@phdthesis{Scheffer2020,
  author    = {Scheffer, David},
  title     = {Einfluss einer Dexamethason/Bortezomib-Kombinationstherapie auf den Glukokortikoidrezeptor und die Tight Junction-Molek{\"u}le Claudin-5 und Occludin in Endothelzellen der Blut-Hirn-Schranke in experimentellen Modellen des Sch{\"a}del-Hirn-Traumas},
  doi       = {10.25972/OPUS-21871},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218712},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2020},
  abstract  = {Das Sch{\"a}del-Hirn-Trauma (SHT) ist ein großes medizinisches Problem. Das Hirn{\"o}dem mit konsekutiv erh{\"o}hten intrakraniellen Dr{\"u}cken ist eine h{\"a}ufige und schwerwiegende Komplikation des schweren SHT. Es ist der signifikanteste Pr{\"a}diktor f{\"u}r ein schlechtes Outcome. Obwohl Glukokortikoide (GK) die Ausbildung eines Hirn{\"o}dems bei neuroinflammatorischen Erkrankungen und manchen Hirntumoren reduzieren k{\"o}nnen, ist diese Substanzklasse im SHT ineffektiv oder sogar sch{\"a}dlich. Nach controlled cortical impact (CCI) in M{\"a}usen, einem etablierten SHT-Modell in-vivo, zeigte sich ein Zusammenbruch der Blut-Hirn-Schranke (BHS). Des Weiteren wurde der BHS-stabilisierende Effekt der GK nach CCI durch proteasomalen Abbau des Glukokortikoidrezeptors (GR) behindert. Eine Inhibierung des Proteasoms durch den Proteasomeninhibitor Bortezomib zusammen mit einer GK-Therapie mit Dexamethason reduzierte den Abbau des GR und sorgte f{\"u}r eine Restitution der BHS-Integrit{\"a}t. Ungl{\"u}cklicherweise ließen sich diese Ergebnisse in-vitro nicht auf in Sauerstoff-/Glukosemangel-Modell in der humanen Hirnendothelzelllinie hCMEC/D3 {\"u}bertragen. Daher konnte f{\"u}r die Kombinationstherapie aus dem Proteasomeninhibitor Bortezomib und Dexamethason kein positiver Effekt gezeigt werden. },
  subject      = {Sch{\"a}del-Hirn-Trauma},
  language  = {de}
}
@phdthesis{Friedrich2024,
  author    = {Friedrich, Anna-Lena},
  title     = {FoxO3-mediated, inhibitory effects of CNP on the profibrotic activation of lung fibroblasts},
  doi       = {10.25972/OPUS-35984},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-359845},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2024},
  abstract  = {Idiopathic Pulmonary Fibrosis (IPF) is a progressive parenchymal lung disease with limited therapeutic treatments. Pathologically altered lung fibroblasts, called myofibroblasts, exhibit increased proliferation, migration, and collagen production, and drive IPF development and progression. Fibrogenic factors such as Platelet derived growth factor-BB (PDGF-BB) contribute to these pathological alterations. Endogenous counter-regulating factors are barely known. Published studies have described a protective role of exogenously administered C-type Natriuretic Peptide (CNP) in pathological tissue remodeling, for example in heart and liver fibrosis. CNP and its cyclic GMP producing guanylyl cyclase B (GC-B) receptor are expressed in the lungs, but it is unknown whether CNP can attenuate lung fibrosis by this pathway. To address this question, we performed studies in primary cultured lung fibroblasts. To examine the effects of the CNP/GC-B pathway on PDGF-BB-induced collagen production, proliferation, and migration in vitro, lung fibroblasts were cultured from wildtype control and GC-B knockout mice. Human lung fibroblasts from patients with IPF and healthy controls were obtained from the UGMLC Biobank. In RIA experiments, CNP, at 10nM and 100nM, markedly and similarly increased cGMP levels in both the murine and human lung fibroblasts, demonstrating GC-B/cGMP signaling. CNP reduced PDGF-BB induced proliferation and migration of lung fibroblasts in BrdU incorporation and gap closure assays, respectively. CNP strongly decreased PDGF-BB-induced collagen 1/3 expression as measured by immunocytochemistry and immunoblotting. Importantly, the protective actions of CNP were preserved in IPF fibroblasts. It is known that the profibrotic actions of PDGF-BB are partly mediated by phosphorylation and nuclear export of Forkhead Box O3 (FoxO3), a transcription factor downregulated in IPF. CNP prevented PDGF-BB elicited FoxO3 phosphorylation and nuclear exclusion in both murine and human control and IPF fibroblasts. CNP signaling and functions were abolished in GC-B-deficient lung fibroblasts. Taken together, the results show that CNP moderates the PDGF-BB-induced activation and differentiation of human and murine lung fibroblasts to myofibroblasts. This effect is mediated CNP-dependent by GC-B/cGMP signaling and FoxO3 regulation. To follow up the patho-physiological relevance of these results, we are generating mice with fibroblast-restricted GC-B deletion for studies in the model of bleomycin-induced pulmonary fibrosis.},
  subject      = {Idiopathische pulmonale Fibrose},
  language  = {en}
}