1. Project Title: ASIC channel blockers; a potential target in the treatment of ALS Mentors: Dr. Áine Behan and Prof. Jochen Prehn, Department of Physiology and Medical Physics, RCSI. Proposed Project:
Motoneuron degeneration and neurodegeneration in ALS are being increasingly linked to
mitochondrial dysfunction and metabolic alterations (Adhihetty and Beal, 2008; Browne et al., 2006; Cassina et al., 2008), due to excessive neuronal Ca2+ influx, axonal transport defects, and accumulation of protein aggregates. Previous work published by our group has demonstrated the involvement of Ca2+ overloading, ATP depletion, and metabolic alterations favouring lactacidosis during Ca2+-mediated neuronal injury (Concannon et al., 2010; Ward et al., 2007; Weisova et al., 2009). In one of these studies, we also suggested the presence of a local hypoxic/ischemic environment in the spinal cords of animal model of ALS (Kieran et al., 2008). Related studies using a Neutral Red assay suggested prominent tissue acidosis in ALS mice during disease progression (unpublished data), in line with earlier observations (Adhihetty and Beal, 2008; Browne et al., 2006; Cassina et al., 2008). Therefore, metabolic acidosis may occur in the spinal cord of an ALS patient as a result of excessive Ca2+ overloading, metabolic impairment or in response to a local hypoxic/ischemic environment.
Acid-sensing ion channels (ASICs), a family of amiloride-sensitive cation channels, play
an important role in facilitating excitatory synaptic transmission (Wemmie et al., 2002), nociception (Bevan and Yeats, 1991) and activate during ischemia and hypoxia where they may cause cell death through significant Ca+ and Na+ influx (Chu et al., 2002; Varming, 1999; Xiong et al., 2004). It has been speculated that local acidosis associated with seizures and ischemia could trigger the activity of these ASIC channels (Varming, 1999). Additionally, recent studies by our group have confirmed that treatment with a specific ASIC channel blocker significantly increased lifespan and motor performance in the SODG93A mouse, an animal model of ALS.
In this SPUR-ON project, we propose to further examine the role of ASIC channel
blockers on motoneuron survival in the spinal cord of the TDP-43 mouse, a second mouse model of ALS. ASIC channel expression in the TDP-43 mouse will be assessed by qPCR and immunohistochemical staining of the ASIC channel mRNA and protein respectively in the spinal cord. The effect of acidosis on motoneuron survival in the spinal cord will be assessed by counting the number of motoneurons in the lumbar spinal cord at 117 days. Role of the Student and Benefit to Student:
The student will work with the mentor to assess motor performance and lifespan analysis
in the TDP-43 mouse. The student will learn the following molecular biology techniques, tissue cryosectioning, Western blotting, immunostaining, qPCR and cell counting.
The student will attend the fortnightly ALS group meeting as well as partaking in the
weekly departmental progress reports. The student will be trained up by Áine Behan and the ALS group on all the aforementioned techniques and will also engage in one-to-one meetings with the mentor of the project, Áine Behan. Finally, the student will give a public presentation to all SPURS participants/college summarising the research carried out over the ten weeks at the end of the SPURs placement. How the Project fits into the Overall Research Objectives of the Host Group:
The ALS group within the Physiology are actively involved in generating pre-clinical data
on the effects in vivo and in vitro of several compounds, including amiloride (and derivatives thereof), and their activity on ASIC channels in several mouse model of ALS. 2. Project Title: Characterisation of the neuronal function of a novel brain enriched protein. Mentors: Dr. Aisling Dunne and Prof. Marina Lynch, Department of Physiology, Trinity College Institute of Neuroscience. Proposed Project: Toll-like receptors (TLRs) are a family of germline-encoded receptors involved in the innate sensing of pathogen-associated molecular patterns and endogenous ‘danger’ associated molecules. TLR4, originally identified as the receptor for endotoxin, has been extensively characterised and functions together with a number of accessory molecules to drive pro- inflammatory cytokine production. We have recently identified a novel component of the TLR4 signalling pathway named TRIL (TLR4 Interactor with Leucine Rich Repeats). The protein is expressed at high levels in the brain and spinal cord and expression is enhanced following stimulation with LPS. In addition, TRIL interacts with both TLR4 and LPS while silencing of the gene abrogates pro-inflammatory cytokine production suggesting that TRIL functions as a component of the TLR4 receptor complex. We have also detected expression of TRIL on neurons and have observed a very significant structural homology between TRIL and members of the Nogo receptor (NgR) and Lingo family of proteins which are known to inhibit neurite outgrowth and promote demyelination. TRIL may therefore represent a novel target for the treatment of diseases such as multiple sclerosis and Parkinson’s disease. This project will address the following questions:
1. Does TRIL interact with members of the NgR complex? 2. Does TRIL interact with NgR ligands?3. Is TRIL involved in the inhibition of neurite outgrowth?
Co-localization and protein-protein interaction studies will be performed on order to determine if TRIL interacts with any member of the NgR receptor complex or the inhibitory myelin components which act as ligands for this complex. Neurite outgrowth will also be assessed in response to these inhibitors by comparing TRIL deficient neurons to wild-type neurons. siRNA knockdown of TRIL will also be performed in neuronal cell lines in order to assess responses to neurite outgrowth inhibitors. Reference: Carpenter, S, Carlson, T., Garcia, A., Hertzog, PJ., Lyons, A.N., Lynch, M., Monie, T., Seidl, K., Dunne, A and O’Neill, L.A. Toll-like receptor (TLR) 4 Interactor with Leucine-rich repeats (TRIL) is an essential component of the TLR4 signalling complex highly expressed in brain. (2009) J. Immunol. 183:3989-95. 3. Project Title: Neuroimaging in adolescents at risk of psychosis Mentors: Professor Mary Cannon (RCSI) and Professor Thomas Frodl (TCD), Department of Psychiatry, RCSI and the Department of Psychiatry, Trinity College Dublin. Proposed Project: Children and adolescents who experience psychotic symptoms are known to be at increased risk for psychosis later in life. As such they represent a novel “high-risk” group for psychosis and will give new insights into the etiopathophysiology of psychosis (Kelleher and Cannon, 2011). This project involves investigating structural and functional connectivity in the brains of adolescents who experience such symptoms compared with those who do not experience such symptoms. These adolescents have been recruited from local schools. They have already undergone a full clinical interview and neuropsychological testing at Beaumont Hospital as part of a HRB funded study. Imaging will be carried out at the Trinity College Institute of Neuroscience (TCIN) in Dublin under the supervision of Professor Thomas Frodl, Director of Functional Imaging at TCIN. Each scan will last for about 50 minutes comprising a (1) A high resolution structural MRI scan (approx 15 mins) and (2) A Diffusion Tensor Imaging scan (approx 20 minutes) and a resting state functional MRI (approx. 10 minutes). Diffusion Tensor Imaging (DTI) is a magnetic resonance imaging (MRI) method, which is designed to study structures in white matter such as myelin sheaths and axon membranes.Resting state functional MRI allows to explore functional connectivity in brain thought to be altered in schizophrenia. Role of the Student and Benefit to Student: The student will co-ordinate the scans and stay with the subject during each scan. He or she will liaise with the radiologist regarding the scan methodology and quality. The student will learn to carry out preprocessing and analyses methods on the scans . He/she will fit into a larger team of Professor Cannon and Professor Frodl involved in the Adolescent Brain Development Study. The student will attend research talks in both RCSI and TCD and will be encouraged to learn from the other members of the team and about other research that is talking place in both institutions. How the Project fits into the Overall Research Objectives of the Host Group: The project will be an important part of the overall follow-up study of adolescents who experience psychotic symptoms which is taking place over the summer months and will be continuing into the next few years. Imaging will be a key part of this project which also comprises clinical interview, neuropsychology and electrophysiology
Reference: Kelleher I., Cannon M. Psychotic-like experiences in the general population: characterizing a new high-risk group for psychosis. Psychological Medicine, 2011 (e pub ahead of print)
4. Project Title: The application of genetic HLA tests as pharmacogenomic predictors of hypersentivity reactions in epilepsy patients. Mentor: Dr. Gianpiero Cavalleri, Dr. Norman Delanty, Dept. Molecular and Cellular Therapeutics, RCSI. Proposed Project: Carbamazepine is the most commonly prescribed anti-epileptic drug. However, in some cases, exposure to the drug causes various forms of adverse hypersensitivity reactions ranging from a mild rash to severe blistering reactions that can be life threatening. Through the application of genome-wide association mapping, our lab has identified a genetic marker that predicts which patients are predisposed to hypersensitivity to carbamazapine, thus offering the potential to tailor treatment based on the genetic profile of the patient. This project will explore the potential of the test as a predictor of hypersensitivity to other anti-epileptic drugs with similar chemical structure and adverse reaction profiles. Role of the Student and Benefit to Student: This is a translational research project involving a combination of lab-based research, computer- based analysis and clinical profilling of patient response to anti-epileptic drug treatment. Working alongside a member of our research team, the student will run HLA genotyping in the lab, handle and analyse genome-wide association data and correlate resulting genetic profiles with adverse reactions in patient groups. The student will learn the basic principals of population genetics and genetic mapping. This project is a fantastic opportunity for a student interested in learning more about human genetic diversity and how this diversity can be used to predict patient response to pharmaceutical treatment. How the Project fits into the Overall Research Objectives of the Host Group: The focus of our lab is genetic mapping – correlating genetic profiles with the development and treatment of complex human diseases including epilepsy and renal failure. We apply combinations of genome-side association and complete genome sequencing to generate genetic profiles of patient and control groups. We use the resulting datasets to map key genetic variants that are important in human disease. For epilepsy we work closely with clinical teams at Beaumont Hospital explore ways in which findings can one day be translated to improved care of patients with this condition. 5. Project Title: Stereological Analysis of Interstitial White Matter Neurons in the Inferior Parietal Lobe in Schizophrenia. Mentor: Dr. Melanie Föcking, Magdalena Hryniewiecka, Prof. David Cotter, Department of Psychiatry, RCSI Proposed Project: Schizophrenia is a severe psychiatric illness, affecting approximately 1% of the population. The pathophysiology of schizophrenia is very complex. Extensive studies point to reduced volume of the prefrontal cortex and the anterior cingulate cortex; alterations in cortical neuronal and glial counts and somal size, an excess in interstitial white matter neurons (IWMN) and reduced density of populations of inhibitory interneurons. Despite this evidence the pathophysiology of schizophrenia still remains unclear. However, IWMN changes support the evidence for a developmental basis to the disorder.
The aim of the proposed project is to assess the total counts and density of IWMN as well
as inhibitory interneurons, which are subpopulations of the IWMN, in the white matter of the Inferior Parietal Lobe (IPL) in schizophrenia. Moreover, the density of those interneurons in the grey matter of the IPL will be assessed in order to show the relationship between increased density of IWMN and density of inhibitory interneurons in grey matter of the IPL.
The densities of IWMN and inhibitory interneurons will be assessed on human post-
mortem tissue using NeuN as a neuronal marker for matured neurons and markers for inhibitory interneurons such as glutamate decarboxylase (GAD67), somatostatin (SST) or neuropeptide Y (NPY). In order to assess total neuronal counts and the density, two dimensional counting using stereological devices will be involved. Role of the Student and Benefit to Student:
The student will undertake the preliminary investigation in order to optimize the methods e.g. testing the antibodies in different concentrations at different time points and temperatures in order to determine the best possible way of handling those tissue samples. The student will be involved in all steps of immunohistochemistry involving processing the tissue, as well as using a microscope with stereology devices to assess the densities of inhibitory interneurons.
Moreover, the student will get experience in literature searches and in writing and
Consequently, the student will get an excellent background for further theoretical and
practical studies together with a good understanding of an emerging and accelerating scientific field. How the Project fits into the Overall Research Objectives of the Host Group.
The host group has undertaken a number of stereological and immunohistochemical studies in different areas of the human brain, providing valuable insights into psychotic diseases including schizophrenia over recent years. This study promises to be an exciting and productive investigation in human brain research. The IPL has been under investigated. However, it isstrongly implicated in schizophrenia. Therefore this study will broaden our knowledge of the field providing information that might have good impact on further investigation for future diagnosis and treatment of schizophrenia. 6. Project Title: TGF-beta receptors in glioblastoma and neural stem cell proliferation, invasiveness and multi-drug resistance. Mentor: Dr. Hans-Georg Koenig, Lecturer in Physiology & Medical Physics Proposed research project Glioblastoma is the most common intrinsic malignant brain tumour characterized by highly aggressive and strong infiltrative growth sustained from cancer stem cells. This behaviour contributes to their devastating lethality rates. In addition, cancer stem cells express drug transporters that make them resistant to many chemotherapy agents. Cytokines of the transforming growth factor (TGF-βs) family are implicated in proliferation, invasion and apoptosis of tumour cells, but also essential in neuronal survival. In a recent study we had demonstrated the expression of an alternative receptor for the TGF-s in the CNS: Activin-like kinase 1 (ALK1) and the canonical ALK5 were expressed in neurons and participated in TGF-β-induced NF-κB activation and survival signaling. Additionally, an essential role for this cytokine in the generation of axons is described. Interestingly, our research revealed that the ALK1 and ALK5 receptor are also expressed in undifferentiated stem cells of the central nervous system and a number of cell lines derived from glioblastoma multiforme tumor cells. Hence, in this research project we will set out to investigate the correlation between ALK1 and ALK5 expression in glioblastoma and neural precursor cells and their proliferative and invasive behavior and compare it to their role in primary neurons. We will use assays of proliferation, invasion and sphere formation and perform analyses of the expression of certain relevant potential target genes downstream of the activation of ALK1 using overexpression and knock-down technologies (siRNA). Among the potentially TGF-β-induced genes is also a member of the so-called multi-drug resistance genes that mediates the unwanted clearance of anti-cancer drugs from tumour cells. So far the role of the ALK1-receptor in neural precursor and glioblastoma cancer cells remains elusive, although strong evidence suggest important roles for cytokines of the TGF-β family in the progression of these types of tumours. A clear elaboration of the pathways involved in TGF-β signalling might help to develop rational strategies to interfere with the proliferation and the destructive effects of its high invasiveness. Benefits to the student/role of student The student will learn some fundamental methods employed in contemporary biomedical research laboratories, and some specialized cell culture techniques in neuroscience (neurospheres). Methods applied in this project will include transfection of plasmid vectors into cell cultures, standard biochemical and molecular biology procedures (PCR and Western-blot), as well as assays of proliferation and invasiveness. Further benefit will arise from an introduction into the logical process of scientific discovery. The student will mainly be instructed by Dr. Hans-Georg Koenig, covering practical instructions and the theoretical implications of the project, the student will also be encouraged to participate in the weekly group meetings within the Physiology department. How project fits into overall research objectives of the group Our group has focused on the signaling mechanisms of neuronal survival and cell death for the last couple of years. Apart from TGF-β signalling pathways, a major part of our research has been conducted on neural pathways converging on NF-κB. Both proteins play major roles in neuronal survival, but also in tumor growth and invasiveness. This project will hence serve us to better understand the complex roles performed by TGF-βs in the central nervous system in tissue development, homeostasis and disease for the development of novel rational drug therapy strategies. 7. Project Title: Cell death in malignant brain tumours Mentor: Dr Brona Murphy, Dept. Physiology and Medical Physics, RCSI. Proposed Project: Gliomas are the most common and malignant brain tumours in humans. Conventional treatments for malignant gliomas, radiation and chemotherapy protocols, are severely hindered by the high resistance of malignant gliomas to apoptotic death. Experimental strategies designed to induce apoptosis in malignant gliomas have important implications for the development of novel therapies.
Mitochondria are a critical point of apoptosis control upon which a variety of cell death-
promoting signals converge including the Bcl-2 family. Individual members of the Bcl-2 family can be classified as pro- or anti-apoptotic. Mcl-1 is one of the anti-apoptotic proteins of the Bcl-2 family and is primarily localised to the outer mitochondrial membrane. Results in our laboratory have shown that higher Mcl-1 expression correlated with shorter progression free survival in glioma patients.
The aim of this project is to determine how the altering the levels of Mcl-1 in glioma cell
lines subsequently effects the cell’s ability to undergo apoptosis upon stimulation with therapeutic agents. In addition the cell death (or survival) signalling pathways involved will be investigated. Role of the Student and Benefit to Student: 1. Develop an understanding of the treatment strategies for malignant brain tumours. 2. Culture glioma cells lines, assess the expression of Mcl-1 and subsequently down-
regulate these levels using siRNA-mediated technology. 3. Investigate the effects of such down-regulation of Mcl-1 expression upon subsequent 4. Identify the key signalling pathways involved. 5. Attain competence in the search and critical analysis of relevant literature 6. Gain the ability to work independently and effectively direct own learning. 7. Learn effective written and oral presentation skills.
The student will join a small active research team and will have the opportunity to interact with and learn from the team on a daily basis. How the Project fits into the Overall Research Objectives of the Host Group: We are currently examining the activation of cell death pathways in malignant brain tumours. We are employing both molecular and translational techniques to tease out the networks. The proposed student will join a post-doctoral research fellow and a PhD student in examining the role of Mcl-1 in this regard. This short project will form an important part of the study, results of which will be used to better understand the cell death phenotype. 8. Project Title: The effect of intravenous minocycline administration following experimental subarachnoid hemorrhage in mice Mentor: Prof Nikolaus Plesnila, Department of Neurodegeneration, RCSI. Proposed project Minocycline is a is a broad spectrum tetracycline antibiotic; recent research has shown that minocycline has possible neuroprotective and anti-inflammatory effects in some neurodegenerative disorders (such as Parkinson’s disease and rheumatoid arthritis). Subarachnoid hemorrhage (SAH) is one of the most common and severe causes of hemorrhagic stroke, with an overall mortality of about 50%, and over 30% of its survivors remaining severely disabled.
The aim of the current research project is to determine whether minocycline improves
outcome in SAH. SAH will be induced in mice by the endovascular puncture method (9-10) as previously described in the laboratory. The endovascular occlusion lasted less than 5 minutes in each animal. Regional cerebral blood flow and intra-cranial pressure will be monitored continuously throughout the experiment.
How project fits into the overall research objectives Prof. Plesnila’s team has a strong expertise in the investigation of acute and subacute brain damage following traumatic brain injury, stroke and subarachnoid haemorrhage by using state-of- the-art in vivo imaging technology, pharmacology, and molecular biology techniques. Role and benefit to the student The student will be actively involved in performing the following assessments:
1) 7-day post-SAH, the brain will be perfused and removed from the skull and cryosections
prepared. Brain slices will be stained with Nissl stain, and morphological brain damage will be quantified by neuronal cell counts in the hippocampus.
2) Brain edema formation will be assessed 24h after SAH. The brains will be removed and
the hemispheres will be separated and weighed to assess their wet weight before being dried to determine the dry weight. Hemispheric water content (%) will be calculated.
3) Body weight will be determined before SAH and on postoperative days 1-7 inclusive. 4) Neurological deficits will be quantified on post-operative days 1, 3 and 7 using a
modification of an established neuroscore; evaluating general behaviour and respiration, cranial nerve function, sensitivity to tactile stimuli, motor function and coordination.
9. Project Title: Craniofacial dysmorphology: developmental biology and image analysis Mentor: Prof. John Waddington, Department of Molecular and Cellular Therapeutics (MCT), RCSI. Proposed Project: The Face3D consortium [www.face3d.ac.uk] is an international collaborative network funded by the Wellcome Trust. It is studying craniofacial dysmorphology at three levels: (i) how to better capture dysmorphology, using both 3D laser surface imaging and stereophotogrammetry; (ii) how to extract 3D craniofacial information using both manual landmarking and automated computer vision techniques; and (iii) how to analyse resultant data statistically, using geometric morphometrics, so as to inform on clinical dysmorphologies. Its two main areas of clinical application are: (a) psychotic illness, primarily schizophrenia and bipolar disorder, where craniofacial dysmorphogenesis is an important, quantitative index of brain dysmorphogenesis [see Hennessy RJ et al, Biol Psychiatry 2007;61:1187-1194 & Schizophr Res 2010;122:63-71]; and (b) reconstructive surgery for cleft lip/palate, where an important challenge is quantification of the extent to which surgical outcome approaches ‘normal’ craniofacies. The Face3D consortium involves the University of Glasgow, RCSI and DCU, together with additional collaborators. Role of the Student and Benefit to Student: The student will join the Face3D consortium in RCSI to carry out work comparing manual landmarking of craniofacial anatomy with automated landmarking via computer vision techniques. He/she will be (i) taught how to identify and designate individual craniofacial landmarks on 3D surface images, and (ii) carry out these procedures on a dataset of 3D craniofacial surface images from patients with psychotic illness and matched control subjects; the landmarked dataset will then be subjected to geometric morphometric analysis.
The student will learn about craniofacial anatomy and dysmorphology and acquire skills in
computer vision techniques relating to 3D surface imaging and anthropometric landmarking; he/she will understand the developmental biology of craniofacial dysmorphologies, the pathobiology of psychotic illness and aspects of craniofacial reconstructive surgery. The student will be encouraged to present his/her findings at local, national and international meetings and will be an author on any resultant publication(s).
The student will join the RCSI arm of the Face3D consortium and be taught the necessary
techniques by an expert Research Fellow; to faciliate training, he/she will visit both the DCU and University of Glasgow arms of the Face3D consortium and have access to all of the collective resources of the consortium. Supervision of the student will be provided by the Mentor, Prof. John Waddington, and Face3D Research Fellows Dr. Stanislav Katina and Dr. Federico Sukno. How the Project fits into the Overall Research Objectives of the Host Group
The Face3D consortium has an established reputation in the area of craniofacial
dysmorphology. It has collected, and continues to collect, several datasets that are now entering analysis. This project will provide the consortium with additional capacity to process and analyse clinical data and provide the student with a rich learning experience that includes craniofacial anatomy, dysmorphology, image analysis and psychotic illness. 10. Project Title: Formulation and evaluation of modified nanoparticles for delivery to the CNS Mentors: Dr. Brian Kirby and Dr. Zeibun Ramtoola, School of Pharmacy, RCSI. Background: Central nervous system (CNS) delivery and subsequent treatment of CNS disorders is a significant challenge due to the difficulty in facilitating drug transport across the blood-brain barrier. Different methods have been studied in an effort to improve drug delivery to this area. Nanoparticulate drug delivery systems have important applications in the area of controlled release and for the targeted delivery of therapeutic agents, including peptides, proteins, antigens and DNA. Our group within the School of Pharmacy has considerable expertise in the formulation of particulate technologies for application to controlled and targeted delivery, particularly to the central nervous system. These techniques may provide advantages over conventional delivery methods due to increased protection of the therapeutic agent, greater control of drug release and the potential to improve delivery to the active site. Our group has demonstrated that nanoparticle properties such as size and surface charge can influence uptake of these particles in vitro cell monolayers and in vivo preclinical models in particular for targeting to the CNS. Project: The aim of this project is to formulate and characterise surface-modified biodegradable poly-lactide-co-glycolide (PLGA) nanoparticles containing the drug loperamide, an opiod agonist which normally does not cross the blood brain barrier using RCSI’s nanoencapsulation technologies. Surface modification will be carried out using putrescine, one of the naturally occurring polyamines, shown to increase central delivery of proteins. Particles formulated will be characterised in vitro for their particle size characteristics using a photon correlation spectroscopy (PCS), their morphology using a scanning electron microscopy (SEM). The particles will be assayed for loperamide content and the release of drug from the particles will be studied in simulated physiological media. Nanoparticle formulations will be administered to a mouse model and evaluated for delivery of loperamide to the brain. Plan of Investigation: Weeks 1&2: Literature review and training on formulation of nanoparticles & in vitro characterisation techniques Weeks 3-6: - Formulation and characterisation of PLGA and putrescine-modified PLGA nanoparticles using Zetasizer, FTIR and SEM. Analysis of the loperamide content and release from nanoparticles will be analysed by UV spectroscopy Data analysis and review. Weeks 7-9: In vivo evaluation of delivery of loperamide from the nanoparticles to the brain using the hot plate nociception mouse model. Week 10: Data compilation and review. Preparation of abstract, research paper and presentation slides. Benefit to the student: The student will form part of the current research group and will have the support of the technical staff and post doctoral scientists on the project. The student will be trained in appropriate procedures and characterisation techniques which he/she will be using and will be encouraged to present and discuss, at meetings, any project data generated, with other members of the group.
1. M. Dunne, O.I. Corrigan and Z. Ramtoola (2000). Influence of particle size and dissolution
conditions on the degradation properties of polylactide-co-glycolide particles.Biomaterials, 21 (16), 1659-68.
2. Ramtoola, Z., Lyons, P., Keohane, K., Kerrigan, S.W., Kirby, B.P., Kelly, JG. (2011)
Investigation of the interaction of biodegradable micro- and nanoparticulate drug delivery systems with platelets. J. Pharm. Pharmacol. 63, 26-32
11. Project Title: Neuroprotective properties of environmental enrichment: the role of morphological changes. Mentor: Dr Áine Kelly, Department of Physiology & Trinity College Institute of Neuroscience, TCD. Proposed Project: Age-related cognitive decline, although not pathological, can cause loss of memory and other cognitive functions that reduce the quality of an individual’s life. Morphological changes such as neuronal and synaptic loss may be responsible, at least in part, for such decline. Magnetic Resonance Imaging (MRI) is a useful non-invasive technique to measure morphological changes in the brain, and current research indicates that changes in brain structure and cerebral blood flow that occur during ageing are measurable using specific MRI techniques. Other structural changes can be assessed at the microscopic level using immunohistochemical analysis. For example, synaptic loss and synaptogenesis can be assessed by analysis of the expression of synaptic vesicle proteins such as synaptophysin and synapsin.
It is widely recognised that simple lifestyle factors such as exercise or cognitive stimulation (in animal models, termed environmental enrichment), are potentially powerful neuroprotective factors. Evidence suggests that structural brain changes in elderly humans and associated memory improvements can be induced through cognitive stimulation. In our laboratory, we use animal models to examine the biological mechanisms underlying such events. Our data indicate that aged rats that have been housed in a standard laboratory environment are cognitively impaired when compared with aged rats that have been housed in a cognitively stimulating, enriched environment. We hypothesise that morphological differences in the brains of both groups may underlie, at least in part, this difference in cognitive ability. In this project, the student will assess brain sections from each group for expression of synaptic vesicle proteins in the hippocampus as an indication of synaptic loss. In parallel, the student will assess MRI scans that have been performed on these animals and will measure grey matter volume as an indication of cell shrinkage or loss. Role of the Student and Benefit to Student: The student will join our laboratory to work on an existing project and will learn specific research techniques including immunohistochemistry, microscopy and analysis of MRI scans. The student will be supervised closely day-to-day by the PhD student who generated the MRI scan images and tissue sections. He/she will participate in our weekly lab meetings and journal clubs and will become a key lab member during his/her time in our laboratory. How the Project fits into the Overall Research Objectives of the Host Group: Our overall research objective is to investigate the cellular mechanisms underlying age-related changes in hippocampus-dependent learning and memory, and to identify strategies to prevent this decline. The data generated by the student will add greatly to our understanding of the mechanisms by which environmental enrichment can induce the profound neuroprotection that we have observed. 12. Project Title: Enhancement of central noradrenergic tone as a novel strategy to combat age-related neuroinflammation and synaptic dysfunction Mentor: Professor Thomas Connor, School of Medicine & Trinity College Institute of Neuroscience, Trinity College Dublin. Proposed Project: Considerable evidence supports the idea that microglial activation and neuroinflammation contribute to the neurodegenerative process in chronic neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease, and also contributes to age-related synaptic dysfunction and cognitive decline. Thus pharmacological strategies that inhibit microglial activation and production of neurotoxic inflammatory mediators represent an attractive therapeutic target in combating neurodegeneration and age-related neuroinflammation and cognitive dysfunction. Considering the endogenous anti-inflammatory actions of the neurotransmitter noradrenaline, in this proposal we addresses the hypothesis pharmacological enhancement of noradrenaline availability in the CNS will inhibit neuroinflammation and synaptic dysfunction in the aged rat. Specifically, we will determine if treatment with noradrenaline reuptake inhibitor (NRI) reboxetine can prevent neuroinflammation and synaptic dysfunction in aged rats. Role of the Student and Benefit to Student: During the course of this research project the student will develop skills in hypothesis based biomedical research, and make the experience a launching pad for a research career. Under the supervision of a post-doctoral fellow the student will learn key laboratory techniques including immunoassay, Western immunoblotting and Real time PCR, and apply these techniques to studying the ability of noradrenaline reuptake inhibitor treatment to combat age-related neuroinflammation and synaptic dysfunction in an animal model. During his/her time in my laboratory the student will receive instruction in experimental design, data handling and statistical analysis, scientific report writing, and will be required to present an oral communication at the end of the research project. The student will participate in weekly laboratory meetings where progress will be monitored, and objectives for the following week will be outlined. How the Project fits into the Overall Research Objectives of the Host Group: The host group has already demonstrated that noradrenaline, and noradrenaline reuptake inhibitors inhibit experimentally-induced neuroinflammation both in vitro and in vivo. This project advances this research by determining whether the ability of noradrenergic enhancement strategies to elicit anti-inflammatory effects in the brain translates into beneficial effects in an animal model of aging.
Pharmaceutical antidepressants are designed to alter the body's biochemistry, for example to increase levels of neurotransmitters such as serotonin that helps keep us happy, or adrenalin/noradrenalin that helps keep us motivated. But brain health and neurotransmitter production can also be improved in other ways. A herbalist can prescribe a mixture of herbs from a wide range of plants that are k
Ruth L. Hillelson, M.D., F.A.C.S. Curriculum VitaePage 1 RUTH LEANNA HILLELSON, M.D., F.A.C.S. PERSONAL Married (Terry L. Whipple, M.D., F.A.C.S.)9900 Independence Park DriveRichmond, Virginia 23233(804)290 0060 EDUCATION College of Medicine, University of Vermont 1975 1977Top one third of classHarvard Medical School 1977 19791978 Children’s Hospital Medical Center1979 Peter Bent Bri