDC7 dependent activation of MCM helicase at "dormant origins" . We will test the hypothesis that CDC7 and FANCI cooperate in the activation origin during normal replication and that the activity of CDC7 inhibitors could be greatly enhanced in FANCI depleted cells. For this we will deplete FANCI from breast derived cells and traet them with different doses of the CDC7 inhibitor XL413. Key goals are 1) reproducible detection of FANCI by western blotting, 2) efficacious depletion of FANCI by siRNA and 3) implementation of DNA replication and cell survival assays.

Vacation biomedical scholarship 24 Jun 2013

Not available

Amount: £21,240
Funder: The Wellcome Trust
Recipient: National University of Ireland Galway

Biomedical Vacation Scholarship 23 Jun 2014

Not available

Amount: £33,750
Funder: The Wellcome Trust
Recipient: National University of Ireland Galway

"Science and technology on the European Periphery" to be held at the National University of Ireland Galway on 17-20 June 2010 13 Apr 2010

Science and Technology on the European Periphery (STEP) is a network (rather than a society, it has no funding) which includes representatives from a wide range of European countries. Members' work focuses on countries other than Britain, Germany and France which arc traditionally viewed as the major players in the history of science. This meeting is the first to take place in Ireland and will particularly serve to incorporate Ireland's history of science, technology and medicine community into broader European networks. The meeting particularly encourages transnational comparisons. Previous STEP meetings have tended to be dominated by the history of physical sciences. The organizers have explicitly sought to involve historians of the biomedical sciences in this conference in order to make the group more inclusive and interdisciplinary. To this end, Professor Nick Jardine of Cambridge University has been confirmed as a plenary speaker. He will speak on natural history and peripheries in the nineteenth century. Papers on the history of medicine were solicited and form a significant component of the programme. We also wish to invite a second plenary speaker, Daniela Bleichmar (University of Southern California) to speak on the subject of colonial botany and eighteenth-century medicine.

Debating Science Issues (DSI) 30 Nov 2011

Not available

Amount: £30,000
Funder: The Wellcome Trust
Recipient: National University of Ireland Galway

The use of plasma treated graphene oxide in critical limb schema 31 May 2018

The aim of this project will be to determine the angiogenic potential of plasma-coated graphene oxide sheets and their effect on cell viability. The objectives will be to place human umbilical cord endothelial cells(HUVECs) in Matrigel with graphene oxides with varying surface coatings on the graphene oxide. First we will use a plasma reactor to modify the surface properties by increasing the O2 and N2 groups on the surface. HUVECs will then be cultured using EGM-2 complete media before being placed onto Matrigel, along with surface treated graphene oxide. In order to determine the cytotoxic effect of each coating, a Live/Dead assay will be carried out on HUVECs that have been cultured in the presence of plasma-treated graphene oxide sheets after a 48hr culture, using fluorescent detection, while the angiogenic properties of each surface coating will be compared against an uncoated control, with complete media with growth factors being used as a positive control, using ImageJ software which will quantify the number/density and size of the vessels compared to the uncoated control. The ideal result would be a coating that has strong angiogenic properties with minimal cytotoxic properties, which would set the ground work for further in-vitro studies.

Developing parameters for improved trapeziometacarpal joint prostheses; data from cadaveric joints 31 May 2018

The first carpometacarpal joint, also known as trapeziometacarpal (TMC) joint is considered one of the most important in joint human body. It's articulated in such a way that in provide a whole range of movement that allow the hand to perform task with great dexterity. However, it is also a very vulnerable joint that will be likely affected on individuals with osteoarthritis, especially in women. To amend the underlying problem, prosthetic material can be made and replace the faulty cartilage during surgery to regain function of thumb. However, the estimated size of the prosthetic material is fairly difficult to customize because cartilage will not show up in normal X-ray, hence the estimate size of prosthetic material cannot be made in advance. This study will also to examine if there is a consistency in size and the pattern of degradation of cartilage in persons who had suffered from osteoarthritis (OA) of this joint. Ultimately, information from this study and other ongoing work will inform the structure and design of joint prostheses, with the particular goal of producing individually customised prostheses by 3D printing

Characterisation of Extracellular Vesicles (EVs) released by 4T1 breast cancer cells 31 May 2018

Extracellular vesicles(EVs) are tiny vesicles that shuttle genetic information between cells, and throughout the circulation. MicroRNAs(miRNAs) are small non-coding RNAs that regulate gene expression. This study will focus on EV-encapsulated microRNAs(EVmiRs). The host group recently published work showing a potent tumor suppressor role for miRNA-379 in breast cancer. Tumour-targeted delivery of the miR was achieved by harnessing the natural homing capacity of Mesenchymal Stem Cells(MSCs) engineered to over-express miR-379. The MSCs were found to release miR-379 in EVs, and the miR-379 enriched EVs were shown to reduce breast cancer growth in vivo. This study was performed in immunocompromised animals and must be expanded to take the host immune system into account. This will be achieved using murine 4T1 breast cancer cells in immune competent animals. It is necessary to first establish the characteristics of EVs released from these cells. The aim of this study is to define the EV-miR profile of 4T1 cells in vitro. The data generated will inform a subsequent In Vivo study, where EVmiRs detected in vitro will be compared to those detected in the bloodstream of mice bearing 4T1 tumours. This will provide a potential biomarker of disease progression or response to MSC-EV therapy.

Sleep Disturbance in Older Adults in the Emergency Department: Prevalence, Predictors and Outcomes Comparing Frail and Non-frail Patients 31 May 2018

The overall aim of this study is to show the impact of poor sleep at baseline and in particular during ED overnight stay on older adults comparing the effects on those identifed as frail or non-frail (robust). The specific objectives are to: (1) Examine the prevalence of pre-existing sleep impairment using a validated sleep measure, (2) Investigate which independent variables are associated with poor sleep in an ED including individual objective (demographics, existing sleep problems, admission diagnosis, Barthel Index ADL score, 4AT delirium score, co-morbidities and polypharmacy including use of hypnotics), subjective (percieved sleep quality and quality of life) environmental (noise levels) and logistical (triage score, total duration boarding in ED, location of trolley in ED) factors. (3) Evaluate the impact of sleep disturbance (baseline and overnight) in the ED on patient satisfaction and adverse healthcare outcomes (including LOS, 30 day-mortality and 30-day redmission rates, need for rehabilitation) adjusting for individual factors, in an older cohort of patients (aged > 70) admitted through the ED of a large Irish university teaching hospital (UHG).