Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn

Funding

Funded Research Programmes

The centre is actively involved in a number of programmes which are funded through a variety of sources:

Science Foundation Ireland

SFI Principal Investigator Programmes

  • BH3-Only Proteins and Cellular Bioenergetics in the Control of Neuronal Survival and Cell Death: Role in Ischaemic Injury and Neurodegeneration

Principal Investigator: Prof. Jochen Prehn and Dr. Heinrich Huber

Stroke and age-related brain disorders are leading causes of death and disability which, with increasing life expectancy in Ireland, impose a growing economic and societal burden. Current treatment regimes are limited in their effectiveness, partially due to a lack of understanding of why nerve cells die or survive during brain injury. This research programme tackles this important question by investigating a family of genes that mediate stress-induced cell death, and by addressing the role of reduced energy supply during brain injury. The programme involves an established collaboration with SIEMENS engineers who will bring essential computational approaches into this research programme that facilitate the analysis of biological networks, and accelerate the identification of new targets for future therapy. The research programme also allows for the development and dissemination of new, Irish born, technology by integrating the activities of LUXCEL Biosciences, a pioneer in oxygen sensing technologies, into the research programme. 

  • Characterisation of neuronal cell death signalling by in vivo imaging

Principal Investigator: Prof Nikolaus Plesnila

Stroke and traumatic brain injury are leading causes of death and disability in adults and children and impose a large economic and societal burden on Irish society. Current treatment strategies are limited in their effectiveness, mostly due to a lack of understanding of the mechanisms responsible for the death of neurones in the living brain. The research programme addresses this important question by developing and using a highly innovative and unique research tool which will allow us to investigate molecular mechanisms of neuronal cell death in the living brain. This will be achieved by generating transgenic mice which express fluorescent-labelled cell death proteins specifically in neurones (or other cellular compartments) and visualising these proteins by 2-photon laser scanning microscopy, a novel technology which allows the detection of fluorescent proteins deep in the living brain

  • Molecular determinants of seizure-induced neuronal death and epileptogenesis

Principal Investigator: Prof. David Henshall

Epilepsy is characterized by a predisposition to recurring seizures; uncontrolled bursts of electrical activity in the brain. It is highly disabling and affects 1 in 100 people in Ireland. Our group is engaged in efforts to understand the effects of seizures on the brain and in particular, learning about the cell and molecular mechanisms responsible for epilepsy and identifying ways to protect the brain. The studies in this proposal address both themes. First, we are using animal models of epilepsy to determine how increased levels of particular proteins known as 14-3-3 influence injury to the brain after a seizure. Second, we are exploring fundamental mechanisms regulating gene expression in the brain, the role of microRNAs, and how they may be de-regulated in epilepsy. We expect our studies will lead to a new understanding of how epilepsy develops and how we can protect patients' brains from potential harm caused by seizures.

  •  SFI UREKA Site - Summer Programme for Undergraduate Research On Neuroscience (SPUR-ON)

Principal Investigator: Prof. Jochen Prehn

The aim of SPUR-ON is to instil enthusiasm for neuroscience research in a new generation of potential scientific PhD students - both from Ireland and abroad.  Therefore, the main objective of the programme is to bring talented undergraduate students from around the world to RCSI and TCD and provide them with the opportunity to undertake cutting edge, interdisciplinary neuroscience research in world-class laboratories. In the laboratories, the students will gain first-hand knowledge of how research is undertaken, what it is like to be a scientist, and a wide range of experimental techniques. They will have the opportunity to interact on a regular basis with established and upcoming scientists and to explore novel ideas in a secure and nurturing environment. It is also important that the SPUR-ON students learn broader skills, which we hope to develop through discussion in Journal Clubs and Workshops. The objective in relation to the Mentors is to provide them with an additional laboratory member to undertake research for the summer. All the projects described in this document are part of ongoing research programmes and have the possibility of genuinely furthering the research of the laboratories. Mentors will also have the chance to work with, and influence, promising undergraduates who may be potential Ph.D. students. Overall, the objectives of SPUR-ON are to provide participating students with real-life research experience, to stimulate their interest in neuroscience and to instil enthusiasm for science and research.

Health Research Board

Health Research Awards:

  • Seizure control in drug-resistant epilepsy by targeting the purinergic P2X7 receptor

Principal Investigator: Prof. David Henshall

The brain's energy "currency" is the molecule ATP. For at least 30 years we have known that this molecule is also a neurotransmitter, capable of modifying communication between nerves throughout the body. One of the receptors on which this molecule acts - called P2X7 - has been found to be present at abnormally high levels in experimental epilepsy. The research will profile the levels of this receptor in pharmacoresistant epilepsy patients and use a pre-clinical model to thoroughly evaluate P2X7 blockers as potential antiepileptic drugs and neuroprotective agents after seizures. Our study should provide detailed understanding of how this receptor may influence seizures and epilepsy development and the possible benefits of drugs targeting its activity. In turn, these findings may translate to treatment options for people at risk of epilepsy development or disease progression.

  • HRB Scholars Programme: Diagnostics and Therapeutics for Human Disease

The aim of the HRB scholars programme is to improve the quality of PhD training in health research by facilitating a broader education for young researchers, and enhancing co-operation between post-graduate students in different research groups. The programme research areas are Cancer Biology, Molecular Medicine, Health Services Research, Neuroscience, Immunology and Diagnostics and Therapeutics for Human Disease. Within RCSI, The PhD Scholars Diagnostics and Therapeutics for Human Disease programme brings together the complementary skills of researchers from Royal College of Surgeons in Ireland, Beaumont Hospital and Dublin City University. There are 7 research themes in this programme, led by Principal Investigators of international standing. One of the themes, led by Prof Jochen Prehn is in Neuro/Psychiatric Disorders.

 

Health Executive Authority

  • National Biophotonics and Imaging Platform Ireland (NBIPI) a trans-institutional research infrastructure programme funded through the Irish Higher Education Authority (HEA) under Cycle 4 of the PRTLI programme

DP 3: Neuroscience:  Visualization and image analysis of neural injury, plasticity and repair 

Lead Investigator: Prof. David Henshall

Emerging data show neuronal microstructures and synaptic contacts are highly plastic, undergoing rapid or long-term adjustments in response to neuronal insults and in the setting of neuronal degeneration. This research programme will apply in vivo imaging tools to investigate responses to ischemic, traumatic and epileptic brain injury to elucidate contributions to chronic conditions such as epilepsy and neuroendocrine disorders. It will also investigate which changes contribute to long-term plasticity and repair during chronic pain and neurodegeneration. In a complementary research strand development and repair processes elicited by neural stem cells will be described ex vivo in real time, and mathematically modelled to determine how intrinsic and micro-environmental factors influence lineage decisions relevant to such repair processes. Using established organotypic  slice cultures in vitro and rodent models of cerebral ischemia, pain, trauma and seizures in vivo, this research programme will employ two-photon microscopy, intravital fluorescence microscopy and GFP reporter mice to capture and analyse images of degenerative and restructuring changes and intracellular metabolic and energetic responses in intact CNS structures and in 3 dimensions. These changes can then be contrasted with the human brain following seizures, pain, trauma and stroke in collaboration with the TCIN MRI facility of the BMSN network, and can identify processes that may be of therapeutic and diagnostic significance.

  • HEA PhD Scholars' Programme in BioAnalysis & Therapeutics (BioAT)

BioAT is a collaborative inter-institutional 4-year structured PhD programme funded by the HEA under Cycle 5 of the Programme for Research in Third-Level Institutions (PRTLI). It brings together the complementary expertise of researchers from the Royal College of Surgeons in Ireland, Dublin City University, National University of Ireland, Maynooth and Institute of Technology, Tallaght. Applications are now invited from students in the Biomedical, Chemical, Physical or Engineering Sciences currently holding or expecting a first or upper second class honours degree. The programme offers students a unique training and educational experience in basic and applied research, advanced technologies, and collaborative clinician-scientist research in hospital-based laboratories (Beaumont and Connolly Hospitals, and the Children's Research Centre at Crumlin Hospital).

European Commission

Seventh Framework Programme

Industry-Academia Partnerships and Pathways:

 

  • OXY-SENSE - A biosensor, image analysis, and work flow system platform for the study of neuronal injury and assessment of cellular bioenergetics.

Ischaemic stroke and neurodegenerative disorders are leading causes of death and disability worldwide and constitute a significant burden to patients and their families. Despite improvements in prevention and emergency treatments for stroke, current treatment regimes are limited in their effectiveness due to a lack of understanding of the development of the neuronal injury within the brain. This results at least in part from limitations in our understanding of why neurons die or survive after stroke. Likewise, for most fatal and progressive neurodegenerative disorders there currently is no cure, and only very limited treatment options exist that address the symptoms but not the cause of the disease. Therefore a need exists for more sensitive and specific sensors and biomarkers that are able to accelerate the discovery process and can be used in more complex test systems such as organotypic cultures and living animals. Finally, the majority of chemical compounds developed in the biotech and pharmaceutical industry fail to enter the clinical phase due to intrinsic toxicity of the compounds. Hence there is an urgent need in the pharmaceutical industry to develop more integrated, effective test systems for drug action and drug toxicity analyses, and to implement new quality assurance guidelines into the R&D process. 

For more information, please visit the website: www.oxy-sense.eu

 

  • MarieCurie Co-fund Scheme with HEA - Career Enhancement Mobility Programme (CEMP)

This is a postdoctoral fellowship programme which is co-funded by the EU FP7 MarieCurie Co-fund Scheme, the Irish Higher Education Authority Programme for Third Level Institutions Cycle 4 and the Italian National Research Council. Within the remit of NBIP, the CEMP funds and supports research fellows undertaking interdisciplinary research and training programmes in biophotonics and imaging applied to cancer, cardiovascular and neuro-degenerative diseases.

 

  • Marie Curie Actions-Intra-European Fellowships (IEF)

 

The Diabetic Brain

Principal Investigators: Prof. Jochen Prehn and Dr. Antonio Gonzalez

Type 2 diabetes is one of the most common chronic diseases in the world, and the number of those affected has been rising dramatically in recent years. In type 2 diabetes the body fails to produce and use insulin effectively, which leads to the chronic increase in blood glucose that characterises the disease. It is not known how the body becomes resistant to insulin, but recent evidence suggests that an imbalance between energy intake, storage, and expenditure can lead to obesity and eventually to the development of insulin resistance. Thus, to gain insight into the origins of diabetes it is crucial to understand how the body senses its metabolic status, and how it integrates that information to effectively achieve energy homeostasis.

Aim: The overall aim of this project is to understand the mechanisms that are used by specific neurones in the lateral hypothalamus to sense changes in extracellular nutrients, and to find whether a failure in these mechanisms may be a fundamental component in the pathophysiology of metabolic diseases.

 

  • Single Cell Imaging of Gene Activation during Oxidative Neuron Death: Towards Quantitative Systems Approaches

 

Principal Investigators: Prof. Jochen Prehn and Dr. David Davila De Leon

Like many other stress stimuli, oxidative stress can activate a set of cell signaling and gene expression pathways. Importantly, these can activate defensive, cytoprotective pathways, but also injury- and cell death-inducing pathways. In the case of oxidative stress, cytoprotective pathways include the activation of the transcription factor Nrf2, which increases the transcription of anti-oxidant genes that have an Antioxidant Response Element (ARE) in their promoter region. Another important cytoprotective pathway represents the activation of the transcription factor HSF-1, which induces the transcription of cytoprotective chaperones such as Hsp70 and Hsp27 that prevent the accumulation of non-functional, misfolded, or toxic proteins and trigger their degradation. Cell injury or death may result when oxidative stress is severe and not overcome by these mechanisms, when cells are intrinsically sensitive to ROS, and/or when additional signalling pathways are being activated. Here, the activation of transcription factors FOXO3 and p53, and the subsequent activation of conserved cell death programmes in particular apoptosis have been increasingly implicated. One of the major challenges in furthering our understanding of the pathophysiology of oxidative neuronal injury during acute or chronic insults to the nervous system is therefore, (i) to explore which stress pathways contribute to the cytoprotective vs. cell death-inducing responses, (ii) which molecular switches determine the different biological outcomes (e.g. death or tolerance), (iii) how different stress signaling pathways co-operate or oppose each other, and (iv) whether cell-type specific differences in the activation of these pathways exist. 

Sixth Framework Programme:

 

  • Marie Curie Transfer of Knowledge Programme -Systems proteomics to implement neuroscience (SPIN)

 

Principal Investigator: Prof. Jochen Prehn

Through technology investment, the RCSI has evolved as the leading Irish institution in proteomics and supporting bioinformatics. RCSI has likewise built a critical mass of leading experts in the pathogenesis of brain injury that are able to model neurological diseases in vitro and in vivo (Neuroscience Team). The transfer of knowledge (TOK) mechanism was used to integrate these programmes by expanding and acquiring competence in systems proteomics and protein/gene manipulation strategies. A ToK Team was assembled to define novel therapeutic target structures, and to develop and deliver gene/protein manipulation strategies that will impact brain injury outcome and will test and refine hypotheses.

Enterprise Ireland

Technology Development Award

Systemic delivery of angiogenin protein for the treatment of ALS: Therapeutic modulation of angiogenin levels in the spinal cord

Principal Investigator: Prof. Jochen Prehn

We aim to develop a technology for the systemic delivery of angiogenin protein or a variant thereof to therapeutically modulate angiogenin levels in the spinal cord and to delay disease progression and increase survival in patients suffering from motoneuron degeneration. This technology is based on the identification of loss-of-function mutations of the angiogenin gene in patients with amyotrophic lateral sclerosis (ALS) (Greenway et al., Nat Genetics, 2006 ), and our proof-of-concept demonstration of the neuroprotective and disease-delaying effect of systemic angiogenin protein delivery in a mouse model of ALS (Kieran et al., J Neurosci, 2008). We aim to achieve a comprehensive pre-clinical description of the effect of systemic angiogenin protein delivery in an in vivo model of motoneuron degeneration required for regulatory approval and further commercialisation

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