Flügel, Alexander

[["dc.bibliographiccitation.firstpage","1930"],["dc.bibliographiccitation.journal","Brain"],["dc.bibliographiccitation.lastpage","1943"],["dc.bibliographiccitation.volume","133"],["dc.contributor.author","Cordiglieri, Chiara"],["dc.contributor.author","Odoardi, Francesca"],["dc.contributor.author","Zhang, B. O."],["dc.contributor.author","Nebel, Merle"],["dc.contributor.author","Kawakami, Naoto"],["dc.contributor.author","Klinkert, Wolfgang E. F."],["dc.contributor.author","Lodygin, Dimtri"],["dc.contributor.author","Luehder, Fred"],["dc.contributor.author","Breunig, Esther"],["dc.contributor.author","Schild, Detlev"],["dc.contributor.author","Ulaganathan, Vijay Kumar"],["dc.contributor.author","Dornmair, Klaus"],["dc.contributor.author","Dammermann, Werner"],["dc.contributor.author","Potter, Barry V. L."],["dc.contributor.author","Guse, Andreas H."],["dc.contributor.author","Fluegel, Alexander"],["dc.date.accessioned","2018-11-07T08:41:30Z"],["dc.date.available","2018-11-07T08:41:30Z"],["dc.date.issued","2010"],["dc.description.abstract","Nicotinic acid adenine dinucleotide phosphate represents a newly identified second messenger in T cells involved in antigen receptor-mediated calcium signalling. Its function in vivo is, however, unknown due to the lack of biocompatible inhibitors. Using a recently developed inhibitor, we explored the role of nicotinic acid adenine dinucleotide phosphate in autoreactive effector T cells during experimental autoimmune encephalomyelitis, the animal model for multiple sclerosis. We provide in vitro and in vivo evidence that calcium signalling controlled by nicotinic acid adenine dinucleotide phosphate is relevant for the pathogenic potential of autoimmune effector T cells. Live two photon imaging and molecular analyses revealed that nicotinic acid adenine dinucleotide phosphate signalling regulates T cell motility and re-activation upon arrival in the nervous tissues. Treatment with the nicotinic acid adenine dinucleotide phosphate inhibitor significantly reduced both the number of stable arrests of effector T cells and their invasive capacity. The levels of pro-inflammatory cytokines interferon-gamma and interleukin-17 were strongly diminished. Consecutively, the clinical symptoms of experimental autoimmune encephalomyelitis were ameliorated. In vitro, antigen-triggered T cell proliferation and cytokine production were evenly suppressed. These inhibitory effects were reversible: after wash-out of the nicotinic acid adenine dinucleotide phosphate antagonist, the effector T cells fully regained their functions. The nicotinic acid derivative BZ194 induced this transient state of non-responsiveness specifically in post-activated effector T cells. Naive and long-lived memory T cells, which express lower levels of the putative nicotinic acid adenine dinucleotide phosphate receptor, type 1 ryanodine receptor, were not targeted. T cell priming and recall responses in vivo were not reduced. These data indicate that the nicotinic acid adenine dinucleotide phosphate/calcium signalling pathway is essential for the recruitment and the activation of autoaggressive effector T cells within their target organ. Interference with this signalling pathway suppresses the formation of autoimmune inflammatory lesions and thus might qualify as a novel strategy for the treatment of T cell mediated autoimmune diseases."],["dc.identifier.doi","10.1093/brain/awq135"],["dc.identifier.isi","000279473900008"],["dc.identifier.pmid","20519328"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6202"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/19486"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Oxford Univ Press"],["dc.relation.issn","0006-8950"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Nicotinic acid adenine dinucleotide phosphate-mediated calcium signalling in effector T cells regulates autoimmunity of the central nervous system"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","10678"],["dc.bibliographiccitation.issue","26"],["dc.bibliographiccitation.journal","PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA"],["dc.bibliographiccitation.lastpage","10683"],["dc.bibliographiccitation.volume","106"],["dc.contributor.author","Dammermann, Werner"],["dc.contributor.author","Zhang, B. O."],["dc.contributor.author","Nebel, Merle"],["dc.contributor.author","Cordiglieric, Chiara"],["dc.contributor.author","Odoardi, Francesca"],["dc.contributor.author","Kirchberger, Tanja"],["dc.contributor.author","Kawakami, Naoto"],["dc.contributor.author","Dowden, James"],["dc.contributor.author","Schmid, Frederike"],["dc.contributor.author","Dornmair, Klaus"],["dc.contributor.author","Hohenegger, Martin"],["dc.contributor.author","Fluegel, Alexander"],["dc.contributor.author","Guse, Andreas H."],["dc.contributor.author","Potter, Barry V. L."],["dc.date.accessioned","2018-11-07T08:28:38Z"],["dc.date.available","2018-11-07T08:28:38Z"],["dc.date.issued","2009"],["dc.description.abstract","The nucleotide NAADP was recently discovered as a second messenger involved in the initiation and propagation of Ca2+ signaling in lymphoma T cells, but its impact on primary T cell function is still unknown. An optimized, synthetic, small molecule inhibitor of NAADP action, termed BZ194, was designed and synthesized. BZ194 neither interfered with Ca2+ mobilization by D-myo-inositol 1,4,5-trisphosphate or cyclic ADP-ribose nor with capacitative Ca2+ entry. BZ194 specifically and effectively blocked NAADP-stimulated [H-3] ryanodine binding to the purified type 1 ryanodine receptor. Further, in intact T cells, Ca2+ mobilization evoked by NAADP or by formation of the immunological synapse between primary effector T cells and astrocytes was inhibited by BZ194. Downstream events of Ca2+ mobilization, such as nuclear translocation of \"nuclear factor of activated T cells\" (NFAT), T cell receptor-driven interleukin-2 production, and proliferation in antigen-experienced CD4(+) effector T cells, were attenuated by the NAADP antagonist. Taken together, specific inhibition of the NAADP signaling pathway constitutes a way to specifically and effectively modulate T-cell activation and has potential in the therapy of autoimmune diseases."],["dc.identifier.doi","10.1073/pnas.0809997106"],["dc.identifier.isi","000267564300053"],["dc.identifier.pmid","19541638"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6205"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/16468"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Natl Acad Sciences"],["dc.relation.issn","0027-8424"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","NAADP-mediated Ca2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Scientific Reports"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Zhang, Bo"],["dc.contributor.author","Watt, Joanna M"],["dc.contributor.author","Cordiglieri, Chiara"],["dc.contributor.author","Dammermann, Werner"],["dc.contributor.author","Mahon, Mary F."],["dc.contributor.author","Flügel, Alexander"],["dc.contributor.author","Guse, Andreas H."],["dc.contributor.author","Potter, Barry V. L."],["dc.date.accessioned","2019-07-09T11:51:04Z"],["dc.date.available","2019-07-09T11:51:04Z"],["dc.date.issued","2018"],["dc.description.abstract","Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+-releasing second messenger known to date, but the precise NAADP/Ca2+ signalling mechanisms are still controversial. We report the synthesis of small-molecule inhibitors of NAADP-induced Ca2+ release based upon the nicotinic acid motif. Alkylation of nicotinic acid with a series of bromoacetamides generated a diverse compound library. However, many members were only weakly active or had poor physicochemical properties. Structural optimisation produced the best inhibitors that interact specifically with the NAADP/Ca2+ release mechanism, having no effect on Ca2+ mobilized by the other well-known second messengers D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] or cyclic adenosine 5'-diphospho-ribose (cADPR). Lead compound (2) was an efficient antagonist of NAADP-evoked Ca2+ release in vitro in intact T lymphocytes and ameliorated clinical disease in vivo in a rat experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Compound (3) (also known as BZ194) was synthesized as its bromide salt, confirmed by crystallography, and was more membrane permeant than 2. The corresponding zwitterion (3a), was also prepared and studied by crystallography, but 3 had more desirable physicochemical properties. 3 Is potent in vitro and in vivo and has found widespread use as a tool to modulate NAADP effects in autoimmunity and cardiovascular applications. Taken together, data suggest that the NAADP/Ca2+ signalling mechanism may serve as a potential target for T cell- or cardiomyocyte-related diseases such as multiple sc"],["dc.identifier.doi","10.1038/s41598-018-34917-3"],["dc.identifier.pmid","30425261"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16042"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59869"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.subject.ddc","610"],["dc.title","Small Molecule Antagonists of NAADP-Induced Ca2+ Release in T-Lymphocytes Suggest Potential Therapeutic Agents for Autoimmune Disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]