Role of Semaphorin 7A in regulating vascular and organ integrity during hypoxia and inflammation
Final Report Abstract
Hypoxia and acute inflammation are associated with a disruption of cellular barriers, migration and infiltration of inflammatory cells into the affected tissue. Semaphorin7A (Sema7A) is well analyzed and defined for its function as neuronal guidance protein (NPG) were it is involved in growth cone tip formation during neuronal development. Besides guidance function in the nervous system Sema7A affects cell proliferation and leukocyte migration. In this project we found that Sema7A expression is induced during hypoxia and through inflammatory cytokines on endothelium and epithelial cells. This induction of Sema7A aggravates the inflammatory organ injury during periods of hypoxia and acute lung injury. Sema7A production is regulated by the transcription factors HIF-1 and NF-kB. Studies to detect tissue-specific functions for Sema7A using bone marrow transplantations to produce Sema7A chimeric mice was successful in identifying the proinflammatory endothelium derived impact of Sema7A during hypoxia. Furthermore, we were able to demonstrate that peptide generated from the Sema7A sequence exerts anti-inflammatory action through the Plexin C1 receptor. Using animals with gene deletion of Plexin C1 we were able to show the protective role of this fragment of Sema7A during acute lung injury. However, the receptor interaction of Sema7A and its potential specific target receptors Plexin C1 and integrin receptors needs to be studied further. In summary, the work in this grant proposal helped to make significant progress in the understanding of the role of Sema7A on organ function and organ injury during pathological changes associated with hypoxia and inflammation.
Publications
- 2012. Die funktionelle Blockade des Plexin C1 Rezeptors beeinflusst den hepatischen Ischämie-Reperfusionsschaden. Hamburg, Germany, 12. Kongress der Deutschen Interdisziplinären Vereinigung für Intensivmedizin und Notfallmedizin (DIVI), Dezember 05-07, 2012, Abstract-CD FPV/01/02
König K, Granja T, Jennewein C, Tran N, Köhler D, Rosenberger P
- 2012. Pulmonary inflammation is controlled by PlexinC1 receptor during ventilator induced lung injury. Hamburg, Germany, 12. Kongress der Deutschen Interdisziplinären Vereinigung für Intensivmedizin und Notfallmedizin (DIVI), Dezember 05-07, 2012, Abstract-CD P/03/10
Granja T, Köhler D, Nelson E, König K, Mirakaj V, Rosenberger P
- 2012. Uncoordinated-5 homolog B (UNC5B) beeinflusst den myokardialen Ischämie und Reperfusionsschaden. Hamburg, Germany, 12. Kongress der Deutschen Interdisziplinären Vereinigung für Intensivmedizin und Notfallmedizin (DIVI), Dezember 05-07, 2012, Abstract-CD EP/01/09
Köhler D, Streißenberger A, König K, Granja T, Hoffmann E, Mager A, Bernardo de Oliveira Franz C, Rosenberger P
- Endothelial Semaphorin 7A promotes neutrophil migration during hypoxia. Proc Natl Acad Sci USA. 2012 Aug 28;109(35):14146-51. Epub 2012 Aug 13
Morote-Garcia JC, Napiwotzky D, Köhler D, Rosenberger P
(See online at https://doi.org/10.1073/pnas.1202165109) - Einfluss des Neuronalen Guidance Proteins Sema7A auf einen akuten Lungenschaden. Tübingen, Deutschland, Forschungskolloquium der Medizinischen Fakultät, Universität Tübingen, Oktober 08, 2013 . Book of Abstracts, S. 64, #40
Roth JM, Köhler D, König K, Granja T Rosenberger P
- Rolle des Neuronalen Guidance Proteins Sema7A während akuter Inflammation anhand der akuten Peritonitis. Tübingen, Deutschland, Forschungskolloquium der Medizinischen Fakultät, Universität Tübingen, Oktober 08, 2013 . Book of Abstracts, S. 81, #57
Schneider M, Köhler D, Granja T, Rosenberger P
- Semaphorin7A (SEMA7A) verstärkt die pulmonale Inflammation während des akuten Lungenschadens. Berlin, Deutschland, 15. Hauptstadtkongress der DGAI für Anästhesiologie und Intensivmedizin 2013, September 19-21, 2013. Book of Abstracts, Supplement Nr. 4 S498
Roth JM, Köhler D, König K, Granja T, Rosenberger P
- The Uncoordinated-5 Homolog B (UNC5B) Receptor Increases Myocardial Ischemia-Reperfusion Injury. PLoS One. 2013 Jul 23;8(7):e69477
Köhler D, Streißenberger A, König K, Granja T, Roth JM, Lehmann R, de Oliveira Franz CB, Rosenberger P
(See online at https://doi.org/10.1371/journal.pone.0069477) - Crucial role of Plexin C1 for pulmonary inflammation and survival during lung injury. Mucosal Immunol. 2014 Jul;7(4):879-91
Granja T, Köhler D, Mirakaj V, Nelson E, König K, Rosenberger P
(See online at https://doi.org/10.1038/mi.2013.104) - Gαi2- and gαi3-deficient mice display opposite severity of myocardial ischemia reperfusion injury. PLoS One. 2014 May 23;9(5):e98325
Köhler D, Devanathan V, Bernardo de Oliveira Franz C, Eldh T, Novakovic A, Roth JM, Granja T, Birnbaumer L, Rosenberger P, Beer-Hammer S, Nürnberg B
(See online at https://doi.org/10.1371/journal.pone.0098325) - The plexin C1 receptor promotes acute inflammation. Eur J Immunol. 2014
König K, Marth L, Roissant J, Granja T, Jennewein C, Devanathan V, Schneider M, Köhler D, Zarbock A, Rosenberger P
(See online at https://doi.org/10.1002/eji.201343968)
