RCSI • Potential to apply for other funded PhD

RCSI has been at the forefront of educating programmes (e.g. Government of Ireland
healthcare professionals since 1784. Today we are Postgraduate Training Programme)
Ireland’s only focused health sciences institution,
Ireland’s largest medical school and one of the ELIGIBILITY
leading health sciences institutions in the world. Eligible students must be entering the final year of
their undergraduate degree programme in basic
Based in Dublin, with students from over 80 science/health sciences after completion of the
countries and four overseas campuses, RCSI has a internship and will have a clear plan to pursue a
global reach through our network of Alumni in 97 PhD. Students can be from any country in the world,
countries. there are no restrictions on nationality and
international applications are encouraged.
RCSI is ranked among the top 2% of universities
worldwide in the 2018 Times Higher Education EXTENT OF FUNDING
(THE) World University Rankings and joint second Students will receive a €2000 stipend and paid
out of the nine institutions in the Republic of Ireland. accommodation in Dublin city centre will be
provided for 8 weeks commencing June 2020.
RCSI’s performance in the rankings is linked in Travel costs are not included and non-EU students
particular to the College’s research strength and it will also require a Garda National Immigration
is ranked first in Ireland for publication citations. Bureau (GNIB) card and appropriate visa.
Assistance in obtaining both for successful
RCSI's Strategic Academic Recruitment (StAR) applicants will be provided.
Programme is an ambitious initiative to accelerate
the delivery of innovative, impactful research to APPLICATION PROCESS
improve human health through innovative Students must submit completed application forms
translational medical research. to [email protected]. Applicants should detail
academic progress to date, CV/Resume and a brief
PURPOSE motivational statement. Applicants should also list
The purpose of the StAR Summer Research their chosen research project in order of preference
Internship Programme is to provide support for high (1-10). Application forms and details of available
calibre undergraduate students to conduct a research projects can be found at
research project at RCSI during the summer. The http://www.rcsi.ie/starugprogramme.
best performing students would be eligible to apply
for the RCSI StAR PhD programme and other DEADLINE
funded PhD programmes. Completed applications must be submitted by
Friday 6th March 2020. Successful candidates will
BENEFITS be notified by end of March 2020.
• Opportunity for an international research
placement as part of your undergraduate ENQUIRIES
training in a world class institution. For informal enquiries about the application
process please contact [email protected]
• Potential to apply for the RCSI StAR PhD
programme.
Project 1

‘Adolescent brain development and risk of psychosis’

Supervisor: Professor Mary Cannon, Department of Psychiatry.

Project summary:

Understanding adolescent brain development and how the mechanisms of structural

neuroanatomical and functional brain development plays a central role in the formative phase
of psychiatric disorders. The limbic system is a core component of emotion, memory, and
executive control featuring key subcortical structures such as the amygdala, hippocampus,
and thalamus in conjunction with known white matter fibre tracts supporting related functional
and cognitive roles. Recent advances in MRI present researchers with additional novel tools
to interrogate and quantify the limbic system on a much fine scale than before. Longitudinal
data analysis will allow highly sensitive quantitative details of the developmental trajectories
of the limbic system. Advanced neuroimaging quantitative and white matter diffusion based
tractography techniques will be employed to measure and model developmental growth
patterns of adolescents experiencing psychotic like systems compared to their neurotypical
peers. Highly sensitive linear mixed modelling statistical approaches will be utilised to clarify
the underlying patterns of limbic circuitry development and identify possible localized regions
of developmental divergence in those experiencing subclinical psychotic symptoms.

This summer project will provide hands on experience of the neuroimaging techniques and
how they can be applied to psychiatric research.

More specifically, the student will learn how to run quantitative MRI analysis of subcortical
hippocampal, amygdala and thalamus including substructure delineation and volumetrics for
subfield and sub nuclei measures. This will be done using the image analysis software suite
called Freesurfer. In addition, the student will gain exposure to diffusion imaging tractography
for the purpose of accurately delineating key white matter pathways of the limbic circuit.
Project 2

‘The interaction between sub-epidermal moisture measurements and moisturising and

protectant/barrier products in healthy adult volunteers’

Supervisor: Professor Zena Moore, School of Nursing & Midwifery.

Project summary:

Sub-epidermal moisture (SEM) is a biophysical marker and is a product of the leak of plasma
after the inflammation process increases local vasculature permeability. When tissue
damage progresses to a greater number of cells, the inflammation markers increase along
with the plasma leakage through the blood vessels. Pressure ulcers, diabetic foot ulcers and
lymphoedema are examples of conditions that trigger the inflammation process causing skin
and soft tissue breakdown, increasing the patient’s risk of infection and death. SEM
measurement, using a handheld device, is able to detect electrical changes in soft tissues at
the very early stages, leading to early diagnosis and prevention of skin and soft tissue
ulceration. However, as part of the daily skincare routine, patients cared for in acute and
community settings routinely have moisturising and protectant/barrier products applied on
the skin surface. It is still unknown how these products applied to the skin affect the reliability
of SEM measurement. Therefore, this study will explore how different moisturising and
protectant/barrier products can interfere with the reliability of SEM measurements over time.
A pre-post study design including healthy adult volunteers will measure the effect of
moisturising and protectant/barrier products applied to heels and sacrum areas on SEM
scores: before application of the products, immediately after products application, after 10
minutes, 20 minutes, 30 minutes, 1 hour and 2 hours. This study has the potential to
significantly improve clinical protocols for the use of SEM measurement in both acute and
community settings, meaning the potentially fatal skin damage can be detected before seen
by the naked eye.
Project 3

‘Synthesis of novel heteroarotinoids based on SHetA2 for ovarian cancer’

Supervisor: Dr James Barlow, Department of Chemistry.

Project summary:

Ovarian cancer is the eighth most commonly occurring cancer in women, and is often difficult
to detect until significantly advanced. Five-year survival rates remain between 30% and 50%.
Therefore, there is a clear need for new and innovative strategies to improve prevention,
detection and treatment. Treatments typically involve the use of surgery, drugs and
sometimes radiation, in various combinations. Many existing drugs are toxic and their efficacy
can become compromised. Novel strategies which seek to improve the efficacy and reduce
the toxicity of established therapies have been shown to be a valid and worthwhile approach
in the treatment of many diseases. In this project, we propose to design, synthesise and test
a series of small molecules based on the anti-cancer ‘lead’ structure SHet-A2, a
heteroarotinoid, designed via its relationship to vitamin A. This small molecule has a defined
molecular target, namely the molecular chaperone mortalin, interaction with which leads to
mitochondrial swelling and mitophagy. Such substances are known to regulate cell growth,
and have demonstrated potential in both prevention and treatment of several cancers,
including ovarian cancer. We propose the synthesis of novel heteroarotinoid scaffolds which
offer a rational design approach towards potent and efficacious therapies for ovarian cancer.
Project 4

‘Genomic analysis of clinical DNA sequence data to identify novel causes of rare neurological
disease’

Supervisor: Professor Gianpiero Cavalleri, School of Pharmacy & Biomolecular Sciences

Project summary:

Genetic changes that are rare in the human population are increasingly recognised as a
cause of a variety of diseases, including neurological disorders. Such knowledge is critical
in the development of precision therapeutics, targeted at the specific underlying cause of an
individual’s disease. Our ability to identify, characterise and interpret rare genetic variation
has exploded in recent years, via the development of next-generation genomic sequencing
technology and associated bioinformatic processes.

The SFI FutureNeuro Research Centre consists of over 60 researchers focused on delivering
faster diagnosis, personalized treatments and patient-centred care for neurological disease.
This internship provides a fantastic opportunity to work in the world class research
environment provided by RCSI and FutureNeuro, studying novel genetic causes of
neurological disease. Specifically, the student will work with genomic trio sequence data
(affected child and unaffected parents) from people with rare forms of epilepsy, to identify
de-novo mutations that are appearing in novel disease genes. The project would involve
training in advanced bioinformatic processes, allowing the student to develop in-demand
research skills in genomics data science.
Project 5

‘Validation of microRNAs as novel diagnostic and therapeutic targets in ischaemic brain

injury’

Supervisor: Dr Shona Pfeiffer, Department of Physiology.

Project summary:

Ischaemic stroke, caused by blockage of the blood supply bringing oxygen and nutrients to
part of the brain by a blood clot, is one of the leading causes of death and disability
worldwide. Without proper blood supply, parts of the brain are deprived of oxygen and start
to die, causing parts of the body controlled by these nerve cells to stop working. The
devastating effects of stroke often lead to poor recovery. Despite decades of research,
treatment options remain limited and time-dependent and there is an urgent need for the
development of new approaches to diagnose and predict patient outcome after suffering a
stroke to achieve better functional recovery.

Identification of a molecule that can be detected by a simple blood test that would accurately
diagnose and predict prognostic factors for each individual patient’s recovery from stroke
would enable clinicians to more effectively determine a rehabilitation strategy that maximizes
individual patient’s potential outcomes. Furthermore, identification of such markers
represents a promising approach for the development of a protective agent that could be
administered to help stop the progress of cell death and damage in the brain.

This study is focused on identifying such biomarkers in the blood that will accurately
diagnose stroke and predict recovery. Any biomarkers found to significantly predict recovery
from stroke can be used to develop personalised rehabilitation and treatment strategies
potentially helping patients regain stroke- impaired function. Such markers also have
potential to be developed into future neuroprotective agents to help prevent the devastating
effects of stroke.
Project 6

‘Delirium in critically ill children - development of a cross-sectional survey of European

practices’

Supervisor: Dr John Hayden, School of Pharmacy & Biomolecular Sciences.

Project summary:

Delirium is the behavioural manifestation of acute brain dysfunction associated with serious
underlying medical illness. It presents as an acute and fluctuating change in mental status,
with disordered attention and understanding. (1) It is a well-known and highly prevalent
problem in adult intensive care, linked to increased morbidity, mortality and healthcare costs.
(1) The problem of delirium in critically ill children is gaining increased attention, although its
detection is more challenging than in adults.

Six years ago an international survey found as a lack of routine delirium screening in PICUs
worldwide and many differences in practice across paediatric intensive care units(PICUs).(2)
However, most of those who responded to the survey were based in American PICUs and
the results are now over eight years old. The last decade has seen significant efforts to
recognise and manage delirium in the PICU with the introduction of nursing based detection
tools and care plans in some PICUs.

Given recent progress in the area, the lack of studies in the European context and the
potential to improve care through practice harmonisation, we wish to develop a survey to be
conducted across European PICUs.

The intern will work with academic and clinical experts in Ireland’s PICUs to develop and pilot
a survey of delirium detection and management practices in Europe.

1. Silver G, et al. PCCM. 2015 May;16(4):303.

2. Kudchadkar SR, et al.. CCM. 2014 Jul;42(7):1592.
Project 7

‘Barriers and facilitators to discontinuing long-term benzodiazepine use: A theory-based

questionnaire’

Supervisor: Dr Cathal Cadogan, School of Pharmacy & Biomolecular Sciences

Project summary:

Benzodiazepines have multiple clinical indications, including anxiety and insomnia.

Guidelines recommend that benzodiazepine prescriptions should be limited to short‐term
use (i.e. ≤4 weeks) to minimise the risk of adverse outcomes such as dependence and
withdrawal symptoms. However, these recommendations are often not adhered to as long‐
term use of these medications persists worldwide. Long‐term benzodiazepine use is
potentially inappropriate and can give rise to a range of adverse effects including cognitive
and psychomotor impairment, particularly in older people.

This project will use a questionnaire to examine patient-reported barriers and facilitators to
discontinuing long-term benzodiazepine use. The questionnaire will be developed using
behaviour change theory in order to provide a detailed understating of patients’ current
behaviour regarding long-term benzodiazepine use. The successful applicant will develop
relevant knowledge and skills in the application of behaviour change theory in addressing
clinical problems, as well as questionnaire development and analysis. The questionnaire
findings will help to inform the development of an intervention to reduce long-term
benzodiazepine use in primary care.
Project 8

‘Novel approaches for the treatment of dry eye disease’

Supervisors: Professor Conor Murphy and Joan Ní Gabhann-Dromgoole, Department of

Ophthalmology and School of Pharmacy & Biomolecular Sciences

Project summary:

Inflammation is a key unifying factor for a range of ocular surface inflammatory diseases
including autoimmune-mediated dry eye disease (DED) and complications with corneal
transplantation (CT). While each condition has a specific presentation there are elements of
overlap among them, most strikingly (i) immune-mediated inflammation driving disease
pathology (ii) use of immune suppression/corticosteroids as a primary treatment option (iii)
lack of mechanisms to effectively deliver therapeutics to the ocular surface and (iv) no
diagnostic tests that allow identification of patients who will go on to develop further
complications. Recently non-coding microRNA species have been shown to regulate
inflammation. Synthetic DNA sequences that mimic or antagonise miR function are a new
class of drugs which exhibit enhanced stability, target specificity and bioactivity. An ability to
effectively modulate miR function and thus ocular inflammation has wide ranging therapeutic
and commercial implications. This proposal aims to address these needs by identifying bio-
markers and targeting the molecular mechanisms that underpin DED disease pathology, with
a strong emphasis on translational application of these findings to develop both diagnostics
and novel therapeutics. We have generated promising preliminary data from epigenetic
studies in Sjogrens Syndrome patients, who present with severe autoimmune mediated DED,
where we have identified novel microRNAs (miRs) that contribute to ocular inflammation and
the development of DED. We will build upon these findings and the strengths of our
multidisciplinary team to progress personalised medicine in ocular surface diseases by
developing and optimising an idealised medical device for effective and targeted delivery of
anti-inflammatory agents.
Project 9

‘A 3D melanoma model to study tumour biology and screen novel therapeutics’

Supervisor: Dr Olga Piskareva, Department of Anatomy & Regenerative Medicine

Project summary:

Skin tissue equivalents are gaining interest and investment for research and drug
development as an alternative to traditional animal-free experimental models of human skin.
3D scaffold-based models are a recent advancement in cancer research because they
bridge the gap between conventional 2D culture and tumours seen in patients. Oncology
drugs tested in 3D models have increased likelihood of FDA approval and the global market
for 3D models is expected to reach $1.7 billion by 2022.

This proposal focuses on the development of a bioengineered 3D in vitro platform MelanoColl

for basic and translational research, clinical development of drugs and precision medicines.
We propose to use well-characterised melanoma cell lines and grow them using collagen-
based scaffolds in 3D (MelanoColl) to replicate the native tumour environment. We
hypothesise that this 3D tumour model can predict patient response to therapy, shifting the
paradigm for the evaluation of current and future therapeutic strategies in skin cancers. The
ability of this model to predict drug response will be confirmed retrospectively using the
clinical drug toxicity data. This platform will allow for an increase in drug screening options
and combinations and a reduction of expensive animal models in pre-clinical research,
accelerating the progression of promising drugs from development stage to patient
treatment. This 3D platform can be used to model other skin-related conditions, e.g.
inflammation by replacing melanoma cells with keratinocytes and macrophages for
toxicological and cosmetic studies complying with the recent European legislation banning
animal testing.
Project 10

‘Super-resolution microscopy of actin nodules in platelets’

Supervisor: Dr Ingmar Schoen, School of Pharmacy and Biomolecular Sciences

Project summary:

Platelets are small blood cells. Upon blood vessel injury, they adhere and aggregate at the
wound site to stop bleeding. Whether they actively participate in the later remodelling of the
blood clot is elusive. A recent report showed that platelets migrate at wound sites (Gaertner
et al. 2017 Cell). How platelets were able to squeeze through the dense clot is not clear.
Immune cells use specialized adhesion structures called podosomes for this purpose. The
discovery of actin-rich ‘nodules’ in platelets that resemble podosomes (Poulter et al. 2015
Nature Communications) thus points towards a potentially similar, yet poorly understood,
mechanism.

The aim of this project is to characterize the nanoscale architecture of actin nodules in
platelets. To this end, the student will use techniques related to blood separation,
immunostaining, state-of-the-art super-resolution microscopy, image analysis, and statistics.
The formation of actin nodules in platelets will be induced. Fixed samples will be fluorescently
stained for typical components of podosomes and imaged by STORM which yields an about
5x higher resolution compared to previous reports. By using one stained component as a
reference, the relative localization of other proteins will be determined and the 3D architecture
of the actin nodule will be reconstructed.

The Schoen Lab is very interdisciplinary. We adapt tools from physics to study cell mechanics
and cell biology. Our research is driven by the need to develop better diagnostics and
treatments for cardiovascular diseases.

Students with a physics or engineering background are specifically encouraged to apply.

Project 11

‘Engineering the virtual heart: reconstructing patient imaging to examine cardiac valvular
disease’

Supervisor: Dr Claire Conway, Department of Anatomy & Regenerative Medicine

Project summary:

An estimated 5 million people have valvular heart disease in the United States alone. Valvular
heart disease is now being described as the ‘next cardiac epidemic’. Given this clinical
landscape, it is imperative that new treatments and devices are developed. Key to innovation
in the valvular disease space, is bettering our understanding of the heart anatomy in both
healthy and dysfunctional states.

In the clinic, different imaging types enable us to look into the patient’s heart, at both its
structure and function. This anonymised imaging data can be reconstructed to create a 3D
virtual heart. Within this project, a virtual reconstruction of the cardiac anatomy of an
individual patient will form the basis for a library or databank of virtual patients. These
reconstructions will also enable detailed examinations of cardiac structure that will be linked
with Dr Conway’s group’s work in computational simulation of the mechanics of valvular
disease and cardiac device simulation.

Within this project, the successful applicant will develop a protocol for cardiac image
segmentation and reconstruction, perform a detailed literature review on cardiac imaging,
and create a library of virtual patient hearts from cardiac imaging linked with clinical metrics
of cardiac function.
Project 12

‘Targeting Tamoxifen Pre-Resistance to prevent disease progression in breast cancer’

Supervisor: Jean McBryan, Department of Surgery.

Project summary:

Tamoxifen is an effective breast cancer drug. It stops estrogen from making cancer cells
grow. However, sometimes cancer cells adapt and find another way to grow. This happens
for 3 out of every 10 patients. It may be years or even decades before it happens. The
adapted cells grow to form a secondary tumour. Once this happens, treatment success is
limited.

Existing strategies to treat breast cancer are based on the biology of the initial tumour or the
biology of the secondary tumour. Our fresh approach is to look at how the initial tumour cells
change in response to therapy. We grow breast cancer cells in the lab and treat them with
Tamoxifen until they adapt and become resistant. Rather than studying the resistant cells, we
look at the genes and proteins that help to keep cells alive before they adapt to become
resistant. By monitoring these molecular changes, we hypothesise that we will find novel
opportunities to treat breast cancer. Indeed, we may already have the necessary drugs in
our armoury; we just don’t know it because no-one has ever studied this survival phase in
detail.

Working in a vibrant lab with basic and clinical scientists, this research project will involve a
range of lab techniques including cell culture, growth assays, PCR and western blot analysis.
The student will work with the research team with the aim of defining a rational drug
combination to prevent the formation of secondary, Tamoxifen-resistant breast cancers.
Project 13

‘ChemoGel - a novel thermoresponsive hydrogel for direct intratumoral delivery in solid

tumours’

Supervisor: Dr Helena Kelly, Department of Pharmacy & Biomolecular Sciences

Project summary:

Systemic intravenous chemotherapy has long been a central pillar of cancer treatment,
however the inherent physiological complexity of solid tumours present a significant barrier
to effective drug delivery and treatment. This results in a need for higher systemic doses of
drug, leading to increased toxicity and patient morbidity, often with limited efficacy.
Thermoresponsive hydrogels loaded with chemotherapeutic drugs, for direct intratumoural
administration in solid tumours have been proposed as a safer and more effective method of
treatment for patients in certain scenarios.

ChemoGel is a novel chemoablative thermoresponsive hydrogel for delivery in solid tumours,

specifically formulated to address past challenges with intratumoural delivery, in particular
poor retention at the required site of action. ChemoGel’s thermoresponsive nature means it
is a liquid at room temperature but a semi-solid gel at physiological temperatures. This
enables direct delivery to a solid tumour via minimally invasive procedures where it will
transition to a gel and be retained for a sustained period allowing for prolonged duration of
action at the tumour site.

ChemoGel offers a platform technology for use in chemical ablation of solid tumours using
existing chemotherapeutic drugs, in conjunction with other treatment approaches. However,
ChemoGel also shows intrinsic anti-tumour activity. The aim of this project is to evaluate the
efficacy and toxicity of ChemoGel and its excipients. The intern will gain experience in
hydrogel formulation and material characterisation. They will also receive training in cell-
culture and in vitro studies on relevant cell-lines, including evaluation of cell viability (e.g.
Live/Dead staining and microscopy) and metabolic assays (e.g. CCK-8).
Project 14

‘Nanomedicines for mucosal drug delivery’

Supervisor: Professor Andreas Heise, Department of Chemistry.

Project summary:

Mucus is a hydrated viscoelastic gel that lines epithelial cells in the respiratory, digestive,
and urogenital systems, as well as the eyes. The delivery of therapeutics through mucosal
surfaces, such as lung airways, GI tract, female reproductive tract, nose and eye, is
particularly attractive as a localized, non-invasive form of drug delivery to target tissue and
also to the systemic circulation. However, the development of biomaterials that efficiently
penetrate mucus and tissues remains challenging due to the fact that the biological role of
the mucus layer is to protect the body by rapidly trapping and removing foreign particles. We
have recently developed new mucus penetrating nanomaterials based on star-shaped
polypeptides which efficiently permeated isolated rat mucus and intestinal jejunal tissue
mounted in Franz diffusion cells. These materials offer significant advantages such as full
biodegradability and straightforward synthesis over other reported mucus penetrating
systems.

The aim of this project is the systematic testing of polypeptide nanocarriers for drug delivery
across the mucosal layer. It will involve the formulation of nanoparticle drug conjugates and
the monitoring of their permeation through artificial mucus layers of various thickness.
Permeation, particle degradation and drug release will be accessed using analytical tools
such as Gel Permeation Chromatography (GPC), High- Performance Liquid Chromatography
(HPLC) and Infrared Spectroscopy (IR). Promising nanoparticle/drug combination will be
tested ex vivo on rat mucus and intestinal jejunal tissue.
Project 15

‘Why does α-synuclein in Multiple System Atrophy not form Lewy bodies like the other
alpha-synucleinopathies?’

Supervisors: Dr Melanie Focking, Dr Conor Fearon, Professor Michael Farrell and Professor
David Cotter, Departments of Psychiatry and Clinical Neurological Service.

Project summary:

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder which can affect
movement, balance and the autonomic nervous system (the part of the nervous system that
controls involuntary action such as blood pressure or digestion). The signs and symptoms
reflect the progressive loss of function and death of specific types of nerve cells in the brain
due to aggregation of the protein α-synuclein in the cytoplasm of oligodendrocytes. α-
synuclein is also the protein responsible for Parkinson’s disease (PD) and Dementia with
Lewy Bodies (DLB), however in these cases, the protein accumulates in the neurons.

Based on the current literature, our research question is:

Why does α-synuclein form neuronal (Lewy body) inclusions in PD and DLB, but forms
cytoplasmic inclusions (GCIs) in oligodendroglial cells in MSA creating two very different
forms of neurodegeneration?

We are planning to initially use mass spectrometry to test different brain regions of both
diseases: substantia nigra (where Lewy bodies should be in greatest concentration in PD),
pons/putamen (where GCIs should be in greatest concentration in MSA) and normal
grey/white matter. This will allow us to detect differential expression of α-synuclein and other
proteins between diseases and compared to healthy controls. We will also use pathway
analysis tools to determine which sets of proteins are most relevant to α-synuclein. Different
methods will then be used to validate the most promising findings (e.g. ELISA, Western
Blotting).
Project 16

‘BET inhibition as a rational therapeutic strategy for Invasive Lobular Breast Cancer (ILBC)’

Supervisor: Dr Elspeth Ward, School of Pharmacy and Biomolecular Sciences.

Project summary:

What’s the project about?

Invasive lobular breast cancer (ILBC) is a form of hormone receptor-positive (ER+) breast cancer
that accounts for about 10-15% of all new breast cancer cases diagnosed. Since it is ER+, it is
treated the same way as all other ER+ breast cancer, with surgery, radiotherapy, anti-hormone
therapy (and in many cases, chemotherapy). However, patients with ILBC do not have the same
clinical course as other ER+ patients. Their cancer is more likely to (i) spread to the ovaries and
the digestive system, (ii) occur in both breasts, (iii) come back in the other breast (iv) be
unresponsive to additional chemotherapy (as well as having the same problems with hormone
therapy-resistance as other forms of ER+ breast cancer). In addition to a different clinical course,
the tests used to determine treatment options for ER+ patients (such as OncotypeDx), give very
different results for ILBC patients, making it difficult to determine the most appropriate treatment
plan. As such, the lack of tailored options for ILBC patients represents an unmet clinical need and
it is time we start to consider ILBC as a distinct type of ER+ breast cancer and devise new
treatment and diagnosis options specifically for these patients. Our research suggests that some
ILBC patients who do not respond to anti- hormone therapy would benefit from using a BET
inhibitor, and the remaining patients from a combination with an anti-FGFR drug. This project will
confirm whether BET inhibitors are a useful treatment option for ILBC patients and which drugs
we need to combine them with to reach the best outcome for ILBC patients.

What will I learn during this project?

The specific aims of this project will be to test the use of BET inhibitors in a pre-clinical model of
ILBC, as well as the combination with anti-FGFR drugs, using BET sensitive and resistant ILBC
cell lines. The student will receive training in cell culture, in vitro growth assays, apoptosis assays,
RNAi technology, Western blotting, qRT-PCR, and determination of drug synergy using
Compusyn software.

The Molecular Oncology Laboratory at the School of Pharmacy & Biomolecular Science
(https://www.rcsi.com/people/profile/darranoconnor), is a young, vibrant and well-funded
research group focused on the identification and mechanistic anchoring of novel cancer
biomarkers and therapeutic targets.

Examples of recent work by the group:

1. Walsh L, Haley K, Moran B, Mooney B, Tarrant F, Madden S, di Grande A, Fan Y, Das S, Rueda O, Dowling C, Vareslija D,
Chin SF, Linn S, Young LS, Jirström K, Crown JP, Bernards R, Caldas C, Gallagher WM*, O’Connor DP*§ & Ní Chonghaile T*.
BET inhibition as a rational therapeutic strategy for invasive lobular breast cancer. Clin Cancer Res 2019 Dec 25 (23), 7139-
7150 (impact factor 10.199) Journal Quartile Rank: Oncology Q1 *Equal Contribution, §Corresponding author
2. Smeets D*, Miller IS*, O'Connor DP*, Das S, Moran B, Depreeuw J, Gaiser T, Betge J, Barat A, Klinger R, van Grieken NCT,
Cremolini C, Prenen H, Boeckx B, Bacon O, Fender B, Brady J, Hennessy BT, McNamara D, Kay EW, Verheul HM, Maarten N,
Gallagher WM, Murphy V, Prehn JHM, Loupakis F, Ebert MP, Ylstra B, Lambrechts D & Byrne AT. Copy number load predicts
outcome of metastatic colorectal cancer patients receiving bevacizumab combination therapy. Nature Commun 2018 Oct
5;9(1):4112. (impact factor 12.353) Journal Quartile Rank: Biochemistry, Genetics and Molecular Biology Q1 *Equal Contribution
3. van Dijk E, Biesma HD, Cordes M, Smeets D, Neerincx M, Das S, Eijk PP, Murphy V, Barat A, Bacon O, Prehn JHM, Betge J,
Gaiser T, Fender B, Meijer GA, McNamara DA, Klinger R, Koopman M, Ebert MPA, Kay EW, Hennesey BT, Verheul HMW,
Gallagher WM, O'Connor DP, Punt CJA, Loupakis F, Lambrechts D, Byrne AT, van Grieken NCT & Ylstra B. Chromosome
18q11.2-18q21.1 loss predicts response to bevacizumab for patients with metastatic colorectal cancer. J Clin Oncol 2018 Jul
10;36(20):2052-2060 (impact factor 26.303) Journal Quartile Rank: Oncology Q1.
Project 17

‘In-silico characterisation of immune checkpoint alterations and evaluation of their

significance in predicting clinical outcome in patients with HER2+ breast cancer from the
TCHL trial?’

Supervisor: Prof Darran O’Connor, School of Pharmacy & Biomolecular Sciences.

Project summary:

Immune checkpoints play a crucial role in tumour progression as these checkpoints regulate
T cells. Deregulation of these molecules allow tumour cells to avoid destruction by the
immune system [1], [2]. Drugs like ipilimumab, pembrolizumab and nivolumab target these
immune checkpoints and have dramatically improved cancer therapy [3]–[5]

Currently none of these novel immunotherapy drugs are approved for treatment in breast
cancer, but it has been shown that the alteration of immune checkpoints are involved in
breast cancer progression and are prognostic markers for recurrence [6].

As part of an ongoing project we are analysing multi-omics (DNA, RNA, DNA Methylation)
data of matched HER2+ breast cancer tissue acquired pre- and post-treatment of docetaxel,
carboplatin and trastuzumab (TCH), and randomised with addition of lapatinib (TCHL). The
aim of this project is a profound characterisation of HER2+ breast cancer, leading to better
understanding of the disease, and identification of clinically prognostic and predictive
characteristics. This information will eventually be used to develop a prototype decision
support tool for the treatment of patients with HER2+ breast cancer.

The student’s project will be to analyse the pre-processed, cleaned multi-omics data with
regards to alteration of immune checkpoints. Part of the project will be a literature review on
genes involved or related to immune checkpoints. The student will further extract the
information for the identified genes from the multi-omics data. In this dataset the student will
investigate the predictive and prognostic roles of immune checkpoint activation in pre-
treatment samples, and the changes in post-treatment samples and how these relate to
treatment and response.

Experience in basic usage of R is beneficial but not required.

[1]D. R. Leach, M. F. Krummel, and J. P. Allison, ‘Enhancement of Antitumor Immunity by CTLA-4
Blockade’, Science, vol. 271, no. 5256, pp. 1734–1736, Mar. 1996, doi:
10.1126/science.271.5256.1734.
[2]G. J. Freeman et al., ‘Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family
member leads to negative regulation of lymphocyte activation’, J. Exp. Med., vol. 192, no. 7, pp. 1027–
1034, Oct. 2000, doi: 10.1084/jem.192.7.1027.
[3]M. Reck et al., ‘Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung
Cancer’, N. Engl. J. Med., vol. 375, no. 19, pp. 1823–1833, 10 2016, doi: 10.1056/NEJMoa1606774.
[4]C. Robert et al., ‘Nivolumab in previously untreated melanoma without BRAF mutation’, N. Engl. J.
Med., vol. 372, no. 4, pp. 320–330, Jan. 2015, doi: 10.1056/NEJMoa1412082.
[5]F. S. Hodi et al., ‘Improved survival with ipilimumab in patients with metastatic melanoma’, N. Engl.
J. Med., vol. 363, no. 8, pp. 711–723, Aug. 2010, doi: 10.1056/NEJMoa1003466.
[6]D.-W. Lee et al., ‘Immune recurrence score using 7 immunoregulatory protein expressions can
predict recurrence in stage I-III breast cancer patients’, Br. J. Cancer, vol. 121, no. 3, pp. 230–236,
Jul. 2019, doi: 10.1038/s41416-019-0511-9.
Project 18

‘Synthesis and functionalisation of gold nanoparticles with attenuated protein corona’

Supervisor: Dr Marco Monopoli, Department of Chemistry

Project summary:

Nanotechnology is one of the primary drivers of technology innovation, where nanoparticles

(NP) of 100nm or less, have the potential to treat chronic diseases as they are capable of
targeting diseased area and carry drugs. Their enhanced therapeutic effect is caused by
their small size as they are actively processed by cellular machineries and they are capable
of crossing the biological barriers and penetrate diseased tissue for a selective and targeted
therapeutic effect. Despite these high expectations, their clinical translation has been
obstructed by many factors affected the NPs efficacy. These factors include, but not limited
to, the NP stability in complex fluid, such as blood or cell culture media, which contain
thousands of biomolecules including proteins, lipids and sugars that can adsorb on the
surface of NPs forming what is called protein corona. The resulting corona constitutes the
actual NPs' surface of interaction with biological cell membranes and strictly dictates the NPs’
biological fate including cellular uptake, toxicity, biodistribution, etc. Therefore, engineering
the NPs’ surface has been used as a successful strategy to control the biomolecular
adsorption on the NP surface can increase their colloidal stability and control the formation
of proteins corona, which can increase/ improve the NPs efficiency. In this context, the object
of this study is to modify the NP surface in order to
Increase the NP colloidal stability and biocompatibility and to prevent the biomolecular
adsorption and maintains corona-free behavior of the NPs in the physiological environment.
Project 19

‘Old drugs new tricks’

Supervisor: Dr Marian Brennan, School of Pharmacy & Biomolecular Sciences.

Project summary:

The development of a new drug is estimated to cost approximately $2.6 billion. While the
costs have gone up year on year, the approval rates have gone down, with only 12% of
candidates entering clinical trials being approved. Many approved drugs have off-target
effects. Some of these can be significant, allowing some drugs to be approved as a treatment
for more than one disease. This is one way to identify a new drug at a lower cost, allowing it
to be fast tracked into the clinic. An alternative is to also investigate drugs that have failed in
clinical trials. Many drugs fail in development due to lack of effect for the disease they are
being tested. This project involves using bioinformatic tools to identify new uses for drugs
that are already approved. This project will also investigate new uses of drugs that have
already completed phase II clinical studies and therefore have been shown to be safe in
humans. We will use 3D structural analysis of disease targets and high-throughput screening
of approved drugs and post phase II compounds in silico. Applying this methodology can
progress drugs to the clinic faster providing benefits to patients. We will look at novel targets
for orphan diseases with no current treatment. It would be beneficial for students who choose
this project to have an interest in bioinformatics, chemoinformatics or programming.
Programming skills are not necessary, but enthusiasm for manipulating large data sets, and
running computational experiments is required.
Project 20

‘Barriers and Enablers in Providing Laparoscopic Cholecystectomy Procedures as Day

Cases’

Supervisors: Professor Jan Sorensen (Health Outcome Research Centre), Professor Deborah
McNamara (National Clinical Programme for Surgery) and Dr Dara Kavanagh (Department
of Surgery).

Project summary:

The national HSE has formulated key performance indicators for Laparoscopic
Cholecystectomy (Lap Chole) which suggest that 60% should be done as day cases. This is
a modest target. Recent data from the National Quality Assurance Information System
(NQAIS) shows that there is huge variation ranging from 0.7% to 95% despite the national
DRG-tariff incentivise day case surgery (same tariff for day case and inpatient). The system
factors that impact the observed variation are poorly understood.

The purpose of this project is to develop clarity to system factors that may differentiate
hospitals with high day case rate from hospitals with low day case rate.

This project will apply a mixed-method approach and use quantitative methods to analyse
hospital episode data from NQAIS and qualitative methods to explore barriers and enablers
of Lap Chole day case provision.

Based on the quantitative analysis we will identify the three top and three bottom ranging
hospitals in terms of Lap Chole day case rates. For these hospitals we will conduct face-to-
face audio recorded interviews with staff representing surgeons, anaesthetists, nurse
managers and general managers from each hospital.

Interview guides will be developed informed by the quantitative analysis and will include
open-ended questions relating to perceived enablers and barriers to the provision of Lap
Chole day case procedures.

Before the interview, consent will be obtained and participants will be informed about the
purpose of the study and that their answers will remain confidential and anonymous.
Interviews will be audio recorded and transcribed verbatim and anonymized.

The transcribed data will be analysed with a grounded theory approach by using
standardised coding system developed during the readings. These codes will be grouped
to identify themes from the texts. Themes will be analysed by background and site of the
interviewees.

The analysis will be documented in a scientific manuscript aimed at publication in a

academic surgical journal.
Project 21

‘Development of a prototype intestinal patch to improve intestinal permeation of poorly

absorbed drugs’

Supervisor: Dr Sam Maher, School of Pharmacy & Biomolecular Sciences.

Project summary:

The oral route of administration is the cornerstone for the successful use of medicines in
healthcare. A growing number of promising bioactive chemical entities are poorly absorbed
via the oral route. Hydrophilic macromolecules such as peptides, proteins and carbohydrates
are often shown to have improves safety, efficacy and tolerability compared to small
molecules, but the size and molecular complexity that imparts these desirable properties also
imparts sub-optimal permeation across the GI tract into the systemic circulation. These
actives must be either formulated as injectable dosage forms or excluded from
pharmaceutical development. There is growing demand for delivery technologies that
address low and variable oral absorption of hydrophilic macromolecules. Technologies that
facilitate absorption of poorly permeable molecules would permit reformulation of several
marketed injectable drugs, diversify discovery screening and enrich the pharmaceutical
pipeline. The objective of this research is to design a prototype bioadhesive intestinal patch
loaded with a poorly permeable active and an absorption modifying excipient. Adhesion of
the patch to the gut wall will create a microclimate where the active can be co-presented with
an excipient that transiently alters intestinal permeability, which may facilitate transport of the
active across the intestinal wall. The successful candidate will prepare a panel of prototype
patches and determine if permeation from the patch is more effective than aqueous solution
in intestinal cell culture monolayers.
Project 22

‘A key role for FKBPL in the regulation of cancer stem cell signalling and the
microenvironment; therapeutic implications for tumour growth and metastasis’

Supervisor: Professor Tracy Robson, School of Pharmacy & Biomolecular Sciences.

Project summary:

Cancer stem cells (CSCs) are a special type of cell found within tumours that are able to
undergo unlimited self-renewal and are highly resistant to therapy. Indeed, these cells are
left behind and go on to divide rapidly, leading to tumour regrowth. Even more worryingly,
this population of cells have special features allowing them to move through the body,
invading vital organs; a process known as metastasis. We have identified a novel protein,
called FKBPL, that occurs naturally in the body and which inhibits tumour blood vessel
development, thereby stopping tumour growth. A therapeutic drug derived from the protein
and designed to harness its therapeutic effects, has successfully completed phase I cancer
clinical trials and was recently granted Orphan Drug status in ovarian cancer by the Food
and Drug Administration (FDA), to facilitate development. However, we have acquired data
which suggests that this protein also targets breast and ovarian CSCs by transforming them
into a more ‘normal’ cancer cell, which can be more easily killed by chemotherapy. This
project will assess the impact of FKBPL on CSCs and other cells within the ovarian tumour
microenvironment that are known to support the growth and survival of CSCs cells in the
primary tumour and at distant sites. We will evaluate exactly how FKBPL controls these cells
and the implications on the ability of CSCs to become metastatic. Understanding how this
protein works will allow us to design future clinical trials that are more likely to demonstrate
better response rates in cancer patients.
Valentine A, O’Rourke M, Yakkundi A, Worthington J, Hookham M, Bicknell R, McCarthy H, McClelland K,
McCallum L, Dyer H, McKeen H, Waugh D, Roberts J, McGregor J, Cotton G, James I, Harrison T, Hirst D, Robson
T FKBPL and peptide derivatives: novel biological agents that inhibit angiogenesis by a CD44-dependent
mechanism. Clin Cancer Res. 2011 Mar 1;17(5):1044-56. PMID: 21364036.

McClements L, Yakkundi A, Papaspyropoulos A, Harrison H, Ablett MP, Jithesh PV, McKeen HD, Bennett R,
Donley C, Kissenpfennig A, McIntosh S, McCarthy HO, O’Neill E, Clarke RB, Robson T. Targeting treatment
resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01, via the CD44 pathway. Clin
Cancer Res. 2013 Jul 15;19(14):3881-93. PMID: 2374106.

Annett S., Moore G., Short A., Marshall, A., McCrudden, C., Yakkundi, A., Das, S., McCluggage, W.G., Nelson,
L., Harley, I., Moustafa, N., Kennedy, C. J., DeFazio, A., Brand, A., Sharma, R., Brennan, D., O’Toole, S., O’Leary,
J., Bates, M., O’Riain, C., O’Connor, D., Furlong, F., McCarthy, H., Kissenpfennig, A., McClements, L., Robson, T.
(2019) FKBPL based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer. British
Journal of Cancer. doi:10.1038/s41416-019-0649-5
Project 23

‘Does substrate stiffness contribute to the inflammatory response of spinal cord glial cells?’

Supervisor: Dr Adrian Dervan, Department of Anatomy & Regenerative Medicine.

Project summary:

Spinal cord injury (SCI) is one of the severest traumatic events suffered by the human body.
Because of the poor outcomes seen after injury, extensive research has identified many of
the pathophysiological processes that occur following cord damage; one such structure is
the complex inhibitory glial scar tissue that develops at the site of injury and is a potent barrier
to axon regrowth. Astrocytes, the major non-neuronal cells of the CNS are a major component
of the glial scar and change to a reactive scar-forming phenotype.

We are developing an axon guidance scaffold (AGS) system based on successes in

peripheral nerve regeneration (e.g. Roche et al. (2017) Stem Cells Trans Med, 6:1894–1904),
for therapeutic insertion into the injured spinal cord to encourage axon growth and restore
function. The scaffold will consist of a complex 3D printed scaffold built from the
biodegradable polymer Polycaprolactone (PCL) that will integrate and bridge the injured cord
tissue. The AGS structure should not exacerbate cellular responses in the lesion site and
scaffold stiffness is known to have a strong effect on cellular physiology (e.g. Moshayedi et
al. (2014) Biomaterials 35: 3919-3925). Understanding the interaction between polymer
stiffness and astrocytes is essential for proper AGS design and functionality. This project will
assess the effects of PCL polymer stiffness on astrocyte physiology and will consist of
culturing glial cells on polymers with three different levels of stiffness and determining
changes using histological staining combined with immunohistochemistry.
Project 24

‘Developing new tools to understand how blood clotting enzymes talk to cells’

Supervisor: Dr Roger Preston, School of Pharmacy & Biomolecular Sciences.

Project summary:

Protease-activated receptor 1 (PAR1) is a cell surface receptor expressed on the surface of

blood vessels that has an important role in transmitting cell signalling by blood coagulation
enzymes. Dysregulated PAR1 activity has been shown to contribute to thrombosis,
inflammatory disease and tumour cell metastasis. The blood protease activated protein C
(APC) activates PAR1 to protect cells from inflammatory or toxic stimuli. Despite this, we do
not fully understand how APC signalling via PAR1 occurs. An enhanced understanding of the
molecular parameters that control PAR1 signalling by APC is particularly important, given the
early promise of recombinant APC variants for the treatment of inflammatory disease.

The objective of this study is to identify how APC activation of PAR1 causes an APC-specific
cell signalling response. This will be achieved using a combination of state-of-the-art
molecular biology and cell signalling techniques that are well-established in the Preston lab.

The project will be performed under the supervision of Dr Roger Preston. The Preston lab
(www.prestonlab.com) is a multi-disciplinary research group with well-established expertise
and an international reputation in the study of the mechanistic basis of coagulation enzyme
signalling.

Willis Fox O, Preston RJS. Molecular basis of protease-activated receptor 1 signaling diversity. J
Thromb Haemost. 2020 Jan;18(1):6-16.
Project 25

‘Epigenomic regulation of breast cancer brain metastasis’

Supervisors: Dr Damir Varešlija and Professor Leonie Young, Department of Surgery.

Project summary:

Our group is focused on the molecular mechanisms underlying metastatic spread in breast
cancer. With a particular focus on breast-cancer-brain-metastasis, we aim to identify new
vulnerabilities that can be exploited as novel therapeutic opportunities.

Although treatment therapies for primary breast cancer have improved, aggressive breast
cancer which spreads to the brain, known as brain metastasis, has inadequate treatment
options and poor survival outcomes. Brain metastases occur in 10-30% of patients with
metastatic breast cancer. Even where treatment is successfully controlling cancer elsewhere
in the body, brain metastases often grow rapidly. More than half of the patients diagnosed
with brain metastases will die within a few months

The objective of our work is to identify the key features which enable a breast tumour to
spread from the breast to brain. We use a variety of molecular profiling and next-generation
sequencing approaches to identify brain metastasis epi-genetic switches (various chemicals
turning genes on/off) that will enable the development of new therapeutic strategies. Our
previous studies of breast cancer patients’ biopsies revealed how cancer cells can transform
to survive in the brain. Using state-of-the-art models of brain metastasis, we test whether
controlling these chemical switches can regulate faulty genes to 1) stop cancer cells from
spreading to the brain; 2) kill growing brain metastasis.

Considering more than half of the patients diagnosed with brain metastases succumb to
disease within months, our proposed research aims to benefit those with very limited
treatment options. Our study will use both genetic and drug based approach to test the
therapeutic benefit of targeting potential vulnerabilities identified in our epi-genomic profiling
of breast cancer brain metastasis.
Project 26

‘Students’ views, experiences and expectations of public and patient involvement and
engagement in healthcare professionals’ education - a qualitative exploration’.

Supervisors: Professor Judith Strawbridge, School of Pharmacy & Biomolecular Sciences.

Project summary:

There is increasing recognition that patients and the public have an integral role in the
teaching of healthcare professionals. Many studies have demonstrated that, not only is it
feasible to have patient and public involvement and engagement (PPI/E) in education, this
involvement has the capacity for motivating students by fostering empathy, demonstrating
the relevance of learning and encouraging the development of key professional skills such
as communication.1 Despite the well-documented benefits of PPI/E, patient involvement in
education is currently at a low level. Attempts are being made by academic institutions to
expand patient involvement so that patients act as central participants in the design of
curricula and in the delivery of education. The primary research question of this project is to
investigate the views, experiences and expectations regarding PPI/E from the students’
perspective. We aim to find out how students would like the public and patients to be involved
in their education, what they have gained from it and/or what they expect to gain from this
involvement. This question will be answered primarily based on information acquired during
focus group sessions, and the data generated will help form recommendations for the
development of a strategic framework for PPI/E.
1 Regan De Bere S, Nunn S. Towards a pedagogy for patient and public involvement in medical
education. Med Educ. 2016;50(1):79-92.
Project 27

‘The development of bioengineered scaffolds with pathological mechanical properties to

recapitulate and understand idiopathic pulmonary fibrosis pathophysiology’

Supervisor: Dr Cian O’Leary, School of Pharmacy & Biomolecular Sciences.

Project summary:

Despite the encouraging clinical impact from recently-approved anti-fibrotic drugs,

idiopathic pulmonary fibrosis (IPF) persists as a devastating disease that requires new
therapies to reduce its significant morbidity and mortality within 3-5 years of diagnosis.
Although IPF pathogenesis is incompletely understood, a central component is dysregulated
communication between epithelial cells and the surrounding stroma within the lung
microenvironment, resulting in excessive extracellular matrix (ECM) deposition by
myofibroblasts that aberrantly remodel alveoli with excessive, fibrotic matrix, and loss of
respiratory function. Accordingly, pathophysiologically-relevant human disease models of
IPF are warranted that accurately integrate the prominent features of stroma in disease
progression. However, current preclinical cell models fail to recapitulate the contribution of
ECM that influences a range of cell and tissue characteristics; for IPF, changes in the
composition and physical properties of the lung tissue can influence pro-fibrotic signalling to
exacerbate disease progression, with possible modulation on pharmacological action of a
novel therapeutic. Thus, it is paramount to not only develop new medicines for the treatment
or improved management of IPF, but also to utilise organotypic cell models that exhibit the
key features of the human pathophysiology for more relevant and robust preclinical data prior
to animal testing and human trials.

Tissue-engineering strategies are capable of improving physiologically-relevant in vitro

disease models by supporting long-term cellular growth and differentiation, in addition to co-
culture with multiple cell types. Previous work by our group has successfully manufactured
collagen-based scaffolds as 3D respiratory co-culture models of the normal tracheobronchial
airway region. Accordingly, the objective of this project is to use our current model as a
platform to develop to develop a bioengineered model of co-cultured IPF cells in a
biomaterial ECM analogue as an organotypic in vitro disease model.

Specifically, the student will utilise scaffold manufacture techniques together with cell culture
and in vitro analysis to create a dynamic model with the capacity to exhibit the stiffness of
fibrotic tissue, and to examine how this stiffness mediates cell behaviour in disease. In this
way, this model will serve as a novel platform to identify new “druggable” disease
mechanisms that can potentially pave the way towards the development of life-saving
therapies in IPF.
Project 28

‘HealthEIR: Developing innovative design-based care models for community-based health

promotion’

Supervisor: Dr Michelle Flood, School of Pharmacy & Biomolecular Sciences.

Project summary:

The challenges of keeping people healthy through promoting health behaviours are well
established, and existing national and international campaigns have demonstrated limited
success. The HealthEIR project is an interdisciplinary project, nationally funded by
Sláintecare that aims to develop, implement, and evaluate new models of health promotion
in community health settings (pharmacy and general practitioner/family doctors).

Drawing together the skills of health workers, patients/public, designers, and researchers,
this project aims to develop radically new ways of delivering health promotion in the
community through combining innovative technology with human-centred design. The
project includes collaborators from the School of Pharmacy and Biomolecular Sciences
(RCSI), Department of General Practice (RCSI), Department of Psychology (RCSI), the
National College of Art and Design (NCAD), and Technological University Dublin (TUD) and
an industry partner.

Working as part of the interdisciplinary team, the student will receive day-to-day support to
conduct research and develop skills in both traditional research (e.g. systematic reviews,
quantitative methods, and qualitative methods) and design research (e.g. fieldwork,
observations, task analysis, usability testing, and service blueprint development). The
student will develop a unique skillset to build on in the future, through dedicated support. The
student will have day-to-day support from both a postdoctoral researcher and interaction
designer, as well as meetings with wider study team several times a week, and be
encouraged to actively contribute ideas as an important member of the team. No specific
previous experience or training is required.
Project 29

‘The effect of serum deprivation on breast cancer cells in a 3D collagen-based scaffold

model’

Supervisor: Dr Caroline Curtin, School of Anatomy & Regenerative Medicine.

Project summary:

Breast cancer, a complex, multifactorial disease that usually presents as solid 3D tumours,
is the most common cancer in women worldwide. Culturing of cancer cells in 2D has
traditionally been used to study complex tumorigenic mechanisms but lacks the structural
microenvironment required for cell-cell and cell-extracellular matrix interactions. The
alternative involves animal xenograft models but also has various limitations. Recently, 3D
cancer cell culturing has been proposed to bridge the gap between conventional 2D culture
and in vivo tumours by enabling cells to acquire phenotypes and respond to stimuli similar
to in vivo biological systems. Collagen-based scaffolds capable of supporting cell culture
have been widely used as 3D cancer models within our laboratory [1, 2]. Recent studies have
demonstrated the involvement of collagen 1 in breast cancer cell survival even in the
presence of serum-depleted conditions in 2D culture [3]. Thus, we are interested to assess
this phenomenon in our 3D collagen-based scaffolds. Briefly, cell-seeded scaffolds will be
deprived of serum following 24hrs of normal cell culture and cultured for a further 48 hours
or 7 days before analysis. Gene expression, histology and DNA assays will be performed.
Apoptosis and Bax expression, which have been shown to decrease in serum-deprived
conditions, will be compared to breast cancer cells grown on plastic and serum-treated cell-
scaffolds.

1. Fitzgerald, K.A. et al. Biomaterials, 2015. 66: p. 53-66.

2. Curtin, C. et al, Acta Biomater, 2018. 70: p. 84-97

3. Badaoui M et al. Oncotarget. 2017. 9(37):24653-24671.

Project 30

‘Targeting mRNA polyadenylation as novel treatment strategy in epilepsy’

Supervisor: Dr Tobias Engel, Department of Physiology.

Project summary:

Epileptogenesis, the process leading to a reduced threshold for seizures after transient brain
insults, is associated with large-scale changes in gene expression which ultimately lead to
the formation of seizure-generating neuronal networks. Targeting single genes has
repeatedly failed to alter the development of epilepsy or reduce the percentage of drug-
refractory patients, suggesting approaches which target larger signaling networks may be
required. First, however, we must precisely understand which pathological changes
contribute to the development of epilepsy and to the maintenance of the epileptic state.

Cytoplasmic polyadenylation is a process by which dormant, translationally inactive mRNA

become activated by the elongation of their poly(A) tails. Cytoplasmic polyadenylation
element binding proteins (CPEBs1-4) are central factors controlling polyadenylation-induced
translation. In the brain, CPEBs mediate numerous cellular processes including long-term
potentiation, synaptic plasticity and neurotransmitter receptor expression, processes altered
during epileptogenesis. Our data shows, for the first time, that CPEB expression is changed
in experimental models of epilepsy and in drug-refractory epilepsy patient brains and by
using mRNA arrays, we have demonstrated mRNA polyadenylation changes affecting up to
20% of the transcriptome during epilepsy. To date, however, neither changes in
polyadenylation, nor the contribution of cytoplasmic polyadenylation to disease progression
have been studied in the setting of epilepsy. By using experimental models of epilepsy and
patient tissue, this project will characterize and decipher an untested layer of gene control
contributing to epileptogenesis and provide a new set of therapeutic target genes with a
different mechanism of action to better treat patients with epilepsy.
Project 31

‘Development of a drug delivery system containing Allopurinol for loco-regional delivery to

the heart post myocardial infarction’

Supervisor: Dr Aamir Hameed, Department of Anatomy & Regenerative Medicine.

Project summary:

Heart failure is defined as inability of the heart to supply adequate blood to the body. It can
occur due to the injury to the heart muscle. The most common cause is blockage of the blood
vessels in the heart, commonly referred to as a ‘heart attack’. As the demographics suggest,
with increasing ageing population, prevalence of heart failure is also increasing. Depending
upon the severity of the disease, the ability of the affected heart muscle to beat and pump
blood around the body can be reduced. Therefore the heart has to do extra work to try and
pump the blood to the whole body. This can cause the heart to become enlarged. One of the
causes of this process is thought to be the inflammatory process following a heart attack.
Current medical care and surgical/device based therapies help in relieving the symptoms
but they do not address the underlying cause. There is a need to reduce the inflammation to
reduce the development of heart failure. In this research project, we will develop a loco-
regional drug delivery platform to deliver the medicines that can effectively reduce the
inflammatory process, thus reducing the damage to the heart. And lowering the likelihood of
developing heart failure.