SFB 1009:  Breaking Barriers - Immune Cells and Pathogens at Cell/Matrix Barriers

• Subject Area: Biology ; Medicine
• Term: from 2012 to 2024
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 194468054

Biological barriers organize compartmentalization within multi-cellular organisms, thereby controlling a number of pivotal processes of cells and perturbations of barrier functions are central in many inflammatory diseases. CRC 1009 addresses fundamental aspects of the formation, function and penetration of biological barriers in homeostasis and inflammatory diseases. Barriers studied in the CRC are endothelial and epithelial monolayers and their associated basement membranes, including those found in the lung, gut, skin and brain. CRC 1009 is structured into two closely linked areas focussing on the development, structure, integrity and cellular penetration of barriers (area A), and the role of barriers as integrative structures for immune responses in infections, allergic and autoimmune diseases (area B). By combining expertise in the fields of immunology, cell biology, microbiology and infectiology and including clinical partners from dermatology, neurology, anaesthesiology and internal medicine we formed an internationally unique and highly interactive research network at the Westfalian-Wilhelms-University of Münster (WWU). Our interdisciplinary approach addressing barrier physiology and pathology resulted in important findings in the past funding period. Among other things, members of CRC 1009 obtained novel insights into the process of barrier formation, unravelled new mechanisms of recruitment, activation and diapedesis of leukocytes and tumour cells, identified unknown strategies used by bacteria and viruses to infect barrier-forming and -penetrating cells and also discovered novel pathways of immune regulation. Importantly, this resulted in the identification of potential targets for future approaches to treat infectious and sterile inflammatory diseases at biological interphases. Towards a mechanistic understanding of inflammation at biological barriers we will now focus on the functional analysis of endothelial and epithelial layers and their associated cells using targeted genome editing, sophisticated genetic mouse models, dynamic in vivo and high-resolution imaging, innovative high-throughput technologies and a growing library of experimental and patient-derived viral and bacterial pathogens. In addition, we will extend our work to innovative therapeutic approaches in preclinical models using unique conditional knock-out/knock-in mouse strains established in CRC 1009, and will analyse disease-specific mechanisms in patient-derived inducible pluripotent stem cells. Translational approaches will also benefit from cohorts of patients suffering from infectious, allergic and autoimmune disorders showing inflammation at barriers in the vasculature, gut, skin, lung, brain, and urinary tract. Our combined efforts will lead to a more comprehensive and dynamic understanding of barrier biology during homeostasis and inflammation, rather than restricting our view on individual barrier components.

• DFG Programme: Collaborative Research Centres

Current projects

• A01 - Leukocyte migration through the blood vessel wall and mechanisms that modulate fluid passage across a specialized endothelium (Project Head Vestweber, Dietmar )
• A02 - Mechanisms of leukocyte penetration of vascular cell basement membranes (Project Head Sorokin, Lydia )
• A03 - Mechanisms and consequences of immune-cell interactions with endothelial cells and pericytes at the blood-brain-barrier (Project Heads Klotz, Luisa ;  Wiendl, Heinz )
• A04 - Analysis of the Drosophila blood-brain barrier (Project Heads Klämbt, Christian ;  Luschnig, Stefan ;  Schirmeier, Stefanie )
• A05 - The role of intracellular calcium regulators in integrin activation and leukocyte recruitment (Project Heads Cappenberg, Anika ;  Zarbock, Alexander )
• A06 - Formyl peptide chemoattractant receptors in leukocyte activation and trans-endothelial migration (Project Heads Gerke, Volker ;  Rescher, Ursula )
• A09 - Interplay of cell adhesion and matrix proteolysis in barrier-braking invadopodia of tumor cells (Project Head Eble, Johannes Andreas )
• A10 - Molecular regulation of endothelial barrier function (Project Head Adams, Ralf H. )
• A12 - Interaction of macrophages with cell matrix niches in lymphoid organs (Project Head Alonso Gonzalez, Noelia )
• A13 - Neutrophils regulate endothelial dysfunction in atherosclerosis (Project Head Söhnlein, Oliver )
• B02 - The role of MAPK pathways in influenza virus replication and bacterial super-infection (Project Heads Börgeling, Yvonne ;  Ehrhardt, Christina ;  Ludwig, Stephan )
• B03 - Autopenetration of bacterial effector proteins and modulation of signalling responses in cellular barriers (Project Heads Rüter, Christian ;  Schmidt, Marcus Alexander )
• B04 - The bacterial secreted combinome: Synergistic host injury by exotoxins of enterohemorrhagic Escherichia coli (Project Head Mellmann, Alexander )
• B05 - Genetic basis involved in host interaction and adaptation of Escherichia coli: Impact on crosstalk with cellular barriers (Project Head Dobrindt, Ulrich )
• B07 - The role of RANK/RANKL signaling for skin homeostasis and barrier function during anti-microbial immune responses (Project Head Loser, Karin )
• B08 - DAMP-induced proinflammatory feedback mechanisms between phagocytes and endothelial / epithelial barriers in infectious diseases (Project Head Vogl, Ph.D., Thomas )
• B09 - Dermal stress response and barrier integrity in allergy and autoimmune diseases (Project Head Roth, Johannes )
• B10 - Calcium mediated actin rearrangement (CAR) in podocyte development and pathogenesis (Project Heads Pavenstädt, Hermann ;  Wedlich-Söldner, Roland )
• B11 - Impact on innate immune signals on hapten-specific immune responses (Project Head Steinbrink, Kerstin )
• B12 - Roles of the CNFY toxin for Yersinia pseudotuberculosis for crossing intestinal barriers, colonization of subepithelial tissue and pathology (Project Head Dersch, Petra )
• B13 - The role of MAPK pathways in SARS CoV-2 infection and COVID-19 disease (Project Head Ludwig, Stephan )
• Z01 - Central Tasks - Management and Public Relations (Project Head Roth, Johannes )
• Z02 - Non-invasive imaging, cell tracking and functional analyses at cellular barriers (Project Heads Faber, Cornelius ;  Loser, Karin ;  Roth, Johannes )
• Z03 - Structured training programs 'Master Experimental Medicine' and 'MedK' (Project Heads Hallmann, Rupert ;  Karch, Helge )

Completed projects

• A07 - Identification and functional analysis of barrier-breaking genes in myeloid cells (Project Head Müller-Tidow, Carsten )
• A08 - Mechanisms of transendothelial fibroblast migration in rheumatoid arthritis (Project Head Pap, Thomas )
• A11 - Myostatin-induced mechanisms of inflammatory bone and cartilage destruction by invasive fibroblast-like synoviocytes (Project Heads Dankbar, Ph.D., Berno ;  Pap, Thomas )
• B01 - Mechanisms of Staphylococcus aureus to breach cellular barriers and to invade host tissue (Project Heads Löffler, Bettina ;  Niemann, Silke ;  Peters, Georg )

• Applicant Institution: Universität Münster
• Participating Institution: Max-Planck-Institut für molekulare Biomedizin
• Spokespersons: Professor Dr. Georg Peters, until 6/2016 (†); Professor Dr. Johannes Roth