Unsere Projekte
Um neue neuroprotektive und neuroregenerative Therapiestrategien zu entwickeln, untersuchen wir die Mechanismen der Gewebsschädigung und –reparatur bei entzündlichen und traumatischen Erkrankungen des Nervensystems. In diesem Rahmen bearbeiten wir u.a. die folgenden Forschungsprojekte (Kurzbeschreibung in englischer Sprache):
In vivo pathogenesis of immune-mediated axon damage
Multiple sclerosis (MS) is an inflammatory disease of the central nervous systems (CNS) and the most common neurological cause of disability in young adults. Disability in MS is caused by immune-mediated damage to axonal connections. However, how immune cells damage axons in MS is unresolved. As a consequence therapeutic options for preventing immune-mediated axon damage are limited. In the first phase of this project we have used advances in modern imaging and transgenic technology to develop a novel in vivo imaging approach to this question. Multi-photon microscopy allows us to follow the interactions of fluorescently labeled immune cells and axons in the inflamed spinal cord of living animals. In the second phase of this project we now use this approach to determine the effector cells and effector mechanisms of immune-mediated axon damage. Based on this knowledge we currently develop and assess novel therapeutic strategies for the prevention of immune-mediated axon damage in multiple sclerosis and other inflammatory CNS disease.
Collaborators: Thomas Misgeld (Institute of Neuroscience, TU Munich), Doron Merkler (Institute of Neuropathology, Georg-August University Göttingen), Derron Bishop (Dept. of Physiology, Indiana School of Medicine, USA)
Support: DFG Emmy Noether Program, Dana Foundation Neuroimmunology Program
Mechanisms of tissue damage in new animal models of multiple sclerosis
The human disease multiple sclerosis is characterized by remarkable heterogeneity both with regard to its clinical presentation and underlying pathology. Standard animal models of MS however represent only limited aspects of the acute disease spectrum. As a result therapeutic agents and diagnostic markers developed in the animal model often fail in the human disease. To overcome this limitation new animal models have been generated that better reflect the clinical and pathological heterogeneity of MS and also mimic aspects of human disease. In the proposed project we want to use a combination of advanced molecular and in vivo imaging technology to characterize the cellular and molecular pathogenesis in the new disease models. In particular we focus our work on the pathogenesis of tissue damage in acute and chronic stages of the disease. By collaborating with the research network we attempt to validate the findings human MS tissue in order to directly translate our results to MS patients in the future. In turn, established therapeutic or diagnostic strategies can be verified and optimized in the appropriate animal model
Collaborators: Wolfgang Brück (Institute of Neuropathology, Georg-August University Göttingen), Alexander Flügel (Institute for Multiple Sclerosis Research, Georg-August University Göttingen), Thomas Misgeld (Institute of Neuroscience, TU Munich), Marco Prinz (Institute of Neuropathology, University of Freiburg), Hartmut Wekerle (MPI of Neurobiology, Martinsried)
Support: Part of the National Competence Network “Understand MS”
Regulation of macrophage migration, differentiation and effector function
Mononuclear phagocytes - macrophages and microglial cells - play a central role in the pathogenesis of autoimmune CNS disease like multiple sclerosis. Their migration, molecular differentiation and effector function determine how pathology arises and when it resolves. The principles that regulate these properties in autoimmune reactions are only incompletely understood. We want to unravel these principles by analysing 3 different paradigms in which mononuclear phagocyte function is differentially regulated. These include the comparison of (i) different disease stages – the induction and remission of autoimmune lesions in experimental autoimmune encephalomyelitis (EAE) - (ii) different diseases localizations – targeted EAE lesions in spinal cord and cortex - and (iii) the interaction with different T cells – after transfer of encephalitogenic and non-encephalitogenic T cell lines. We use in vivo imaging, ex vivo gene-expression profiling and neuro-immune co-cultures to assess the migratory behaviour, molecular differentiation and effector function of mononuclear phagocytes in these paradigms. We hope that this project will help us to identify critical regulatory switches that determine the phenotype of mononuclear phagocytes in autoimmune CNS lesions. This information should provide the basis for new therapeutic approaches that counter phagocyte-mediated tissue destruction in multiple sclerosis and related autoimmune disease.
Collaborators: Wolfgang Klinkert, Hartmut Wekerle (MPI of Neurobiology, Martinsried)
Support: Part of the Collaborative Research Centre 571 “Autoimmune reactions: From manifestations and mechanisms to therapy”
Molecular regulation of axonal growth induction
Spinal cord injury (SCI) leads to severe and persistent functional deficits due to the limited repair of severed axonal connections in the central nervous system (CNS). Therapeutic options are insufficient and their further development has been hampered by the lack of reliable tools to quantify axonal regeneration or reorganization in animal models. We have developed a multi-layered approach to evaluate repair in the injured spinal cord based on the use of transgenic animals, simultaneous tracing of multiple axon tracts and in vivo imaging. This combined approach allows us to (1) reliably quantify CNS regeneration, (2) assess axonal reorganization on multiple anatomical levels and (3) image CNS regeneration in vivo. We can now use this combination of techniques to evaluate new therapeutic strategies. The regulation of axonal regeneration depends on numerous growth-promoting and growth-inhibitory signals that converge on common intracellular signaling cascades. Thus directly targeting downstream regulators of such common pathways is a promising strategy. One example of such a common downstream target are transcription factors of the STAT (signal transducers and activators of transcription) family. Recent work by us and others indicates that lack of STAT upregulation is correlated with failure to regenerate: Indeed, while injured peripheral neurons express STAT persistently until complete regeneration to their targets, CNS neurons show only transient STAT upregulation and abortive regeneration. Interestingly, our own data further indicates that STAT transcription factors are induced by therapies that stimulate axonal growth in the CNS. To directly assess the contribution of STAT transcription factors we now genetically manipulate STAT expression in peripheral and central projections neurons and image the resulting neuronal growth response in vivo.
PIs: Florence Bareyre, Martin Kerschensteiner
Collaborators: Shizuo Akira (Dept. of Host Defense, Osaka University, Japan), Hildegard Büning (Dept. of Internal Medicine, University of Cologne), Thomas Misgeld (Institute of Neuroscience, TU Munich)
Support: International Foundation for Research in Paraplegia
Regulation of axon guidance and synapse formation after spinal cord injury
The incidence of Spinal Cord Injury (SCI) in Germany is estimated at about 36 cases per million of the population, which translates to about 3000 new spinal cord injured patients per year. Most of these patients are young adults injured at work or during traffic accidents who will have to live the rest of their life disabled due to the limited repair capacity of severed central axons. Recently, therapeutic options have emerged that can promote some level of axonal outgrowth after SCI. However, our work emphasizes that axonal outgrowth is in itself insufficient and that regrowing axons have to be integrated into reorganized intraspinal networks to promote functional recovery. To achieve this aim the following questions need to be addressed: (i) How do regrowing axons find the correct path to their intermediate or final targets? (ii) How do regenerating axons make appropriate synaptic connections? (iii) Which therapeutic strategies can support axons during pathfinding and synapse formation? The answers to these questions in SCI are essentially unknown. However axonal pathfinding and synapse formation have been studied extensively in the developing nervous system and many of the key mechanisms have been identified. Transfer of this knowledge to SCI has, so far, been limited, partly due to the lack of appropriate techniques to follow axonal pathfinding and synapse formation after injury. Over the recent years we have therefore developed novel approaches to (i) observe and modulate the growth and pathfinding of injured spinal axons in vivo, (ii) visualize and regulate synapse formation in intraspinal circuits and (iii) reliably assess therapeutic effects on axonal repair after SCI. In this project we use these powerful new tools to identify the molecular cues that guide regrowing axons, to determine the molecules that modulate the formation of new synaptic contacts and to develop novel therapeutic strategies that improve axonal pathfinding, synaptic reconnection and functional recovery after injury.
PI: Florence Bareyre
Collaborators: Jeroen Pasterkamp (Dept. of Neuroscience and Pharmacology, University of Utrecht, The Netherlands), Hisashi Umemori (Molecular and Behavioral Neuroscience Institute, University of Michigan Medical School, USA)
Support: BMBF Independent Research Groups in the Neurosciences
Activity-dependent regulation of detour circuit formation after spinal cord injury
The transection of axonal connections leads to motor and sensory deficits in many traumatic, ischemic and inflammatory conditions of the central nervous system (CNS). Despite the fact that axonal regeneration generally fails in the CNS, dramatic functional recovery can be observed in particular after incomplete lesions to brain and spinal cord.
Our recent work indicates that spontaneous recovery of motor function can be mediated by the formation of intraspinal detour circuits. Detour circuits are formed in the following steps: First, a subpopulation of transected projection neurones forms new collaterals that contact intraspinal relay neurones. Initially these collaterals contact relay neurones irrespective of their projection pattern. However over the following weeks only those sprouts which contact neurones that connect to the original target area are maintained while other sprouts are eliminated. Electrophysiological and behavioural experiments confirm that intraspinal detour circuits are key anatomical substrates of functional recovery.
To understand when and where detour circuits can be formed and which regulatory principles guide their formation we now study: (1) whether the formation of detour circuits is also possible in the somatosensory system and is thus a general blueprint for both motor and sensory recovery, (2) if and how neuronal activity guides the stabilization or elimination of newly formed connections and (3) whether we can design training or activity paradigms that enhance the formation of detour circuits and thereby improve functional recovery after CNS injury.
PIs: Florence Bareyre, Martin Kerschensteiner
Collaborators: Karl-Klaus Conzelmann (Genzentrum, LMU München), Daniel Kerschensteiner (Dept. of Opthalmology and Visual Sciences, Washington University School of Medicine, USA)
Support: Part of the Collaborative Research Centre 870 “Assembly and function of neuronal circuits in sensory processing””
