TY - JOUR A1 - Hennings, Johannes M. A1 - Kohli, Martin A. A1 - Czamara, Darina A1 - Giese, Maria A1 - Eckert, Anne A1 - Wolf, Christiane A1 - Heck, Angela A1 - Domschke, Katharina A1 - Arolt, Volker A1 - Baune, Bernhard T. A1 - Horstmann, Sonja A1 - Brückl, Tanja A1 - Klengel, Torsten A1 - Menke, Andreas A1 - Müller-Myhsok, Bertram A1 - Ising, Marcus A1 - Uhr, Manfred A1 - Lucae, Susanne T1 - Possible Associations of NTRK2 Polymorphisms with Antidepressant Treatment Outcome: Findings from an Extended Tag SNP Approach JF - PLoS ONE N2 - Background: Data from clinical studies and results from animal models suggest an involvement of the neurotrophin system in the pathology of depression and antidepressant treatment response. Genetic variations within the genes coding for the brain-derived neurotrophic factor (BDNF) and its key receptor Trkb (NTRK2) may therefore influence the response to antidepressant treatment. Methods: We performed a single and multi-marker association study with antidepressant treatment outcome in 398 depressed Caucasian inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Two Caucasian replication samples (N = 249 and N = 247) were investigated, resulting in a total number of 894 patients. 18 tagging SNPs in the BDNF gene region and 64 tagging SNPs in the NTRK2 gene region were genotyped in the discovery sample; 16 nominally associated SNPs were tested in two replication samples. Results: In the discovery analysis, 7 BDNF SNPs and 9 NTRK2 SNPs were nominally associated with treatment response. Three NTRK2 SNPs (rs10868223, rs1659412 and rs11140778) also showed associations in at least one replication sample and in the combined sample with the same direction of effects (\(P_{corr}\) = .018, \(P_{corr}\) = .015 and \(P_{corr}\) = .004, respectively). We observed an across-gene BDNF-NTRK2 SNP interaction for rs4923468 and rs1387926. No robust interaction of associated SNPs was found in an analysis of BDNF serum protein levels as a predictor for treatment outcome in a subset of 93 patients. Conclusions/Limitations: Although not all associations in the discovery analysis could be unambiguously replicated, the findings of the present study identified single nucleotide variations in the BDNF and NTRK2 genes that might be involved in antidepressant treatment outcome and that have not been previously reported in this context. These new variants need further validation in future association studies. KW - brain KW - bipolar disorder KW - mood disorder KW - treatment response KW - genome-wide association KW - major depressive disorder KW - neurotrophic factor gene KW - VAL66MET polymorphism KW - sequence variations KW - messenger RNA Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130924 VL - 8 IS - 6 ER - TY - THES A1 - Klengel, Torsten T1 - Molekulare Charakterisierung der Carboanhydrase Nce103 im Kontext des CO2 induzierten Polymorphismus in Candida albicans T1 - Molecular characterisation of the carbonic anhydrase Nce103 in the context of carbon dioxide induced polymorphism in Candida albicans N2 - Die Detektion von Umweltsignalen und die gezielte zelluläre Reaktion ist eine zentrale und für das Überleben aller Lebewesen essentielle Fähigkeit. Candida albicans, als dominierender humanpathogener Pilz, ist hochgradig verschiedenen biochemischen und physikalischen Umweltbedingungen ausgesetzt, welche sowohl die Zellmorphologie als auch die Virulenz dieses Erregers beeinflussen. In der vorliegenden Arbeit wurde der Einfluss von Kohlendioxid, als ubiquitär vorkommendes Gasmolekül, auf die Zellmorphologie und Virulenz untersucht. Erhöhte Konzentrationen von Kohlendioxid stellen ein äußerst robustes Umweltsignal dar, welches die morphologische Transition vom Hefewachstum zum hyphalen Wachstum, einem Hauptvirulenzfaktor, in Candida albicans stimuliert. In diesem Zusammenhang wurde die Rolle der putativen Carboanhydrase Nce103 durch die Generation von knock – out Mutanten untersucht. Die Disruption von NCE103 in C. albicans führt zu einem Kohlendioxid – abhängigen Phänotyp, welcher Wachstum unter aeroben Bedingungen (ca. 0,033% CO2) nicht zulässt, jedoch unter Bedingungen mit einem erhöhten CO2 Gehalt von ca. 5% ermöglicht. NCE103 ist also für das Wachstum von C. albicans in Wirtsnischen mit aeroben Bedingungen essentiell. Durch Untersuchungen zur Enzymkinetik mittels Stopped – flow wurde in dieser Arbeit gezeigt, dass Nce103 die Funktion einer Carboanhydrase erfüllt. Die biochemische Funktion dieser Carboanhydrase besteht in der Fixation von CO2 bzw. HCO3ˉ in der Zelle zur Unterhaltung der wesentlichen metabolischen Reaktionen. Weiterhin konnte gezeigt werden, dass die Induktion hyphalen Wachstums durch CO2 in C. albicans nicht durch den Transport von CO2 mittels des Aquaporins Aqy1 beeinflusst wird. CO2 bzw. HCO3ˉ aktiviert in der Zelle direkt eine Adenylylcyclase (Cdc35), welche sich grundlegend von den bisher gut charakterisierten G-Protein gekoppelten Adenylylcylasen unterscheidet. Die Generation von cAMP beeinflusst in der Folge direkt die Transkription hyphenspezifischer Gene und nachfolgend die morphologische Transition vom Hefewachstum zum elongierten, hyphalen Wachstum. Dieser Mechanismus konnte sowohl in Candida albicans als auch in Cryptococcus neoformans nachgewiesen werden, was auf einen panfungal konservierten Signaltransduktionsmechanismus schliessen lässt. Die Inhibition dieser spezifischen Kaskade eröffnet neue Ansätze zur Entwicklung spezifischer antimykotischer Wirkstoffe. N2 - Detection of environmental signals and subsequently directed reaction is essential for the survival of all living organisms. Candida albicans, as the predominant human fungal pathogen is exposed to severely different physical and chemical conditions, which influence cell morphology as well as virulence in human. In the present work, the influence of carbon dioxide as ubiquitous gaseous molecule on virulence and cell morphology was analysed. Elevated concentrations of carbon dioxide are a robust signal to induce the morphological transition from yeast growth to an elongated hyphal growth form, which is believed to be one of the main virulence factors in Candida albicans. The role of the putative carbonic anhydrase Nce103p in carbon dioxide signalling is reviewed by generating knockout mutant strains, which exhibited a carbon dioxide dependent phenotype. Growth under aerobic conditions (0,033 % carbon dioxide) is inhibited but feasible in 5% carbon dioxide. Therefore, Nce103p is essential for growth in host niches with aerobic conditions. Analysis of the biochemical properties of Nce103p by stopped – flow kinetics revealed carbonic anhydrase activity. It is hypothesised, that Nce103p is essential for fixation of carbon dioxide and bicarbonate within the cell in order to sustain basic metabolic reactions. Furthermore, the induction of hyphal growth was independent of aquaporine-mediated transport of carbon dioxide. Bicarbonate rather carbon dioxide activates directly the adenylyl cyclase Cdc35p generating cyclic AMP as second messenger and influencing the transcription of hyphal specific genes in Candida albicans thus promoting the morphological transition from yeast growth to elongated hyphal growth. This signal transduction cascade is present in Candida albicans as well as Cryptococcus neoformans and it is believed to be a pan fungal signal transduction cascade. The specific inhibition of carbon dioxide mediated polymorphism may serve as a new target for antifungal therapeutic agents. KW - Candida KW - Candida albicans KW - Kohlendioxid KW - Kohlendioxidfixierung KW - Virulenz KW - Morphologie KW - Signaltransduktion KW - Cyclo-AMP KW - Soor KW - Carboanhydrase KW - Cryptococcus neoformans KW - Morphogenese KW - Hyphe KW - Hefeartige Pilze KW - Knockout KW - Aquaporin KW - Candida albicans KW - Morphology KW - carbon dioxide KW - carbonic anhydrase KW - aquaporine Y1 - 2008 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-34573 ER -