TRR 128:  Initiating/Effector versus Regulatory Mechanisms in Multiple Sclerosis - Progress towards Tackling the Disease

• Subject Area: Medicine
• Term: from 2012 to 2024
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 213904703

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system (CNS). This CRC elucidates the complex crosstalk between the immune and the nervous system at molecular, cellular and systems biology levels, using a highly interdisciplinary and translational approach. Projects within this consortium are organized into research subclusters focusing on i) immune regulatory networks and disease initiation, ii) immune cell trafficking, iii) immune-mediated damage and repair and iv) environment. The third funding period will continue this successful organization but with the integration of novel information across i) models, ii) modalities and iii) patient cohorts, thus enhancing the strong clinical translational perspective of this CRC. Based on ambitiously fostering mechanistic insights in MS pathology, with the overall goal to improve patients’ fate, a first strategic pillar is the integration of different well-curated cohorts with multidimensional clinical, imaging and biological data acquisition (analysed within the central clinical translation platform Z02). The integration of information across models (experimental), modalities (e.g., immune phenotypes, MRI phenotypes, soluble markers/signatures) and patient cohorts (including exploratory trials) allows an iterative refinement of pathogenetic and therapeutic principles applicable to MS and related neuroimmunological diseases (triangulation of evidence, forward, reverse and refined translation). A second strategic pillar is the use of cutting-edge technologies and analytic approaches (e.g., single cell approaches, high-end imaging) in different, partly under-investigated compartments (e.g., lymph nodes, meninges) to better understand the functional specialization of immune and nervous system crosstalk under steady-state, inflammatory and therapeutic conditions. A third strategic pillar is the implementation of exploratory human studies (serving hypothesis generation and/or validation). This will aid the development and validation of markers as well as therapeutic targets. Taken together, the vision for the next funding period is to contribute to the development of pathomechanistic knowledge and patient-relevant deliverables to help drive the worldwide search for prognostic and therapeutic improvement in the field of multiple sclerosis, and thus neuroimmunology.

• DFG Programme: CRC/Transregios

Current projects

• A01 - Gut microbiome metabolites in MS inflammation and neurodegeneration (Project Heads Gold, Ralf ;  Haghikia, Aiden ;  Krishnamoorthy, Ph.D., Gurumoorthy )
• A03 - Interplay between pro-inflammatory cytokines and chromatin-remodeling enzymes in the regulation of central nervous system demyelination and repair (Project Heads Jacob, Claire ;  Waisman, Ari ;  Wettschureck, Nina )
• A07 - Role of IL-6 in shaping local immune milieus in the CNS (Project Heads Korn, Thomas ;  Waisman, Ari )
• A08 - Impact of diet and intestinal microbiota on the gut-CNS-axis – implications for CNS autoimmunity (Project Heads Klotz, Luisa ;  Schuppan, Detlef )
• A09 - Analysis and therapeutic modifications of innate immune regulatory networks in controlling T-cell activation in MS (Project Heads Groß, Catharina C. ;  Wiendl, Heinz )
• A10 - Skin-sensing of environmental factors and their impact on the development of multiple sclerosis (Project Heads Loser, Karin ;  Wiendl, Heinz )
• A11 - MOG Antibody-Induced CNS Demyelination: from Specificity to Function (Project Heads Lünemann, Jan ;  Meinl, Edgar )
• A12 - Provenance mapping of immune cells in the CSF (Project Heads Korn, Thomas ;  Lehmann-Horn, Klaus )
• B01 - Immune regulation at the CNS barriers and in the CNS: role of immune cell trafficking (Project Heads Schwab, Ph.D., Nicholas ;  Zarbock, Alexander )
• B03 - Molecular mechanisms and sites of action of the gelatinases in autoimmune CNS inflammation: do MMP-2/-9 contribute to meningeal inflammation and secondary cortical damage? (Project Heads Meyer zu Hörste, Gerd ;  Schäfers, Michael ;  Sorokin, Lydia )
• B04 - Unraveling the role of myeloid cells and metabolism in clinical progression of MS (Project Heads Bittner, Stefan ;  Bopp, Tobias ;  Zipp, Frauke )
• B05 - Topological patterns of damage and compensation in chronic neuroinflammation (Project Heads Groppa, Sergiu ;  Meuth, Sven G. ;  Muthuraman, Ph.D., Muthuraman ;  Zipp, Frauke )
• B06 - The role of the kallikrein-kinin system to functional and structural impairment of network activity in multiple sclerosis (Project Heads Budde, Thomas ;  Göbel, Kerstin ;  Meuth, Sven G. ;  Pape, Hans-Christian )
• B07 - Linking cholesterol metabolism in myeloid cells to remyelination in mice and humans (Project Heads Kuhlmann, Tanja ;  Simons, Mikael Jakob ;  Trotter, Ph.D., Jacqueline )
• B08 - B cells and B cell directed therapies in CNS inflammation (Project Heads Hohlfeld, Reinhard ;  Meinl, Edgar ;  Peters, Anneli )
• B09 - Rebalancing cortical neuronal hyperactivity as a new treatment strategy in Neuroinflammation (Project Heads Ellwardt, Erik ;  Stroh, Albrecht ;  Zipp, Frauke )
• B10 - Molecular dissection of autoimmune lesion induction and resolution in the CNS (Project Heads Kawakami, Naoto ;  Kerschensteiner, Martin )
• B12 - Balancing glutamate and cation channel signaling in inflammatory neuronal injury (Project Head Bittner, Stefan )
• B13 - Disturbed iron metabolism in phagocytes as a driver of chronic inflammation – a model for MS progression? (Project Heads Kerschensteiner, Martin ;  Simons, Mikael Jakob )
• B14 - NfL and EGFL7 as biomarkers for neuroaxonal damage and BBB-integrity in neuroinflammation: A translational approach (Project Heads Uphaus, Timo ;  Zipp, Frauke )
• B15 - Spatiotemporal effects of IL-4 and designed novel compounds on CNS repair during neuroinflammation (Project Heads Vogelaar, Ph.D., Christina Francisca ;  Zipp, Frauke )
• V - Central tasks of the CRC (Project Head Wiendl, Heinz )
• Z02 - Clinical translational Unit (Project Heads Fleischer, Vinzenz ;  Gold, Ralf ;  Hemmer, Bernhard ;  Hohlfeld, Reinhard ;  Klotz, Luisa ;  Kuhlmann, Tanja ;  Kümpfel, Tania ;  Lehmann-Horn, Klaus ;  Lüssi, Felix ;  Meyer zu Hörste, Gerd ;  Wiendl, Heinz ;  Zipp, Frauke )

Completed projects

• A02 - The role of phagocyte-specific stress signaling for inflammatory processes in Multiple Sclerosis (Project Head Roth, Johannes )
• A04 - Tissue specific regulation of ion channels and immunological responses in multiple sclerosis (Project Heads Hemmer, Bernhard ;  Lehmann-Horn, Klaus )
• A05 - Synoptic analysis of adaptive immune reactions in very early multiple sclerosis: Repertoires and target antigens of B and T cells (Project Heads Dornmair, Klaus ;  Hohlfeld, Reinhard )
• A06 - Immune responses at the gliovascular interface (Project Head Korn, Thomas )
• B02 - Molecular mechanisms of T cell diapedesis through the endothelium of the blood brain barrier (Project Head Vestweber, Dietmar )
• B11 - A role for meningeal lymphatic vessels in the regulation of CNS inflammation (Project Head Kipnis, Jonathan )
• Z01 - Neuro-histology unit (Project Head Kuhlmann, Tanja )

• Applicant Institution: Universität Münster
• Co-Applicant Institution: Johannes Gutenberg-Universität Mainz; Ludwig-Maximilians-Universität München; Technische Universität München (TUM)
• Participating University: Ruhr-Universität Bochum
• Spokesperson: Professor Dr. Heinz Wiendl