Molecular mechanisms and sites of action of the gelatinases in autoimmune CNS inflamma-tion: do MMP-2/-9 contribute to meningeal inflammation and secondary cortical damage?

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Meningeal inflammation results in cortical damage and correlates with disability in MS, but is poorly understood. We showed that gelatinases (matrix metalloproteinase (MMP)-2 and -9) control leuko-cyte penetration of the blood-brain barrier at postcapillary venules and propose that they serve simi-lar functions at the meningeal-brain border. We will investigate gelatinases in the meninges of MS patients and mouse experimental atoimmune encephalomyelitis (EAE), identify novel gelatinase substrates that induce meningeal inflammation, and test these substrates in patients. Meningeal T cells will be tracked in mice lacking MMP-2/-9. By understanding meningeal inflammation, we aim to understand drivers of disability in MS. Our project is guided by these questions:

    1. What is the difference between the meninges of MS patients and healthy controls? This question will be answered based on an unbiased cellular map of the meninges in human MS which will be compared with cortical pathology.
    2. Whereare gelatinases expressed? H how do they contribute to inflammation in the meninges?
    3. Which gelatinase substrates mediate meningeal inflammation induced by Th17 cells? Can they be traced in cerebrospinal fluid?
    4. Do gelatinases affect meningeal T cell trafficking in vivo?

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MMP-2/-9 actvity at sites of leukocyte penetration of the CNS parenchyma
in postcapillary venules and meninges

 

Principal Investigators:
Univ.-Prof. Dr. rer. nat. Lydia Sorokin
Institut für Physiologische Chemie und Pathobiochemie
Münster
sorokin@uni-muenster.de

Priv.-Doz. Dr. med. Gerd Meyer zu Hörste
Klinik für Neurologie mit Institut für Translationale Neurologie
Münster
gerd.meyerzuhoerste@ukmuenster.de

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