RCSI RCSI has been at the forefront of educating healthcare professionals since 1784. Today we are Ireland’s only focused health sciences institution, Ireland’s largest medical school and one of the leading health sciences institutions in the world. Based in Dublin, with students from over 80 countries and four overseas campuses, RCSI has a global reach through our network of Alumni in 97 countries. RCSI has been ranked among the top 2% of universities worldwide in the 2018 Times Higher Education (THE) World University Rankings and joint second out of the nine institutions in the Republic of Ireland. RCSI’s performance in the rankings is linked in particular to the College’s research strength and it is ranked first in Ireland for publication citations and has a field-weighted citation impact (2.06) that is twice the world average. RCSI's Strategic Academic Recruitment (StAR) Programme is an ambitious initiative to accelerate the delivery of innovative, impactful research to improve human health through innovative translational medical research. PURPOSE: The purpose of this initiative is to provide support for high calibre undergraduate students to conduct a research project at RCSI during the summer. The best performing students would be eligible to apply for the ongoing RCSI StAR PhD programme and other funded PhD programmes.

BENEFITS • Opportunity for an international research

placement as part of your undergraduate training in a world class institution

• Potential to apply for RCSI’s ongoing StAR PhD programme

• Potential to apply for additional funded PhD programmes (e.g. Government of Ireland Postgraduate Training Programme)

ELIGIBILITY: Eligible students must be entering the final year of their undergraduate degree programme in basic science/health sciences after completion of the internship and will have a clear plan to pursue a PhD. Students can be from any country in the world, there are no restrictions on nationality.

EXTENT OF FUNDING: Students will receive a €2000 stipend and paid accommodation in Dublin city centre will be provided for 8 weeks commencing June 2019. Travel costs are not included and non-EU students will also require a Garda National Immigration Bureau (GNIB) card and appropriate visa. Assistance in obtaining both for successful applicants will be provided.

APPLICATION PROCESS Applicants should detail academic progress to date, including class rank, CV/Resume and a brief motivational statement describing your career plans. Applicants should also list their chosen research project in order of preference (1-10). Details of available research projects, the application form and the application process can be found at http://www.rcsi.ie/starugprogramme

DEADLINE Completed applications must be submitted by Friday 4th January 2019. Successful candidates will be notified by end of January 2019.

ENQUIRIES For informal enquiries or questions about the application process please contact StARintern@rcsi.ie

Project 1

‘Scaling up Safe Surgery for District and Rural Populations in Africa (SURG- Africa)’

Supervisors: Professor Ruairi Brugha & Dr Jakub Gajewski, Dept of Epidemiology and Public Health Medicine.

Project summary:

The purpose of this summer internship is to support senior researchers in analysing and writing up the results of Scaling up Safe Surgery for District and Rural Populations in Africa (SURG-Africa), 2017-2020. The project is rigorously evaluating an intervention for building the surgical capacity of district hospitals in Malawi, Zambia and Tanzania with a view to generating practical solutions for policy-makers to make life-saving essential surgical services accessible, equitable and sustainable in underserved rural areas (see www.surgafrica.eu).

SURG-Africa is a mixed methods controlled trial comprising a set of quantitative and qualitative studies. The successful candidate will have the opportunity to develop her/his skills in all key aspects of research, from data management (data entry, quality control and cleaning), to quantitative and qualitative methods, report writing and presentation skills, under the supervision of experienced researchers and working with an international research team from European and African institutions.

The internship involves: 1 week project familiarisation and data management activities to assess skills and training needs – on data management and literature searching; 4 weeks supervised data management and analysis; 2 weeks supervised writing up of research findings; 1 week review / feedback on skills and planning next steps. The successful candidate, if s/he performs to the required standard and demonstrates ongoing commitment to the project, can expect to have authorship opportunities in scientific publications produced by the project, and potential for ongoing involvement in the SURG-Africa project.

Project 2

‘Cyclin-dependent kinase inhibitors as a novel therapy for glioblastoma’

Supervisor: Dr Brona Murphy, Dept. of Physiology and Medical Physics.

Project summary:

Average survival expectancy for patients with glioblastoma (GBM), the most common primary brain tumour is dismal, at approximately 12-15 months. Hugely contributing to these shocking survival rates is the lack of alternative therapies when current treatment strategies fail. Despite intense effort to combat GBM with surgery, radiation and temozolomide (TMZ) chemotherapy, 90-95% of patients succumb to the disease within 5 years of diagnosis and nearly all patients experience disease recurrence, usually within 6-8 months of treatment onset. New and better treatments are urgently required. My group is interested in understanding and developing the potential of cyclin dependent kinase (CDK) inhibitors as a novel treatment option for GBM patients. CDKs are a family of enzymes first discovered as regulators of the cell cycle but are now understood to also have pivotal functions in the regulation of transcription, DNA repair and metastatic spread. As a result, there has been tremendous interest in the clinical applicability of CDK inhibitors as anti-cancer agents. Our interest in CDK inhibitors has originated from observations that R-roscovitine, a first generation CDK inhibitor was able to down-regulate the anti-apoptotic protein Mcl-1, in GBM cell lines. Such inhibition in turn sensitised resistant GBM cell lines to apoptosis-inducing agents. The aim of this project is to assess the therapeutic effects of a second-generation cyclin dependent kinase inhibitor, CYC065 in preclinical models of GBM. CYC065 is mechanistically similar to R-roscovitine, but with significantly improved potency and metabolic stability, giving it the propensity to be an even better therapeutic candidate.

This proposal will assess a novel therapeutic for the treatment of glioblastoma. The outcomes of this research have the potential to impact the lives of every GBM patient, in the long term, as it could improve their care with a novel treatment plan.

Project 3

‘3D collagen-based scaffolds as platforms for gene therapy delivery to breast cancer cells’

Supervisor: Dr Caroline Curtin, Dept of Anatomy.

Project summary:

Gene therapy is a potential method for cancer treatment but successful delivery remains a problem for its clinical use. This study aims to create a three-dimensional (3D) lab-based model of breast to mimic primary and secondary tumours, and to assess their ability when combined with gene delivery particles, as effective anticancer platforms. Traditionally, growth of cancer cells has used 2D tissue culture plastic but it lacks the 3D tumour shape. The alternative uses animal models but also has limitations. Recently, 3D cell growth has been proposed to bridge the gap between 2D cell growth and animal models as cells can respond naturally to the tumour environment. Scaffolds, made of natural materials including collagen, allow cell growth and are used as platforms to deliver genes for tissue engineering within our laboratory. We believe collagen scaffolds may act as 3D lab “tumours” that mimic primary tumours while collagen-nanohydroxyapatite scaffolds may be used to study secondary cancer tumours in bone (metastasis) as hydroxyapatite may be involved in the bone metastasis process. Early work by the academic sponsor has demonstrated successful gene delivery in collagen nanohydroxyapatite scaffolds mimicking prostate cancer bone metastasis so it is believed this model may also be used to successfully study gene delivery in a breast cancer model. Furthermore, these gene delivery scaffold-based models may be used for the development of new treatment targets for various cancers.

Project 4

‘On-demand delivery of DNA-origami nanodevices at precise timepoints’

Supervisor: Dr Cathal Kearney, Dept of Anatomy.

Project summary:

DNA origami is a technique where a long strand of DNA is folded by adding short strands of DNA that bind to select regions of the long strand and fold it. By adding the correct recipe of short strands the folding results in a precise nanoscale shape. These shapes are being designed to improve delivery of drugs into cells, to measure levels of specific markers in the body among other applications. One challenge for the DNA origami field is translating the devices designed in labs into the body as they are sensitive to the environment in the body.

The Kearney Lab designs local drug delivery devices (i.e., device capable of delivering drugs at a specific site in the body) that can respond to external signals that trigger the release of therapeutics. In this project, we will design a drug delivery device that will release DNA origami therapeutics at select timepoints.

Project 5

‘Validation of a novel method to measure the volume of blood platelets’

Supervisor: Dr. Ingmar Schoen, Dept of Molecular and Cellular Therapeutics.

Project summary:

Platelets are the smallest cells in the blood. When you cut your finger, platelets aggregate at the injury site to stop bleeding. If out of control, this process can give rise to thrombosis, causing e.g. stroke. A key clinical problem is to find properties of patients’ platelets that correlate with the risk for such cardiovascular events. Two routinely measured properties are platelet count (number of platelets per microliter of blood) and mean platelet volume (how large a platelet is on average). However, current instruments do not measure platelet volume directly, they rather calculate it in different ways, and models from different vendors give divergent results. A gold-standard technique to measure platelet volume is lacking. Moreover, platelet volume varies among the platelet population. A technique to assess subpopulations could be important to refine the role of platelets in thrombosis.

This project investigates a new approach to measure platelet volume. The aims are (i) to validate the volume measurement with micron-sized beads of known dimensions and (ii) to compare the effect of different platelet preparation procedures on measured volume. To this end, the student will use techniques related to blood separation, microfluidics, microscopy, image analysis, and statistics.

The Schoen Lab has a key interest in platelets, thrombosis and bleeding. To go beyond the state-of-the- art, we follow conceptionally novel approaches. Our particular strength is to adapt tools from physics to obtain a more holistic picture of platelet function and platelet mechanobiology.

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

Project 6

‘Understanding the impact of the Biomolecular Corona on nanomaterials’

Supervisor: Dr. Marco Monopoli, Dept. of Chemistry.

Project summary:

Recent advances in synthetic chemistry have enabled the large-scale production of materials of 100nm or smaller in diameter, called nanoparticles (NP) which possess exciting novel properties that have the potential to revolutionise medical treatments, especially in cancer pathologies. Because of their small size, they can directly interact with biomolecules , and their behaviour in biological milieu is not fully understood. One in biological fluids, NPs rapidly interact with biomolecules from the environment that strongly and rapidly bind to the NP surface forming the long-lived biomolecular corona. It is now unwell established that it is the corona, rather than the NP surface, that regulates the way the NP interact with cells and biological barriers while the pristine surface remains irreversibly covered and buried in this environment. This project will characterise the nanomaterial behaviour in biological fluid and will identify the biomolecules from the biological milieu that will be adsorbed on the nanoparticle surface and will understand how the NP surface properties will affect the biomolecular corona formation and composition.

Project 7

‘Defining the role of activated protein C receptors in protease-activated receptor 1 directed cell signalling’

Supervisor: Dr Roger Preston, Dept. of Molecular and Cellular Therapeutics.

Project summary:

Protease-activated receptor 1 (PAR1) is a G protein coupled-receptor expressed on the surface of endothelial cells and platelets. It has a critical role in maintaining vascular homeostasis and its dysregulated activation has been proposed to contribute to a range of cardiovascular and inflammatory diseases. Unusually, PARs become activated not when bound by ligands, but when cleaved by specific proteases. The blood protease activated protein C (APC) activates PAR1 to confer cell protection from inflammatory, pro-apoptotic or toxic stimuli. Despite its physiological importance, the molecular basis for how cytoprotective PAR1 signalling is achieved by APC remains poorly understood. An enhanced understanding of the molecular parameters that control PAR1 signalling by APC is important given the early promise of recombinant APC variants that promote PAR1 cytoprotective signalling for the treatment of inflammatory vascular disease.

The objective of this study is to define how different APC co-receptors enable cytoprotective PAR1 signalling by APC. Specifically, the project will compare the role of APC co-receptors in PAR1 activation and furthermore, determine whether APC receptor co-operativity further facilitates signalling efficacy. Ultimately, this will enable generation of new pharmacological strategies to facilitate preferential skewing of PAR1 signalling output for therapeutic benefit.

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 PAR1 signalling. The student will receive training and experience in a combination of state-of-the-art molecular biology and cell signalling techniques.

Project 8

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

Supervisor: Dr Shona Pfeiffer, Dept 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 9

‘Examining the role of long non-coding RNAs in regulating microcalcification in ductal carcinoma in situ (DCIS)’

Supervisors: Dr Sudipto Das and Dr Maria Morgan, Dept. of Molecular and Cellular Therapeutics.

Project summary:

Breast cancer is the most common cancer in women worldwide with incidence rates increasing and survival rates largely varying depending on early detection and treatment. Ductal carcinoma in situ (DCIS) is often regarded as a precursor to invasive breast cancer, which is often regulated by several genes which possibly control processes involved in development of common features associated with breast cancer such as microcalcification. One such class of genes known as long non-coding RNA (lncRNA) has been shown to control how certain classes of genes function across various diseases. Despite ongoing research in both lncRNAs and DCIS, very little is known about the exact role of these lncRNAs in modulating processes such as mineralisation in DCIS. The main aim of this study would be to examine if there are a certain class of lncRNAs which have been identified as being possibly involved in DCIS patients also may have a role in mineralisation commonly associated with DCIS. To study this, we will investigate the potential of DCIS cells to mineralise when grown in the laboratory. Once mineralisation conditions are established we will induce mineralisation in DCIS cells and examine the levels of these lncRNAs before and after mineralisation. Completion of this study, will not only allow us to test if DCIS cells undergo mineralisation but also for the first time provide an insight into a possible role of lncRNAs in DCIS mineralisation.

Project 10

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

Supervisor: Prof Tracy Robson, Dept. of Molecular and Cellular Therapeutics.

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 worrying, 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 FDA. 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 easily killed by chemotherapy. This project will assess the impact of FKBPL on 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.

Project 11

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

Supervisor: Dr Darran O’Connor, Dept. of Molecular and Cellular Therapeutics.

Project Summary:

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-BCL2 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.

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-BCL2 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 Dept. of Molecular & Cellular Therapeutics (https://www.researchgate.net/profile/Darran_Oconnor), is a young, vibrant and well-funded research group focused on the identification and mechanistic anchoring of novel cancer biomarkers and therapeutic targets.

Project 12 Development of a drug delivery system containing Allopurinol for loco-regional delivery to the heart post myocardial infarction

Supervisor: Dr Aamir Hameed, Dept. of Anatomy.

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.