| dc.contributor.advisor | Katschinski, Dörthe Prof. Dr. | |
| dc.contributor.author | Leinhos, Lisa | |
| dc.date.accessioned | 2019-05-20T09:16:23Z | |
| dc.date.available | 2019-05-20T09:16:23Z | |
| dc.date.issued | 2019-05-20 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-002E-E63F-7 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7454 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7454 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7454 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 610 | |
| dc.title | Myofibroblast differentiation in hypoxia: a novel role for ArhGAP29 | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Katschinski, Dörthe Prof. Dr. | |
| dc.date.examination | 2019-04-17 | |
| dc.description.abstracteng | Myofibroblasts are crucial for normal wound healing and tissue remodelling and play an es-sential role in the pathogenesis of ischemic tissue fibrosis. Due to their contractile features, myofibroblasts support wound closure; however, overactive myofibroblasts will cause severe scarring that can lead to organ dysfunction. The transition of fibroblasts to myofibroblasts is initiated by a wide range of microenvironmental stimuli, such as mechanical stress, cytokine signalling or alteration of oxygen supply. However, the oxygen-dependent molecular regula-tory mechanisms underlying the myofibroblast programme remain unclear.
In this doctoral thesis, the effect of reduced oxygen availability (hypoxia) on the myofibroblast differentiation process was investigated in vitro. Under hypoxic conditions, decreased ex-pression of αSMA, the signature protein of myofibroblast differentiation, and actin filament remodelling were paralleled by reduced cell contractility. This led to the conclusion that hy-poxia reverts myofibroblast differentiation. Dedifferentiation of myofibroblasts was also ob-served when RhoA activity was inhibited in normoxia. In this study, reduced RhoA activity was observed in hypoxia, indicating that oxygen availability influences RhoA activity and myofibroblast differentiation. The Rho GTPase activating protein ArhGAP29 was identified to be involved in fine-tuning the RhoA response in hypoxia as its expression is induced in hy-poxia in a HIF-1α-dependent manner.
By regulating RhoA activity, ArhGAP29 plays an important role in the MRTF/SRF signalling pathway and thus has a critical impact on the myofibroblast differentiation programme in hy-poxia. The oxygenation state of tissue is of importance in the wound healing process, hence the presented new link between hypoxia and the regulation of the RhoA-MRTF/SRF signal-ling axis provides both new insights into the molecular mechanisms underlying the myofibro-blast differentiation and promising therapeutic targets for tissue remodelling and fibrosis in an ischemic context. | de |
| dc.contributor.coReferee | Lutz, Susanne Prof. Dr. | |
| dc.subject.eng | ARHGAP29 | de |
| dc.subject.eng | Hypoxia | de |
| dc.subject.eng | Hypoxia-inducible-factor | de |
| dc.subject.eng | MRTF-A | de |
| dc.subject.eng | Myofibroblast | de |
| dc.subject.eng | RhoA | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-002E-E63F-7-6 | |
| dc.affiliation.institute | Medizinische Fakultät | |
| dc.subject.gokfull | Molekularbiologie {Medizin} (PPN619875186) | de |
| dc.identifier.ppn | 1666651362 | |