@article{RiveroAlhamaRibaKuetal.2021,
  author    = {Rivero, Olga and Alhama-Riba, Judit and Ku, Hsing-Ping and Fischer, Matthias and Ortega, Gabriela and {\´A}lmos, P{\´e}ter and Diouf, David and van den Hove, Daniel and Lesch, Klaus-Peter},
  title     = {Haploinsufficiency of the Attention-Deficit/Hyperactivity Disorder Risk Gene St3gal3 in Mice Causes Alterations in Cognition and Expression of Genes Involved in Myelination and Sialylation},
  series = {Frontiers in Genetics},
  volume    = {12},
  journal   = {Frontiers in Genetics},
  issn      = {1664-8021},
  doi       = {10.3389/fgene.2021.688488},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246855},
  year      = {2021},
  abstract  = {Genome wide association meta-analysis identified ST3GAL3, a gene encoding the beta-galactosidase-alpha-2,3-sialyltransferase-III, as a risk gene for attention-deficit/hyperactivity disorder (ADHD). Although loss-of-function mutations in ST3GAL3 are implicated in non-syndromic autosomal recessive intellectual disability (NSARID) and West syndrome, the impact of ST3GAL3 haploinsufficiency on brain function and the pathophysiology of neurodevelopmental disorders (NDDs), such as ADHD, is unknown. Since St3gal3 null mutant mice display severe developmental delay and neurological deficits, we investigated the effects of partial inactivation of St3gal3 in heterozygous (HET) knockout (St3gal3±) mice on behavior as well as expression of markers linked to myelination processes and sialylation pathways. Our results reveal that male St3gal3 HET mice display cognitive deficits, while female HET animals show increased activity, as well as increased cognitive control, compared to their wildtype littermates. In addition, we observed subtle alterations in the expression of several markers implicated in oligodendrogenesis, myelin formation, and protein sialylation as well as cell adhesion/synaptic target glycoproteins of ST3GAL3 in a brain region- and/or sex-specific manner. Taken together, our findings indicate that haploinsufficiency of ST3GAL3 results in a sex-dependent alteration of cognition, behavior and markers of brain plasticity.},
  language  = {en}
}
@phdthesis{Klaus2021,
  author    = {Klaus, Laura-Christin},
  title     = {Generierung und Charakterisierung eines neuen Mausmodells des Morbus Parkinson durch AAV1/2 vermittelte {\"U}berexpression von humanem mutiertem A53T-α-Synuclein in der Substantia nigra},
  doi       = {10.25972/OPUS-23921},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239217},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2021},
  abstract  = {Auch wenn die {\"A}tiopathogenese von Morbus Parkinson bis heute nicht vollst{\"a}ndig gekl{\"a}rt ist, scheint α-Synuclein (α-Syn) eine zentrale Rolle zu spielen. Die Entdeckung als genetische Ursache der Erkrankung, als Hauptbestandteil der Lewy-K{\"o}rper (LK) und seine Assoziation mit verschiedenen anderen potenziellen {\"a}tiologischen Faktoren verdeutlichen dies. Bei Ratten und Affen f{\"u}hrte eine AAV1/2-vermittelte {\"U}berexpression von A53T-α-Syn zu einer Degeneration dopaminerger Neurone in der Substantia nigra (SN), einem striatalen dopaminergen Defizit sowie Verhaltensauff{\"a}lligkeiten. In Anbetracht bestimmter Vorteile der Mausspezies, war es das Ziel dieser Dissertation - die im Rahmen eines kollaborativen Projektes mit dem Toronto Western Research Institut in Ontario, Kanada entstanden ist - dieses auf AAV1/2-A53T-α-Syn basierende Parkinson-Modell auf M{\"a}use zu {\"u}bertragen. Dazu wurde AAV1/2-A53T-α-Syn oder leerer AAV1/2-Vektor in einer Dosis von 1,5 µl mit einer Konzentration von 5,16 x 10^12 gp/ml stereotaktisch einseitig in die rechte SN von C57BL/6-wt-M{\"a}usen injiziert. {\"U}ber einen Zeitraum von 11 Wochen wurden verschiedene Verhaltensexperimente durchgef{\"u}hrt und die beiden Versuchstiergruppen miteinander verglichen. Post-mortem erfolgten verschiedene immunhistochemische Untersuchungen. Es konnte gezeigt werden, dass die einseitige Injektion von AAV1/2-A53T-α-Syn in die SN bei M{\"a}usen eine weit verbreitete {\"U}berexpression von A53T-α-Syn in dopaminergen Neuronen der SN induzierte, die innerhalb von 10 Wochen zu signifikanten fr{\"u}hen und persistierenden motorischen Verhaltensauff{\"a}lligkeiten, nigrostriataler Degeneration und Entwicklung einer Lewy-{\"a}hnlichen Pathologie f{\"u}hrte. Durch die Generierung und Charakterisierung dieses neuen Parkinson-Mausmodells, das klinische und histopathologische Merkmale der menschlichen Erkrankung widerspiegelt, besteht nun die M{\"o}glichkeit es weiterzuentwickeln und z.B. auf transgene M{\"a}use zu {\"u}bertragen, um u.a. molekulare Mechanismen der Parkinson-Krankheit zu entschl{\"u}sseln und pr{\"a}klinische Tests von krankheitsmodifizierenden Therapien durchzuf{\"u}hren.},
  subject      = {Parkinson-Krankheit},
  language  = {de}
}
@article{SchaeferZhengvanBrederodeetal.2018,
  author    = {Schaefer, Natascha and Zheng, Fang and van Brederode, Johannes and Berger, Alexandra and Leacock, Sophie and Hirata, Hiromi and Paige, Christopher J. and Harvey, Robert J. and Alzheimer, Christian and Villmann, Carmen},
  title     = {Functional Consequences of the Postnatal Switch From Neonatal to Mutant Adult Glycine Receptor α1 Subunits in the Shaky Mouse Model of Startle Disease},
  series = {Frontiers in Molecular Neuroscience},
  volume    = {11},
  journal   = {Frontiers in Molecular Neuroscience},
  number    = {167},
  issn      = {1662-5099},
  doi       = {10.3389/fnmol.2018.00167},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196056},
  year      = {2018},
  abstract  = {Mutations in GlyR α1 or β subunit genes in humans and rodents lead to severe startle disease characterized by rigidity, massive stiffness and excessive startle responses upon unexpected tactile or acoustic stimuli. The recently characterized startle disease mouse mutant shaky carries a missense mutation (Q177K) in the β8-β9 loop within the large extracellular N-terminal domain of the GlyR α1 subunit. This results in a disrupted hydrogen bond network around K177 and faster GlyR decay times. Symptoms in mice start at postnatal day 14 and increase until premature death of homozygous shaky mice around 4-6 weeks after birth. Here we investigate the in vivo functional effects of the Q177K mutation using behavioral analysis coupled to protein biochemistry and functional assays. Western blot analysis revealed GlyR α1 subunit expression in wild-type and shaky animals around postnatal day 7, a week before symptoms in mutant mice become obvious. Before 2 weeks of age, homozygous shaky mice appeared healthy and showed no changes in body weight. However, analysis of gait and hind-limb clasping revealed that motor coordination was already impaired. Motor coordination and the activity pattern at P28 improved significantly upon diazepam treatment, a pharmacotherapy used in human startle disease. To investigate whether functional deficits in glycinergic neurotransmission are present prior to phenotypic onset, we performed whole-cell recordings from hypoglossal motoneurons (HMs) in brain stem slices from wild-type and shaky mice at different postnatal stages. Shaky homozygotes showed a decline in mIPSC amplitude and frequency at P9-P13, progressing to significant reductions in mIPSC amplitude and decay time at P18-24 compared to wild-type littermates. Extrasynaptic GlyRs recorded by bath-application of glycine also revealed reduced current amplitudes in shaky mice compared to wild-type neurons, suggesting that presynaptic GlyR function is also impaired. Thus, a distinct, but behaviorally ineffective impairment of glycinergic synapses precedes the symptoms onset in shaky mice. These findings extend our current knowledge on startle disease in the shaky mouse model in that they demonstrate how the progression of GlyR dysfunction causes, with a delay of about 1 week, the appearance of disease symptoms.},
  language  = {en}
}
@article{WeiderWegenerSchmittetal.2015,
  author    = {Weider, Matthias and Wegener, Am{\´e}lie and Schmitt, Christian and K{\"u}spert, Melanie and Hillg{\"a}rtner, Simone and B{\"o}sl, Michael R. and Hermans-Borgmeyer, Irm and Nait-Oumesmar, Brahim and Wegner, Michael},
  title     = {Elevated in vivo levels of a single transcription factor directly convert satellite glia into oligodendrocyte-like cells},
  series = {PLoS Genetics},
  volume    = {11},
  journal   = {PLoS Genetics},
  number    = {2},
  doi       = {10.1371/journal.pgen.1005008},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144123},
  pages     = {e1005008},
  year      = {2015},
  abstract  = {Oligodendrocytes are the myelinating glia of the central nervous system and ensure rapid saltatory conduction. Shortage or loss of these cells leads to severe malfunctions as observed in human leukodystrophies and multiple sclerosis, and their replenishment by reprogramming or cell conversion strategies is an important research aim. Using a transgenic approach we increased levels of the transcription factor Sox10 throughout the mouse embryo and thereby prompted Fabp7-positive glial cells in dorsal root ganglia of the peripheral nervous system to convert into cells with oligodendrocyte characteristics including myelin gene expression. These rarely studied and poorly characterized satellite glia did not go through a classic oligodendrocyte precursor cell stage. Instead, Sox10 directly induced key elements of the regulatory network of differentiating oligodendrocytes, including Olig2, Olig1, Nkx2.2 and Myrf. An upstream enhancer mediated the direct induction of the Olig2 gene. Unlike Sox10, Olig2 was not capable of generating oligodendrocyte-like cells in dorsal root ganglia. Our findings provide proof-of-concept that Sox10 can convert conducive cells into oligodendrocyte-like cells in vivo and delineates options for future therapeutic strategies.},
  language  = {en}
}
@article{KarleSchueleKlebeetal.2013,
  author    = {Karle, Kathrin N. and Sch{\"u}le, Rebecca and Klebe, Stephan and Otto, Susanne and Frischholz, Christian and Liepelt-Scarfone, Inga and Sch{\"o}ls, Ludger},
  title     = {Electrophysiological characterisation of motor and sensory tracts in patients with hereditary spastic paraplegia (HSP)},
  series = {Orphanet Journal of Rare Diseases},
  volume    = {8},
  journal   = {Orphanet Journal of Rare Diseases},
  number    = {158},
  issn      = {1750-1172},
  doi       = {10.1186/1750-1172-8-158},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124763},
  year      = {2013},
  abstract  = {Background: Hereditary spastic paraplegias (HSPs) are characterised by lower limb spasticity due to degeneration of the corticospinal tract. We set out for an electrophysiological characterisation of motor and sensory tracts in patients with HSP. Methods: We clinically and electrophysiologically examined a cohort of 128 patients with genetically confirmed or clinically probable HSP. Motor evoked potentials (MEPs) to arms and legs, somato-sensory evoked potentials of median and tibial nerves, and nerve conduction studies of tibial, ulnar, sural, and radial nerves were assessed. Results: Whereas all patients showed clinical signs of spastic paraparesis, MEPs were normal in 27\% of patients and revealed a broad spectrum with axonal or demyelinating features in the others. This heterogeneity can at least in part be explained by different underlying genotypes, hinting for distinct pathomechanisms in HSP subtypes. In the largest subgroup, SPG4, an axonal type of damage was evident. Comprehensive electrophysiological testing disclosed a more widespread affection of long fibre tracts involving peripheral nerves and the sensory system in 40\%, respectively. Electrophysiological abnormalities correlated with the severity of clinical symptoms. Conclusions: Whereas HSP is primarily considered as an upper motoneuron disorder, our data suggest a more widespread affection of motor and sensory tracts in the central and peripheral nervous system as a common finding in HSP. The distribution patterns of electrophysiological abnormalities were associated with distinct HSP genotypes and could reflect different underlying pathomechanisms. Electrophysiological measures are independent of symptomatic treatment and may therefore serve as a reliable biomarker in upcoming HSP trials.},
  language  = {en}
}
@phdthesis{Duechs2011,
  author    = {D{\"u}chs, Matthias},
  title     = {Effects of Toll-like receptor agonists on the pathogenesis of atopic asthma in mice},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-66369},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2011},
  abstract  = {In the last decades, both the incidence and the severity of asthma have steadily increased. Furthermore, available therapies only treat the symptoms but do not cure the disease. Immune modulation induced by TLR agonists may be a promising novel approach to effectively treat asthma as it targets the underlying immunopathology directly rather than one mediator alone. The aim of this thesis was to investigate if the immunostimulatory properties of Toll-like receptor (TLR) agonists can be utilized to develop novel therapeutic intervention strategies for the treatment of asthma using murine models of allergic inflammation. For this purpose five different TLR agonists were tested in preclinical mouse models of acute and chronic asthma, both in preventive and therapeutic settings. Firstly, TLR-2, 3, 4, 7/8 and 9 agonists were delivered intratracheally at different doses before pulmonary allergen exposure in the asthma model of acute inflammation. TLR9 agonist CpG-containing oligodeoxynucleotides (CpG) > TLR7 agonist Resiquimod (R848) > TLR3 agonists poly(I:C) strongly reduced allergen induced airway eosinophilia and IL-4 levels in a dose-dependent manner. All TLR agonists increased neutrophil numbers, TLR4 agonist lipopolysaccharide (LPS) > TLR2 agonist lipoteichonic acid (LTA) > poly(I:C) > CpG > R848 and, with the exception of R848, the amount of pro-inflammatory cytokines in the airways. Suppressive effects were not dependent upon IFN-γ and IL-10 or associated with increased numbers of regulatory T cells in the airways. All TLR agonists, except LTA, similarly reduced airway eosinophilia and IL-4 levels when applied therapeutically after allergen challenge. These results show that the TLR agonists have different suppressive effects on TH2 responses in the airways which further depend on the dose and the experimental setup in which they were tested. Interestingly, all agonists induced airway neutrophilia, albeit to different degrees, raising the question if TLR ligands are safe for human use when applied directly into the lung. Different TLR agonists are also being developed for human use as adjuvants combined with allergen in specific immunotherapy. Recent clinical data suggest that this may be achieved by induction of allergen-specific TH1 responses. For this reason, the ability of different TLR agonists to induce allergen-specific TH1 and suppress allergen-specific TH2 responses in a preclinical setting was investigated in this thesis. Different doses of the TLR agonists were applied together with allergen, then mice were exposed to allergen aerosol. CpG > LPS >LTA dose-dependently strongly suppressed the development of airway eosinophilia with poly(I:C) and R848 having no effect. The decrease in eosinophilic numbers was associated withincreased neutrophils present in the airways. IL-4 and IL-5 levels in the bronchoalveolar lavage fluid were also decreased when poly(I:C), LPS, and CpG were used. All TLR agonists increased allergen-specific IgG2a, and with the exception of poly(I:C), reduced allergen-specific IgE levels in the serum. Cutaneous anaphylaxis to allergen was completely prevented when LPS or CpG were given as adjuvant. The strongest TH1 responses were induced by CpG and poly(I:C), characterized by the presence of IFN-γ in the bronchoalveolar lavage and the highest allergen-specific IgG2a levels in the serum. This data supports approaches to use TLR9 or TLR4 agonists for human therapy as adjuvant in combination with allergen in novel specific immunotherapy formulations. In the last part of the thesis, it was investigated if TLR activation can also affect the pathology of severe chronic asthma. Therapeutic administration of R848 or CpG reduced features of inflammation and remodeling. Both agonists showed superior effects to dexamethasone, with CpG being more efficient than R848. This result again supports a TLR9-based therapy as a viable option for the treatment of severe chronic asthma which may present a potential alternative for anti-inflammatory therapy with steroids. Taken together, the results of this thesis support the use of TLR agonists to treat asthma. The most favorable efficacy/safety ratio is to be expected from TLR-based therapies combining TLR4 or TLR9 agonists with allergen in specific immunotherapy. In regard to TLR agonist monotherapy, R848 and CpG showed the most promising profiles, CpG particularly in a model of severe chronic asthma. However, since all TLR agonists used in this study also showed pro-inflammatory potential, the safety aspect of such an approach needs to be taken into account.},
  subject      = {Toll-like Rezeptor},
  language  = {en}
}
@article{SpitzelWagnerBreyeretal.2022,
  author    = {Spitzel, Marlene and Wagner, Elise and Breyer, Maximilian and Henniger, Dorothea and Bayin, Mehtap and Hofmann, Lukas and Mauceri, Daniela and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan},
  title     = {Dysregulation of immune response mediators and pain-related ion channels is associated with pain-like behavior in the GLA KO mouse model of Fabry disease},
  series = {Cells},
  volume    = {11},
  journal   = {Cells},
  number    = {11},
  issn      = {2073-4409},
  doi       = {10.3390/cells11111730},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-275186},
  year      = {2022},
  abstract  = {Fabry disease (FD) is a rare life-threatening disorder caused by deficiency of the alpha-galactosidase A (GLA) enzyme with a characteristic pain phenotype. Impaired GLA production or function leads to the accumulation of the cell membrane compound globotriaosylceramide (Gb3) in the neurons of the dorsal root ganglia (DRG) of FD patients. Applying immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT PCR) analysis on DRG tissue of the GLA knockout (KO) mouse model of FD, we address the question of how Gb3 accumulation may contribute to FD pain and focus on the immune system and pain-associated ion channel gene expression. We show a higher Gb3 load in the DRG of young (<6 months) (p < 0.01) and old (≥12 months) (p < 0.001) GLA KO mice compared to old wildtype (WT) littermates, and an overall suppressed immune response in the DRG of old GLA KO mice, represented by a reduced number of CD206\(^+\) macrophages (p < 0.01) and lower gene expression levels of the inflammation-associated targets interleukin(IL)1b (p < 0.05), IL10 (p < 0.001), glial fibrillary acidic protein (GFAP) (p < 0.05), and leucine rich alpha-2-glycoprotein 1 (LRG1) (p < 0.01) in the DRG of old GLA KO mice compared to old WT. Dysregulation of immune-related genes may be linked to lower gene expression levels of the pain-associated ion channels calcium-activated potassium channel 3.1 (KCa3.1) and transient receptor potential ankyrin 1 channel (TRPA1). Ion channel expression might further be disturbed by impaired sphingolipid recruitment mediated via the lipid raft marker flotillin-1 (FLOT1). This impairment is represented by an increased number of FLOT1\(^+\) DRG neurons with a membranous expression pattern in old GLA KO mice compared to young GLA KO, young WT, and old WT mice (p < 0.001 each). Further, we provide evidence for aberrant behavior of GLA KO mice, which might be linked to dysregulated ion channel gene expression levels and disturbed FLOT1 distribution patterns. Behavioral testing revealed mechanical hypersensitivity in young (p < 0.01) and old (p < 0.001) GLA KO mice compared to WT, heat hypersensitivity in young GLA KO mice (p < 0.001) compared to WT, age-dependent heat hyposensitivity in old GLA KO mice (p < 0.001) compared to young GLA KO mice, and cold hyposensitivity in young (p < 0.001) and old (p < 0.001) GLA KO mice compared to WT, which well reflects the clinical phenotype observed in FD patients.},
  language  = {en}
}
@phdthesis{Burow2020,
  author    = {Burow, Wera Tamara},
  title     = {Die Rolle des CEACAM1-Molek{\"u}ls bei der Entstehung von neurogener Entz{\"u}ndung in den Atemwegen},
  doi       = {10.25972/OPUS-20933},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-209331},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2020},
  abstract  = {Neurogene Entz{\"u}ndung ist charakterisiert durch Vasodilatation, Plasmaextravasation und Leukozytenmigration. Im Zuge dieser Dissertationsarbeit konnte ein in vivo Versuchsmodell zur Quantifizierung neurogener Entz{\"u}ndungsreaktionen in den Atemwegen etabliert werden. Der bakterielle Bitterstoff Cycloheximid ist in der Lage, eine Erh{\"o}hung der Plasmaextravasation und Migration neutrophiler Granulozyten zu bewirken. Somit kann Cycloheximid nicht nur protektive Schutzreflexe ausl{\"o}sen, sondern f{\"u}hrt auch lokal zu einer neurogenen Entz{\"u}ndungsreaktion. Das carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) ist an der Regulierung der endothelialen Barrierefunktion beteiligt. Die Versuche zeigen bei CC1-/--M{\"a}usen eine Verminderung der basalen Permeabilit{\"a}t in trachealen postkapill{\"a}ren Venolen. Nach Stimulation mit Cycloheximid zeigen CC1-/--M{\"a}use im Vergleich mit WT-M{\"a}usen eine verminderte Plasmaextravasation in bronchialen postkapill{\"a}ren Venolen. Auch die Permeabilit{\"a}t des Endothels f{\"u}r neutrophile Granulozyten scheint durch CEACAM1-Defizienz in trachealen und bronchialen Venolen herabgesetzt zu werden. Die Anwesenheit des CEACAM1-Molek{\"u}ls verursacht offenbar eine verminderte Stabilit{\"a}t der endothelialen Barriere in postkapill{\"a}ren Venolen der Atemwege. Diese Ergebnisse zeigen eine gegenteilige Funktion von CEACAM1 in postkapill{\"a}ren Venolen der Atemwege im Vergleich mit großen, herznahen Blutgef{\"a}ßen. Des Weiteren scheint sich die Rolle von CEACAM1 in der Entstehung von akuten und chronischen Entz{\"u}ndungsreaktionen zu unterscheiden. Das in dieser Arbeit etablierte Versuchsmodell stellt eine M{\"o}glichkeit dar, neurogene Entz{\"u}ndungsreaktionen als Reaktion auf verschiedene gustatorische Stimulanzien zu testen und zu quantifizieren.},
  subject      = {Entz{\"u}ndung},
  language  = {de}
}
@phdthesis{Rosel2007,
  author    = {Rosel, Eva Annemarie},
  title     = {Die Rolle der endothelialen Stickstoff-Monoxid-Synthase (eNOS) in der Endothelaktivierung},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-27824},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2007},
  abstract  = {Im Mittelpunkt der Arbeit stand die Rolle der endothelialen Stickstoff-Monoxid-Synthase (eNOS) f{\"u}r die Endothelaktivierung. F{\"u}r diese Untersuchungen wurde die MLEC-Zellkulturtechnik (murine lung endothelial cells) und die Gegen{\"u}berstellung des Wiltyp- und eNOS-Knockout-Genotyps verwendet. Die MLEC-Kulturen wurden aus dem mikrovaskul{\"a}ren Stromgebiet der Lungen von C57Bl6-Wildtyp-M{\"a}usen (WT) und von eNOS-Knockout-M{\"a}usen (KO) angelegt und immunomagnetisch (Anti-CD102) zweifach selektioniert. Die Reinheit der Kulturen f{\"u}r Endothelzellen nach zwei Selektionen lag bei {\"u}ber 95\%. WT-Endothelzellen produzieren eine basale Menge an Stickstoff-Monoxid (NO). Sie steigern ihre NO-Produktion nach Stimulation mit VEGF (vascular endothelium growth factor), mit dem Kalzium-Ionophor Ionomycin sowie unter Scherkraftexposition. Die eNOS-Proteinexpression erh{\"o}ht sich dementsprechend nach 12 Stunden Scherkraftexposition. WT- und eNOS-KO-Endothelzellen unterscheiden sich unter basalen Bedingungen nicht in ihrer Oberfl{\"a}chenexpression der Adh{\"a}sionsmolek{\"u}le ICAM-1, E-Selektin, P-Selektin und VCAM-1. Nach Zytokin-Stimulation erh{\"o}hen beide Genotypen ihr Adh{\"a}sionsmolek{\"u}lprofil in gleicher Weise. Sowohl WT- als auch eNOS-KO-Endothelzellen verf{\"u}gen zudem {\"u}ber einen schnellen Mechanismus, der die Hochregulation der P-Selektin-Oberfl{\"a}chenexpression nach Stimulation mit Thrombin oder Menadion in gleicher Weise erm{\"o}glicht. Auf Stimulation mit Thrombin oder Menadion reagieren WT-Zellen mit einem signifikanten Anstieg der Produktion von freien Sauerstoff-Radikalen (ROS, rapid oxygen species). eNOS-KO-Zellen zeigen eine im Vergleich zum WT erh{\"o}hte basale ROS-Produktion. Diese l{\"a}sst sich auch nach Stimulation nicht weiter steigern. Die experimentellen Ergebnisse zeigen, dass die MLEC-Zellkulturtechnik ein verl{\"a}ssliches Modell f{\"u}r Untersuchungen an Gef{\"a}ßendothelzellen darstellt. eNOS-KO-Zellen exprimieren nicht automatisch mehr Adh{\"a}sionsmolek{\"u}le an der Zelloberfl{\"a}che als WT-Zellen. Allerdings ist die basale Produktion von ROS in eNOS-KO-Zellen vermehrt. Folglich ist in diesem Modell eNOS nicht f{\"u}r die konstitutive Suppression der endothelialen Aktivierung verantwortlich. Der NO-Effekt kann nicht in einer direkten und kontinuierlichen Unterdr{\"u}ckung der endothelialen Oberfl{\"a}chenaktivierung liegen. Das Fehlen von NO f{\"u}hrt vielmehr zu einer Verschiebung des Gleichgewichts zwischen dem Radikalf{\"a}nger NO und O2- (Superoxid) zugunsten von O2-. Aufgrund dieses Ungleichgewichts ist die basale ROS-Produktion von eNOS-KO-Zellen vermutlich erh{\"o}ht. Damit wird die Endothelzelle empfindlicher gegen{\"u}ber zus{\"a}tzlichem oxidativen Stress. Die eNOS-KO-Zellen k{\"o}nnen die h{\"o}here ROS-Belastung in den durchgef{\"u}hrten Untersuchungen kompensieren. Es ist aber denkbar, dass bei zus{\"a}tzlichem oxidativen Stress ein erh{\"o}htes Maß an O2- das Startsignal f{\"u}r die Abl{\"a}ufe der endothelialen Aktivierung darstellt.},
  subject      = {Stickstoffmonoxid},
  language  = {de}
}
@article{GruenewaldLangeWerneretal.2017,
  author    = {Gr{\"u}newald, Benedikt and Lange, Maren D and Werner, Christian and O'Leary, Aet and Weishaupt, Andreas and Popp, Sandy and Pearce, David A and Wiendl, Heinz and Reif, Andreas and Pape, Hans C and Toyka, Klaus V and Sommer, Claudia and Geis, Christian},
  title     = {Defective synaptic transmission causes disease signs in a mouse model of juvenile neuronal ceroid lipofuscinosis},
  series = {eLife},
  volume    = {6},
  journal   = {eLife},
  number    = {e28685},
  doi       = {10.7554/eLife.28685},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170004},
  year      = {2017},
  abstract  = {Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3\(^{Δex1-6}\)) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition.},
  language  = {en}
}