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Improvement of the research competitiveness in neuroscience at the Ernst Moritz Arndt University of Greifswald

Final Report Summary - IMPACTG (Improvement of the research competitiveness in neuroscience at the Ernst Moritz Arndt University of Greifswald)


Executive Summary:

4.1.1 Executive summary

Neuroscience is the fastest growing area in basic scientific research. Neuroscience is an interdisciplinary field designed to improve our understanding of neural communication mechanisms in health and disease. Treatments, cures, and, above all, knowledge are the possibilities that continue to be discovered through neuroscientific research. The Neuroscience Group at the Medical Faculty of the University of Greifswald promotes interdisciplinary investigations from the level of gene expression in single neurons to imaging of localized regions of the human brain and neurorehabilitation. The Neuroscience Group at the Ernst-Moritz-Arndt University is located in a convergence region, and the paucity of high-tech, expensive equipment for research, the lack of a critical mass of experienced researchers, a reduced level of experience and knowledge of researchers as well as fewer international collaborations with highly competitive groups put severe limitations on the impact of our publications and our capacity to attract research funds from EU programs. Therefore the major aim of this proposal was to redress this balance by (i) stimulating the realization of the full research potential of our Neuroscience Group by acquisition of cutting-edge technology and equipment; (ii) increasing the quality and international impact of our research by cooperation with high profile institutions and recruitment of experienced researchers; (iii) improving S&T experience and knowledge of researchers by short term and long term trainings with our Strategic Partners and exchange of know-how and experience with the scientific experts; (iv) organization of workshops to facilitate knowledge transfer at international level; (v) plenary meetings; (vi) dissemination and promotional activities. The equipment was timely delivered. Since then it has been in use and allowed studies on genetic studies in aging and brain diseases. The confocal laser microscope is used to study cellular structures at 3D level. The MagPro X100 Magnetic Stimulator is a high-performance, non-invasive magnetic stimulator for use in both the clinic and in medical research. By the use of MagPro X100 patterned transcranial stimulation, e.g. TBS could be introduced in the neurorehabilitation research unit. To improve S&T experience and knowledge of researchers in molecular and cellular neuroscience by training studies six experienced researchers have been sent to our cooperating partners. At the same time the project leaders and the corresponding project partners did exchange know-how in specific areas of neuroscience. Three international open workshops on (i) brain regeneration after injuries, (ii) on brain stimulation and brain repair mechanisms, (iii) transport processes in neurodegenerative and neuromuscular diseases, have been organized. On these occasions three booklets for the presentation and publicity of the project achievements have been published along with five publications with our cooperating partners. The workshops have been preceded by press conferences.

These measures allowed the Neuroscience Group in Greifswald to (i) increase our international visibility by organizing 3 workshops; (ii) acquire a highly competitive research infrastructure; (iii) publish a number of good publications. Unfortunately, until to date, it did not help to successfully contribute to other EU Framework Program projects.

Project Context and Objectives:

4.1.2. Summary description of project context and objectives (max 4 pages)

Project context

Neuroscience is a systemic approach helping us to understand the molecular basis but also physiology of brain disorders. Knowledge, treatments and cures continue to be discovered through brain research. The combination of structural and functional studies allows the integrative investigation of neural development, cellular responses to injury, diseases and genetic modification. Further, the mechanisms that underlie communication between nerve cells and the processing of information through brain and spinal cord circuits can be elucidated. The recent development of probes and microscopic techniques for localizing critical molecules in neurons as well as new noninvasive imaging methods that can directly link brain function to behavior, have provided breakthroughs in the way we view the brain, revealing the diversity and complexity of the constituent neurons and circuits.

The Neuroscience Group at the Medical Faculty of the University of Greifswald promotes interdisciplinary investigations from the level of gene expression in single neurons to imaging of localized regions of the human brain and neurorehabilitation. Ongoing studies encompass: behavioral neuroscience; neurorehabilitation; functional neuroimaging and sensorimotor integration; molecular neurophysiology; molecular and cellular mechanisms underlying recovery of brain tissue and function after stroke; adult brain neurogenesis and tissue regeneration. Although there are quite a number of neuroscience institutions in Europe conducting high quality research, there is a growing need for research and development in this area. The Neuroscience Group at the Ernst Moritz Arndt University (EMAU) Greifswald is located in a convergence region, and the paucity of high-tech, expensive equipment for research, the lack of a critical mass of experienced researchers, a reduced level of experience and knowledge of researchers as well as fewer international collaborations with highly competitive groups put severe limitations on the impact of our publications and our capacity to attract research funds from EU programs.

Progress beyond the state of the art

Laboratory of Molecular Neurobiology

The goal of regenerative medicine is to restore cells, tissues and structures that are lost or damaged after disease, injury or ageing in humans. The Laboratory of Molecular Neurobiology is an entity devoted to research and development that is located in the Clinic of Neurology of the Ernst Moritz Arndt University in Greifswald. The overall objectives of the studies in this work program are to study the molecular and cellular reactions to injury in those (mammalian) systems which do not classically regenerate and to ask whether the early events following injury evoke inhibitory responses and/or characteristic responses in stem cells which can be traced by monitoring the transcriptome and proteome profiles. The specific aims of our group are to (i) uncover cellular and molecular mechanisms underlying neurorehabilitation after stroke in aged rats, (ii) examine the role of adult brain neurogenesis for tissue repair after injuries, (iii) investigate possibilities to positively influence/augment adult neurogenesis from stem cells and therefore improve neurorehabilitation after tissue damage in the CNS; (iv) to monitor the recovery of function after injuries to the central nervous system. To this end we will use a battery of functional tests including: (1) sensorimotor tests like the Rota-rod; Cylinder Test; Adhesive Tape Removal Test; (2) learning and memory tests including the Morris water maze; Elevated Plus Maze; T-Maze; (3) fear conditioning, including the startle box test.

Although we are addressing highly relevant areas of neuroscience research, we are aware that our investigative approach is not causal. In order to identify specific genetic mechanisms underlying recovery of tissue and function after stroke we have to turn to transgenic mice and use functional genomics and proteomics in conjunction with in vitro models to identify specific genes and proteins that are involved in the recovery process after stroke. By this project we shall significantly improve the research infrastructure in neuroscience. Using new technology acquired by this measure we aim at discovering regeneration-relevant genes. Further, by exchange of know-how we hope to establish new methods of investigation in brain repair. Gene expression will be modulated using double-stranded small interfering RNA (siRNA). Further, the acquired experience will allow us to study axonal outgrowth of embryonic CNS axons on organotypic slice cultures. Such studies require the acquisition of the following equipment: (1) a modern confocal laser scanning microscope for the analyses and phenotyping of cells in the nervous system and 3D reconstructions of biological structures, and (2) a quantitative real-time PCR system.

These ambitious projects require adequate equipment and the expertise of experienced strategic partners like the Institute of Brain Research (BRI) in Zurich represented by Dr. Oliver Raineteau and the Laboratory of Neural Stem Cell Biology, University of Lund, represented by Dr. Zaal Kokaia. The Institute of Brain Research is one of the outstanding and experienced laboratories in Europe devoted to studying molecular and cellular mechanisms underlying tissue and functional recovery after injuries to the central nervous system.

The Laboratory of Neural Stem Cell Biology has pioneered the clinical application of cell transplantation in the human brain and provided the proof of principle that neuronal replacement can restore motor function in patients with Parkinson’s disease. This partner has also discovered a novel mechanism for self-repair after stroke based on neuronal replacement from the adult brain’s own neural stem cells (NSCs). Strengthening the research and technological development capacities will be based on advanced demonstrative training studies concerning the acquired equipment and the transfer of knowledge from Zürich and Lund to Greifswald by short- and long-term term trainings. The newly recruited personnel of the molecular neurobiology group will visit the Brain Research Institute in Zurich to learn and acquire new techniques related to (i) conditional expression of genes both in vivo and in vitro (ii) an overlay assay using postnatal slices from various brain regions as a substrate to study influence of secreted cues onto cell migration and differentiation in the brain; (iii) organotypic slice cultures from cortex and hippocampus with the aim to investigate gene function, functional imaging and behavior of different cell types in situ; (iv) creation of artificial structures which support the migration of neuronal precursor cells in the injured brain (v) learn various paradigms of behavioural recuperation after injuries to the central nervous system.

The newly recruited personnel of the molecular neurobiology and the experimental neurology groups will be trained in Lund how to dissect the embryonic and adult rodent brains to remove the neurogenic zones such as ventricular and sub-ventricular zones. They will also learn how to dissociate dissected tissue into single cell suspension and plate to expand as monolayer culture or neurospheres. The researchers will be trained to follow the growth of the culture and after sufficient expansion prepare the cell suspension for the intracerebral transplantation. They will also get familiarized with rodent stereotaxic frame for intracebral injection of NSCs in the defined brain regions. The training of the researchers will also include transcardial perfusion of the rodents with implanted NSCs, sectioning of the brains for immunocytochemical staining as free-floating sections and fluorescent microscopy for identification and characterization of implanted NSCs. The researchers will also be trained in behavioural methods aimed at assessing recovery after injuries to the central nervous system.

In addition, the researcher capacity in Greifswald will benefit from the exchange of know-how and experience on specific topics related to regenerative medicine through trans-national two-way secondments of experts between the molecular neurobiology and experimental neurology groups and the Institute of Brain Research in Zurich and the Laboratory of Neural Stem Cell Biology, University of Lund.

Laboratory of Neurorehabilitation

Previous research of the neurorehabilitation research group focused on (a) the detailed analysis of behavioural deficits after stroke, i.e. “behavioural plasticity”, in conditions such as somatosensory deficits, paresis, and apraxia, (b) clinical scale development to monitor impairment and activity limitations, (c) related alterations of brain network activities and prediction of recovery based on cognitive performance and brain activity [EEG analysis], (d) development and clinical evaluation (RCTs) of neuroscience-based training techniques for motor recovery after stroke, and (e) a first concomitant investigation of lesion- and training-induced cortical plasticity [TMS].

The objective of this support action is to further exploit the group’s research potential, thus contributing to the regional development with stroke (and its rehabilitation) being one major health and disability challenge of a European regional population with demographic changes indicating higher proportions of elderly patients. This exploitation will be fostered by taking advantage of the knowledge and experience existing in other regions of Europe.

So far, rehabilitation techniques developed by the group were based on therapist-centred interventions. The research group’s results are competitive and achieved international attention. The group does, however, not hold expertise in potential future rehabilitation interventions based on brain stimulation. This will be sought during this support action. The action plan as indicated below will enable the research group to participate in this research that could have a major impact on stroke rehabilitation in the near future. Another specific research development strategy of the neurorehabilitation research group will be to establish the technical equipment as well as knowledge and training of researchers, to engage in research using neuro-navigation based brain diagnostics and stimulation (rTMS) in stroke patients and focusing on brain recovery and plasticity by innovative interventions. Equipment for brain stimulation (rTMS) will be purchased. Research staff of the neurorehabilitation research group will visit the Physiology and Pathophysiology of Human Motor Control Research Group at the Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, London, U.K. and the Department of Cognitive Neuroscience, Faculty of Psychology, Maastricht University, the Netherlands, to be educated in brain stimulation and neuro-navigation techniques. Experts from these centres will be invited to visit the neurorehabilitation research group in Greifswald.

Laboratory of Molecular Neurophysiology

The combination of molecular biological methods, cellular imaging and cell physiological techniques allows the functional analysis of ion channels in the neuromuscular system. Dysfunction of ion channels, altered gene expression or altered regulation of channel proteins can lead to disturbances of cellular excitability, to cell damage and even to cell death and these conditions can cause severe neuromuscular diseases. The Laboratory of Molecular Neurophysiology is part of the Institute of Pathophysiology at the Ernst Moritz Arndt University of Greifswald. Our overall objectives in this program are to characterize gene expression, cellular localization and function of cation channels that are responsible for the background Ca2+ influx into muscle fibers. A disturbed cellular Ca2+ homeostasis can lead to muscle fiber necrosis and cell death and seems to play a key role in muscular dystrophies. Antagonists of ion channels that inhibit the background Ca2+ influx may be promising tools or at least lead structures to develop a pharmacotherapy for muscular dystrophy.

Our strategic partners are Drs. Hanns Lochmüller and Volker Straub from the Institute of Human Genetics in Newcastle, UK. Dr. Lochmüller is an expert for construction and application of reporter systems in vivo and in vitro. Transfection of reporter molecules into cultured muscle cells and isolated fibres will be established in collaboration with our partner. Distribution of TRPC3 channels in normal and dystrophin-deficient muscle fibres will be studied by confocal laser microscopy.

Carrying out the suggested studies requires the acquisition of a modern confocal laser scanning microscope. Using this microscope will make it possible to analyze the cellular localization and trafficking of TRP channels in living cells. The combination of confocal microscopy and electrophysiology will give new insights in the functional activation of TRP cation channels. Confocal microscopy relies on the use of fluorescent reporter molecules, a technique that is well developed in the laboratory of the strategic partner at the Institute of Human Genetics in Newcastle. Exchange of researchers, collaboration and visits will improve the research potential and competitive position of the Laboratory of Molecular Neurophysiology in Greifswald.

Laboratory of Molecular Neuropathology

Deposition of the beta-amyloid peptide (Abeta) in the brain occurs during normal aging and is augmented in Alzheimer’s disease (AD). Since cells of the brain continuously produce Abeta, it has been suggested that decreased clearance of the peptide from the brain at the blood brain barrier (BBB) could contribute to the buildup of Abeta. Mechanistic studies on Alzheimer’s disease require clearly the use of transgenic animals and the expertise of an experienced strategic partner like the Institute of Neuropathology of the University of Zurich represented by Prof. Dr. Adriano Aguzzi. This institute is one of the outstanding and experienced laboratories in Europe devoted to studying the molecular and cellular mechanisms underlying neurodegenerative diseases like Alzheimer’s disease or Creutzfeldt-Jakob-Disease. Strengthening the research and technological development capacities will be based on advanced demonstrative training studies and the transfer of knowledge from Zurich to Greifswald by long-term trainings. The scientific staff members of our group will visit the Institute of Neuropathology to learn and acquire new techniques including (1) preparation of Abeta using brain extracts from humans with AD or APP/PS1 transgenic mice; (2) injection of Abeta preparations intracerebrally into FVBAPP/PS1-MDR1a/b-/-- mice and FVBAPP/PS1-MDR1a/b+/+ mice, respectively. In addition, the researcher capacity in Greifswald will benefit from exchange of know-how and experiences.

Objectives

The major objectives of this project were:

1. Acquisition, development or upgrading of research equipment of the Neuroscience Group at the Medical Faculty, Ernst Moritz Arndt University of Greifswald Including a confocal microscope devoted to live imaging and molecular physiology.
2. Recruitment of incoming experienced researchers. The Neuroscience Group in Greifswald does not have a critical mass of skilled researchers. Therefore a team of 6 researchers will be recruited. Each of them will be involved in collaborative research involving at least two network laboratories.
3. Improve S&T experience and knowledge of researchers by exchange of know-how and experience with scientific experts from several Strategic Partners.
4. The network will have a strong focus on training of the integrative researchers and other young scientists in the participating laboratories. The training includes demonstrative applications with acquired equipment and collaborative sessions with several strategic partners
5. Organization of three workshops with international participation to facilitate knowledge transfer at international level.
6. Plenary meetings. Each year there will be a plenary meeting involving all the members of the Neuroscience Group in Greifswald, the integrative researchers and members of our Strategic Partners who will be invited as plenary speakers. At the plenary meetings there will be a press office and access for patient groups.
7. Dissemination and promotional activities like a Neuroscience Group’s Webpage and Booklets on Regenerative Medicine and Stroke.

Project Results:

4.1.3. This part cannot be copied into this entry mask, because it contains illustrative figures. Thus, we decided to upload a word-document (Publishable summary-2_HB_3006). The file contains als chapters 4.1.1. to 4.1.4.

Potential Impact:

4.1.4. The potential impact (including the socio-economic impact and the wider societal implications of the project so far) and the main dissemination activities and exploitation of results (not exceeding 10 pages).

Introduction

The impact of the recently completed project for the University of Greifswald and beyond that cannot be overestimated. The impact has become visible and obvious on several levels: (i) for integration and collaboration between the local research groups in the field of neuroscience and neuromuscular research, (ii) for neuroscience research at the Faculty of Medicine (now called University Medicine Greifswald), (iii) for the University of Greifswald and its development and growing relevance in biomedical sciences, (iv) for the visibility of Greifswald as an important place of teaching an research in Germany, preferentially in the field of biomedical sciences and medicine and (v) for the town itself, the region Vorpommern in the North-East of Germany and its relevance, visibility and economical development. Further, the project strengthened the collaboration between researchers in Greifswald and partners at important places in Europe and linked local research groups to strategic partners all over Europe. The latter point will have far-reaching consequences for further collaboration and upcoming projects.

Strategic impact

With this project, the Ernst Moritz Arndt University of Greifswald aimed to improve its research capacity in Molecular Neurobiology, Behavioural Neuroscience, Experimental Neurology, Molecular Neurophysiology, Molecular Neuropathology and Neurorehabilitation by

• improvement of equipment capacity
• achievement of a researcher capacity
• improvement of S&T experience by collaboration with strategic partners and training

The improvement of research capacities in terms of advanced analytical equipment and trained neuroscientists has been achieved. However, we cold not hire all scientists on a long term. Close cooperation with the strategic partners has been achieved. Some will continue after the project ended. Three international dissemination workshops on research and training in neuroscience were realized, an International Workshop on "Brain Regeneration after Injuries" in March 2010, an International Workshop on "Brain Stimulation and Brain Repair Mechanisms" in Sept. 2010 and an International Workshop on “Transport Processes in Neurodegenerative and Neuromuscular Diseases” in Sept. 2011. All workshops were of great success, were well recognized by the University and the local and national press. Further, the workshops brought together well-respected experts from all over Europe in three specific fields of neuroscience research. These contacts and up-to-date information will be very valuable for future plans.

We also aimed to make our Neuroscience Group more competitive in attracting research grants both at national and international levels and to attract more researchers in the field of neuroscience. This has partly been achieved. In 2009 Oliver von Bohlen und Halbach (Prof. of Anatomy and Cell Biology), a neuroscientist, joined the Medical Faculty in Greifswald. This has further strengthened our capacity in molecular and cellular neuroscience. We are confident in rising further funds for neuroscience in the next years in two disciplines: Molecular and cellular neuroscience on the one hand and clinical brain imaging on the other hand. These two disciplines had been combined in the current project, but it turned out that their methodological and scientific approaches are too different to successfully attract common grants. Thus, Greifswald has to attain the critical mass of researchers in both disciplines molecular neuroscience and brain imaging.

The Neuroscience Group’s greatest impact is in the field of regenerative medicine. Regenerative medicine is essentially a collaborative effort. The combination of structural and functional studies represent an integrative focus for experimental investigation of neural development; cellular responses to injury, disease, or genetic modification; and the mechanisms that underlie communication between nerve cells and the processing of information through brain and spinal cord circuits. The chosen strategic partners from different European countries, all with excellent research achievements in their respective field, constituted an ideal complementary mentoring group to back our progress towards strengthening the research profile of neuroscience in Greifswald. Such an integrative composition of strategic partners was only possible at the European level.

Socio-economic impact

The EU funds enabled us to create the intellectual and physical infrastructure that will nurture and sustain physician-neuroscientists in the region.

After the 3 year funding period provided by the EU, we anticipated that the researchers hired will continue to strengthen and expand the neurosciences at the Medical Faculty of Greifswald in the following ways:

1. The EU funds will enable the training and long-term integration of young scientists into the nascent neuroscience community in Greifswald. These young scientists will be in an excellent position to fill sorely needed openings at the University. For example, two permanent positions in Neuropathology at the Institute of Pathology will need to be filled in 2012.
2. The Institute of Pathophysiology and the Rehabilitation Hospital intended to employ two of the hired researchers for at least another 3 years after the funding period ended in April 2012. This has been achieved and the sustained our capacity in neuroscience research. The researcher in the Institute of Pathophysiology obtained her Ph.D. within the funding period and has qualified for a post-doc position in the institute. The researcher hired for the neurorehabilitation group, an MD, has been offered a position in the Rehabilitation Hospital. He is now mainly doing clinical work, but with his background in basic research he is very valuable for the initiation of basic and/or clinical research in the field of neurorehabilitation.
3. In addition, the Clinic of Neurology has permanent openings for young physicians who wish to pursue a career in translational neuroscience, with an emphasis on stroke, Parkinson’s disease, Alzheimer’s disease and epilepsy.
4. Last but not least, through the support of the EU we expect to greatly increase our competitiveness in neuroscience at the University of Greifswald by enhancing the ability of the new researchers to establish independent, extramurally funded research programs at the University. We also anticipate that the sustainability of the initiative will be strengthened by enhanced collaborative interactions among scientists both within the University and throughout the EU.

For the training in partner laboratories an obligatory return mechanism has been implemented in their individual contracts. All scientists returned to Greifswald but eventually we could not give contracts to all to continue the projects initiated by this measure.

List of Websites:

http://www.medizin.uni-greifswald.de/neuroscience_group/index.php?id=381

Contact:

Prof. Dr. Heinrich Brinkmeier
Institute for Pathophysiology
University of Greifswald
Greifswalder Strasse 11c
17495 Karlsburg
Germany

Phone: +49-3834-86 19 319
Fax: +49-3834-86 19111
Email: heinrich.brinkmeier@uni-greifswald.de

Project assistance
Dipl.-Biochem. Christine Pöhlke
Neuroimmunology research group
Department of Neurology
Ernst-Moritz-Arndt University Greifswald
Sauerbruchstrasse NK
D-17475 Greifswald
Germany

Phone: +49-3834-86 68 58
Facsimile: +49-3834-86 53 58
Email: cpoehlke@uni-greifswald.de