14018
2011
eng
53-62
08. Okt
17
article
1
2016-11-10
--
--
Gene expression profiling of connective tissue growth factor (CTGF) stimulated primary human tenon fibroblasts reveals an inflammatory and wound healing response in vitro
Purpose:
The biologic relevance of human connective tissue growth factor (hCTGF) for primary human tenon fibroblasts (HTFs) was investigated by RNA expression profiling using affymetrix (TM) oligonucleotide array technology to identify genes that are regulated by hCTGF.
Methods:
Recombinant hCTGF was expressed in HEK293T cells and purified by affinity and gel chromatography. Specificity and biologic activity of hCTGF was confirmed by biosensor interaction analysis and proliferation assays. For RNA expression profiling HTFs were stimulated with hCTGF for 48h and analyzed using affymetrix (TM) oligonucleotide array technology. Results were validated by real time RT-PCR.
Results:
hCTGF induces various groups of genes responsible for a wound healing and inflammatory response in HTFs. A new subset of CTGF inducible inflammatory genes was discovered (e.g., chemokine [C-X-C motif] ligand 1 [CXCL1], chemokine [C-X-C motif] ligand 6 [CXCL6], interleukin 6 [IL6], and interleukin 8 [IL8]). We also identified genes that can transmit the known biologic functions initiated by CTGF such as proliferation and extracellular matrix remodelling. Of special interest is a group of genes, e.g., osteoglycin (OGN) and osteomodulin (OMD), which are known to play a key role in osteoblast biology.
Conclusions:
This study specifies the important role of hCTGF for primary tenon fibroblast function. The RNA expression profile yields new insights into the relevance of hCTGF in influencing biologic processes like wound healing, inflammation, proliferation, and extracellular matrix remodelling in vitro via transcriptional regulation of specific genes. The results suggest that CTGF potentially acts as a modulating factor in inflammatory and wound healing response in fibroblasts of the human eye.
Molecular Vision
urn:nbn:de:bvb:20-opus-140189
Molecular Vision 2011; 17:53-62
IZKF (Interdisziplinäres Zentrum für Klinische Forschung), Universität Würzburg
false
true
Axel Seher
Joachim Nickel
Thomas D. Mueller
Susanne Kneitz
Susanne Gebhardt
Tobias Meyer ter Vehn
Guenther Schlunck
Walter Sebald
eng
uncontrolled
Bone morphogenetic protein-2
eng
uncontrolled
Smooth-muscle-cells
eng
uncontrolled
Myofibroblast differentiation
eng
uncontrolled
TGF-beta
eng
uncontrolled
CYR61
eng
uncontrolled
Proliferation
eng
uncontrolled
Mechanisms
eng
uncontrolled
Apoptosis
eng
uncontrolled
Receptor
eng
uncontrolled
Cancer
Medizin und Gesundheit
open_access
Augenklinik und Poliklinik
Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II)
Julius-von-Sachs-Institut für Biowissenschaften
Theodor-Boveri-Institut für Biowissenschaften
Lehrstuhl für Tissue Engineering und Regenerative Medizin
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/14018/060_Seher_Mol_Vis.pdf
6403
2011
eng
article
1
2013-02-05
--
--
Differential Effects of Prenatal Stress in 5-Htt Deficient Mice: Towards Molecular Mechanisms of Gene x Environment Interactions
Prenatal stress (PS) has been shown to influence the development of the fetal brain and to increase the risk for the development of psychiatric disorders in later life. Furthermore, the variation of human serotonin transporter (5-HTT, SLC6A4) gene was suggested to exert a modulating effect on the association between early life stress and the risk for depression. In the present study, we used a 5-Htt6PS paradigm to investigate whether the effects of PS are dependent on the 5-Htt genotype. For this purpose, the effects of PS on cognition, anxiety- and depression-related behavior were examined using a maternal restraint stress paradigm of PS in C57BL6 wild-type (WT) and heterozygous 5-Htt deficient (5-Htt +/2) mice. Additionally, in female offspring, a genome-wide hippocampal gene expression profiling was performed using the Affymetrix GeneChipH Mouse Genome 430 2.0 Array. 5-Htt +/2 offspring showed enhanced memory performance and signs of reduced anxiety as compared to WT offspring. In contrast, exposure of 5-Htt +/2 mice to PS was associated with increased depressive-like behavior, an effect that tended to be more pronounced in female offspring. Further, 5-Htt genotype, PS and their interaction differentially affected the expression of numerous genes and related pathways within the female hippocampus. Specifically, MAPK and neurotrophin signaling were regulated by both the 5-Htt +/2 genotype and PS exposure, whereas cytokine and Wnt signaling were affected in a 5-Htt genotype6PS manner, indicating a gene6environment interaction at the molecular level. In conclusion, our data suggest that although the 5-Htt +/2 genotype shows clear adaptive capacity, 5-Htt +/2 mice –particularly females– at the same time appear to be more vulnerable to developmental stress exposure when compared to WT offspring. Moreover, hippocampal gene expression profiles suggest that distinct molecular mechanisms mediate the behavioral effects of the 5-Htt genotype, PS exposure, and their interaction.
urn:nbn:de:bvb:20-opus-75795
7579
In: PLoS ONE (2011) 6(8): e22715. doi:10.1371/journal.pone.0022715
Daniel Van den Hove
Sissi Brigitte Jakob
Karla-Gerlinde Schraut
Gunter Kenis
Angelika Gertrud Schmitt
Susanne Kneitz
Claus-Jürgen Scholz
Valentina Wiescholleck
Gabriela Ortega
Jos Prickaerts
Harry Steinbusch
Klaus-Peter Lesch
deu
swd
Medizin
Medizin und Gesundheit
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/6403/vandenHove_journal.pone.0022715.pdf
6292
2011
eng
article
1
2012-11-26
--
--
Retinoic acid pathway activity in Wilms tumors and characterization of biological responses in vitro
Background: Wilms tumor (WT) is one of the most common malignancies in childhood. With current therapy protocols up to 90% of patients can be cured, but there is still a need to improve therapy for patients with aggressive WT and to reduce treatment intensity where possible. Prior data suggested a deregulation of the retinoic acid (RA) signaling pathway in high-risk WT, but its mode of action remained unclear. Results: The association of retinoid signaling and clinical parameters could be validated in a large independent tumor set, but its relevance in primary nephrectomy tumors from very young children may be different. Reduced RA pathway activity and MYCN overexpression were found in high risk tumors as opposed to tumors with low/ intermediate risk, suggesting a beneficial impact of RA especially on advanced WT. To search for possible modes of action of retinoids as novel therapeutic options, primary tumor cell cultures were treated in vitro with all-trans-RA (ATRA), 9cis-RA, fenretinide and combinations of retinoids and a histone deacetylase (HDAC) inhibitor. Genes deregulated in high risk tumors showed opposite changes upon treatment suggesting a positive effect of retinoids. 6/7 primary cultures tested reduced proliferation, irrespective of prior RA signaling levels. The only variant culture was derived from mesoblastic nephroma, a distinct childhood kidney neoplasm. Retinoid/HDAC inhibitor combinations provided no synergistic effect. ATRA and 9cis-RA induced morphological changes suggestive of differentiation, while fenretinide induced apoptosis in several cultures tested. Microarray analysis of ATRA treated WT cells revealed differential expression of many genes involved in extracellular matrix formation and osteogenic, neuronal or muscle differentiation. The effects documented appear to be reversible upon drug withdrawal, however. Conclusions: Altered retinoic acid signaling has been validated especially in high risk Wilms tumors. In vitro testing of primary tumor cultures provided clear evidence of a potential utility of retinoids in Wilms tumor treatment based on the analysis of gene expression, proliferation, differentiation and apoptosis.
urn:nbn:de:bvb:20-opus-69137
6913
In: Molecular Cancer (2011) 10:136, doi:10.1186/1476-4598-10-136
Jenny Wegert
Sabrina Bausenwein
Susanne Kneitz
Sabine Roth
Norbert Graf
Eva Geissinger
Manfred Gessler
deu
swd
Krebs
eng
uncontrolled
Wilms tumor
eng
uncontrolled
nephroblastoma
eng
uncontrolled
primary tumor cell culture
eng
uncontrolled
tumor model
eng
uncontrolled
retinoic acid
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2011
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/6292/Gessler138_1476_4598_10_136.pdf
6276
2011
eng
article
1
2012-11-20
--
--
Infection of Human Coronary Artery Endothelial Cells by Group B Streptococcus Contributes to Dysregulation of Apoptosis, Hemostasis, and Innate Immune Responses [Research Article]
Early onset sepsis due to group B streptococcus leads to neonatal morbidity, increased mortality, and long-term neurological deficencies. Interaction between septicemic GBS and confluent monolayers of human coronary artery endothelial cells (HCAECs) was analyzed by genome wide expression profiling. In total, 124 genes were differentially expressed (89 upregulated, 35 downregulated) based on a more than 3-fold difference to control HCAEC. Regulated genes are involved in apoptosis, hemostasis, oxidative stress response, infection, and inflammation. Regulation of selected genes and proteins identified in the gene array analysis was confirmed by Real-time RT-PCR assay (granulocy te chemotactic protein 2), ELISA (urokinase, cyclooxygenase 2, granulocyte chemotactic protein 1), and western blotting (Heme oxygenase1, BCL2 interacting protein) at various time points between 4 and 24 hours. These results indicate that GBS infection might influence signalling pathways leading to impaired function of the innate immune system and hemorrhagic and inflammatory complications during GBS sepsis.
urn:nbn:de:bvb:20-opus-68834
6883
In: Mediators of inflammation (2011), Article ID 971502, 8 p. doi:10.1155/2011/971502
Claudia Beyrich
Jürgen Löffler
Anna Kobsar
Christian P. Speer
Susanne Kneitz
Martin Eigenthaler
deu
swd
Medizin
Medizin und Gesundheit
open_access
Institut für Klinische Biochemie und Pathobiochemie
Förderzeitraum 2011
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/6276/Beyrich108_971502.pdf
5862
2011
eng
article
1
2012-05-10
--
--
The Temporal Dynamics of Differential Gene Expression in Aspergillus fumigatus Interacting with Human Immature Dendritic Cells In Vitro
No abstract avDendritic cells (DC) are the most important antigen presenting cells and play a pivotal role in host immunity to infectious agents by acting as a bridge between the innate and adaptive immune systems. Monocyte-derived immature DCs (iDC) were infected with viable resting conidia of Aspergillus fumigatus (Af293) for 12 hours at an MOI of 5; cells were sampled every three hours. RNA was extracted from both organisms at each time point and hybridised to microarrays. iDC cell death increased at 6 h in the presence of A. fumigatus which coincided with fungal germ tube emergence; .80% of conidia were associated with iDC. Over the time course A. fumigatus differentially regulated 210 genes, FunCat analysis indicated significant up-regulation of genes involved in fermentation, drug transport, pathogenesis and response to oxidative stress. Genes related to cytotoxicity were differentially regulated but the gliotoxin biosynthesis genes were down regulated over the time course, while Aspf1 was up-regulated at 9 h and 12 h. There was an up-regulation of genes in the subtelomeric regions of the genome as the interaction progressed. The genes up-regulated by iDC in the presence of A. fumigatus indicated that they were producing a pro-inflammatory response which was consistent with previous transcriptome studies of iDC interacting with A. fumigatus germ tubes. This study shows that A. fumigatus adapts to phagocytosis by iDCs by utilising genes that allow it to survive the interaction rather than just up-regulation of specific virulence genes.
urn:nbn:de:bvb:20-opus-68958
6895
PLoS One (2011) 6:1, doi:10.1371/journal.pone.0016016
Charles O. Morton
John J. Varga
Anke Hornbach
Markus Mezger
Helga Sennefelder
Susanne Kneitz
Oliver Kurzai
Sven Krappmann
Hermann Einsele
William C. Nierman
Thomas R. Rogers
Juergen Loeffler
deu
swd
Dendritische Zelle
Medizin und Gesundheit
open_access
Medizinische Klinik und Poliklinik II
Förderzeitraum 2011
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/5862/Loeffler_journal.pone.0016016.pdf
13774
2011
eng
151
12
article
1
2016-08-26
--
--
Disorder-specific effects of polymorphisms at opposing ends of the Insulin Degrading Enzymegene
Background
Insulin-degrading enzyme (IDE) is the ubiquitously expressed enzyme responsible for insulin and amyloid beta (Aβ) degradation. IDE gene is located on chromosome region 10q23-q25 and exhibits a well-replicated peak of linkage with Type 2 diabetes mellitus (T2DM). Several genetic association studies examined IDE gene as a susceptibility gene for Alzheimer's disease (AD), however with controversial results.
Methods
We examined associations of three IDE polymorphisms (IDE2, rs4646953; IDE7, rs2251101 and IDE9, rs1887922) with AD, Aβ42 plasma level and T2DM risk in the longitudinal Vienna Transdanube Aging (VITA) study cohort.
Results
The upstream polymorphism IDE2 was found to influence AD risk and to trigger the Aβ42 plasma level, whereas the downstream polymorphism IDE7 modified the T2DM risk; no associations were found for the intronic variant IDE9.
Conclusions
Based on our SNP and haplotype results, we delineate the model that IDE promoter and 3' untranslated region/downstream variation may have different effects on IDE expression, presumably a relevant endophenotype with disorder-specific effects on AD and T2DM susceptibility.
BMC Medical Genetics
10.1186/1471-2350-12-15
urn:nbn:de:bvb:20-opus-137744
BMC Medical Genetics 2011, 12:151. DOI 10.1186/1471-2350-12-15
Jasmin Bartl
Claus-Jürgen Scholz
Margareta Hinterberger
Susanne Jungwirth
Ildiko Wichart
Michael K. Rainer
Susanne Kneitz
Walter Danielczyk
Karl H. Tragl
Peter Fischer
Peter Riederer
Edna Grünblatt
eng
uncontrolled
Insulin Degrading Enzyme
Krankheiten
open_access
Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie
Förderzeitraum 2011
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13774/Bartl_1471-2350-12-151.pdf
13511
2011
eng
e22715
8
6
article
1
2016-06-17
--
--
Differential Effects of Prenatal Stress in 5-Htt Deficient Mice: Towards Molecular Mechanisms of Gene x Environment Interactions
Prenatal stress (PS) has been shown to influence the development of the fetal brain and to increase the risk for the development of psychiatric disorders in later life. Furthermore, the variation of human serotonin transporter (5-HTT, SLC6A4) gene was suggested to exert a modulating effect on the association between early life stress and the risk for depression. In the present study, we used a 5-HttxPS paradigm to investigate whether the effects of PS are dependent on the 5-Htt genotype. For this purpose, the effects of PS on cognition, anxiety-and depression-related behavior were examined using a maternal restraint stress paradigm of PS in C57BL6 wild-type (WT) and heterozygous 5-Htt deficient (5-Htt +/-) mice. Additionally, in female offspring, a genome-wide hippocampal gene expression profiling was performed using the Affymetrix GeneChip (R) Mouse Genome 430 2.0 Array. 5-Htt +/- offspring showed enhanced memory performance and signs of reduced anxiety as compared to WT offspring. In contrast, exposure of 5-Htt +/- mice to PS was associated with increased depressive-like behavior, an effect that tended to be more pronounced in female offspring. Further, 5-Htt genotype, PS and their interaction differentially affected the expression of numerous genes and related pathways within the female hippocampus. Specifically, MAPK and neurotrophin signaling were regulated by both the 5-Htt +/- genotype and PS exposure, whereas cytokine and Wnt signaling were affected in a 5-Htt genotypexPS manner, indicating a genexenvironment interaction at the molecular level. In conclusion, our data suggest that although the 5-Htt +/- genotype shows clear adaptive capacity, 5-Htt +/- mice -particularly females-at the same time appear to be more vulnerable to developmental stress exposure when compared to WT offspring. Moreover, hippocampal gene expression profiles suggest that distinct molecular mechanisms mediate the behavioral effects of the 5-Htt genotype, PS exposure, and their interaction.
PLoS ONE
10.1371/journal.pone.0022715
urn:nbn:de:bvb:20-opus-135111
PLoS ONE 6(8): e22715. doi:10.1371/journal.pone.0022715
false
true
Daniel Van den Hove
Sissi Brigitte Jakob
Karla-Gerlinde Schraut
Gunter Kenis
Angelika Gertrud Schmitt
Susanne Kneitz
Claus-Jürgen Scholz
Valentina Wiescholleck
Gabriela Ortega
Jos Prickaerts
Harry Steinbusch
Klaus-Peter Lesch
eng
uncontrolled
Serotonin transporter polymorphism
eng
uncontrolled
Acute tryptophan depletion
eng
uncontrolled
Anxiety-like behavior
eng
uncontrolled
Long-term depression
eng
uncontrolled
Knock-out mice
eng
uncontrolled
Major depression
eng
uncontrolled
Interferon-alpha
eng
uncontrolled
Physiological functions
eng
uncontrolled
Restraint stress
eng
uncontrolled
Bipolar disorder
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13511/036_vandenHove_PlosONE.PDF