Lab Projects

To develop new neuroprotective treatment strategies we are investigating the mechanisms that lead to tissue damage and limit tissue repair in animal models of multiple sclerosis. Currently our lab is focussing on the following projects:

Pathogenesis and prevention 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 molecular 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 (Department of Pathology and Immunology, Geneva Faculty of Medicine), Derron Bishop (Dept. of Physiology, Indiana School of Medicine, USA)

Regulation of phagocyte effector function in neuroinflammatory conditions

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. Recent work from our group has shown that the release of reactive oxygen and nitrogen species (ROS/RNS) by monoclear phagocytes is a key step in the induction of inflammatory axon damage in Multiple Sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). In this project we now want to better understand (i) how reactive species induce mitochondrial pathology and ultimately cause axon degeneration, (ii) when and where these species are released in vivo, and (iii) how their release is regulated during the formation and resolution of neuroinflammtory lesions. New transgenic reporter mouse lines are used in combination with spinal in vivo imaging to directly follow the behavior, phenotype and reactive species’ release of phagocytes and its downstream consequences in neuroinflammatory lesions. We believe that a better understanding of the generation and actions of reactive species in vivo will help us develop more efficient therapeutic strategies for Multiple Sclerosis.

 

Collaborators: Tobias Dick (German Cancer Research Institute Heidelberg), Thomas Misgeld (Institute of Neuroscience, TU Munich), Collaborative Research Centre TRR 128

Neuronal pathology and plasticity in cortical multiple sclerosis

The classical pathological correlate of multiple sclerosis is the inflammatory demyelinating lesion located in the white matter of brain or spinal cord. However recent evidence indicates that multiple sclerosis pathology is not restricted to the white matter and – in particular in the later stages of the disease - also prominently affects the gray matter of the CNS. Gray matter pathology including the damage of cortical neurons is now recognized as an important structural correlate for cognitive dysfunction, a major impairment for many patients in the chronic-progressive stage of MS. How neurons are damage in cortical MS lesions is currently only incompletely understood. In this project we now aim to characterize how neuronal structures are altered in human and experimental inflammatory lesions of the cortex and elucidate the cellular, subcellular and molecular mechanisms that mediate neuronal damage and recovery in these lesions in vivo. We believe that these experiments will provide new insights into the sequence of events that leads to neuronal damage in cortical MS lesions and thereby provide the basis for the development of therapeutic strategies to prevent cognitive dysfunction in MS patients.

 

Collaborators: Doron Merkler (Department of Pathology and Immunology, Geneva Faculty of Medicine), Thomas Misgeld (Institute of Neuroscience, TU Munich), SyNergy Munich Cluster for Systems Neurology

 
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Director

Prof. Dr.

Reinhard Hohlfeld

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Prof. Dr.

Martin Kerschensteiner

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