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1
Dibenedetto, Silvia. "Direct activation of endogenous Calcineurin A : biological impact of selective peptide aptamers." Phd thesis, Ecole normale supérieure de lyon - ENS LYON, 2011. http://tel.archives-ouvertes.fr/tel-00757018.
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Therapeutic approaches leading to the stimulation of regeneration, and/or inhibition of degeneration processes in neuromuscular disorders are believed to offer valid therapeutic strategies that would preserve muscle tone and contribute to the quality of life while lengthening patient life span. Activation of CalcineurinA (CnA), a threonine-serine phosphatase, controls gene regulatory programs in skeletal muscle by stimulating slow muscle fiber (type I) gene expression. This phosphatase has been also identified as a key mediator in the hypertrophic response and in skeletal muscle regeneration. Activation of CnA is, therefore, considered as a potentially interesting means of stimulating muscle regeneration in myopathies. We have identified a peptide aptamer that activates CnA in vitro, in cells and in vivo. In a mouse model for denervation-induced muscle atrophy, CnA-activating peptide aptamers show significant positive impact. This is reflected in larger overall muscle cross-sectional surface area due to an increased number of fibers and larger individual fiber surface area. Insight into the biological mechanism is afforded by observation of increased levels of nuclear NFAT transcription factor in these fibers, in agreement with peptide aptamer-mediated activation of CnA. Furthermore, a significant increase in central nuclei, characteristic of the presence of new fibers, is observed in muscles treated with the peptide aptamers specifically activating CnA. Identification of the specific binding site of the peptide aptamer on CnA was achieved using several truncations of the phosphatase, offering insight into the molecular mechanism of action. Together, these studies offer the first proof that direct activation of endogenous CnA has a measureable impact on cellular responses resulting in stimulation of muscle regeneration and enhancement of pathophysiological state in selected animal models.
2
Aichem, Annette. "Calcineurin B in Dictyostelium discoideum." [S.l. : s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=960377670.
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Cook, Erik C. "Calcineurin: From Activation to Inhibition." UKnowledge, 2016. http://uknowledge.uky.edu/biochem_etds/29.
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Calcineurin is a Ser/Thr phosphatase whose function is implicated in critical physiological processes such as immune system activation, fetal heart development, and long-term depression in neurons. Calcineurin has been implicated in the progression of Alzheimer’s disease and cardiac hypertrophy. It is not well understood how calcineurin is activated on a molecular level by Ca2+ and its activating protein calmodulin. Previous data from our lab show that calmodulin interaction induces the folding of the intrinsically disordered regulatory domain of calcineurin in two discrete and distant regions into α-helical conformations and that this folding is critical for complete activation of calcineurin. It was also discovered that one of the helical elements which we call the “distal helix” was unstable at a human body temperature of 37°C in dilute buffer. This raises the question; how can a structure critical for the complete activation of calcineurin be unstable at average human body temperature? Proteins do not exist in solutions of the dilute buffer, but rather in a crowded cosmos that ranges between 200 and 400 g/L of macromolecules such as proteins, DNA, and other cellular components. We show here that phenomenon known as macromolecular crowding can stabilize the distal helix and that stabilization increases the activity of calcineurin at human body temperature.
Much about intrinsically disordered proteins (IDPs) remains a mystery, especially what influences the rate at which they interact with their target molecules. IDPs lack any sort of stable three-dimensional structure because of their lack of sufficient hydrophobic or aromatic amino acids while having a large proportion of polar and charged amino acids. Because of the high degree of charged amino acids, electrostatic forces play a significant role in their interaction other proteins. This is known to be the case for calmodulin which is net negatively charged protein that has over 300 binding targets of which are usually basic amphipathic alpha-helices. The calmodulin-binding site located in the intrinsically disordered regulatory domain of calcineurin is net positively charged, and, interestingly, is flanked by acidic patches on either side. These acidic patches might perturb attractive electrostatic forces between the calmodulin-binding site and calmodulin. Using fluorescence spectroscopy in conjunction with a stopped-flow apparatus to measure the kinetics between calmodulin and calcineurin we seek to characterize the influence of the steric and electrostatic forces between the two proteins.
Also, we present data on RCAN1-4 (Regulator of Calcineurin Isoform 1-4) which has been shown to be an inhibitor in some contexts and an activator of calcineurin in other. RCAN1-4 is expressed in the heart and its upregulation has been shown to prevent calcineurin-mediated pathological cardiac hypertrophy suggesting that it plays an inhibitory role in this context. The work shown demonstrates that RCAN1-4 is a competitive inhibitor of calcineurin and whose binding affinity is modulated by Ca2+/calmodulin. These data unveil a binding site utilized by RCAN1-4 which is commonly used among other calcineurin substrates.
4
Dunlap, Victoria B. "THE DISORDERED REGULATION OF CALCINEURIN: HOW CALMODULIN-INDUCED REGULATORY DOMAIN STRUCTURAL CHANGES LEAD TO THE ACTIVATION OF CALCINEURIN." UKnowledge, 2013. http://uknowledge.uky.edu/biochem_etds/9.
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Calcineurin (CaN) is a highly regulated Ser/Thr protein phosphatase that plays critical roles in learning and memory, cardiac development and function, and immune system activation. Alterations in CaN regulation contribute to multiple disease states such as Down syndrome, cardiac hypertrophy, Alzheimer’s disease, and autoimmune disease. In addition, CaN is the target of the immunosuppressant drugs FK506 and cyclosporin A. Despite its importance, CaN regulation is not well understood on a molecular level. Full CaN activation requires binding of calcium-loaded calmodulin (CaM), however little is known about how CaM binding releases CaN’s autoinhibitory domain from the active site. Previous work has demonstrated that the regulatory domain of CaN (RD) is disordered. The binding of CaM to CaN results in RD folding. Folding of the RD in turn causes the autoinhibitory domain (AID) located C-terminal to the RD to be ejected from CaN’s active site. This binding-induced disorder-to-order transition is responsible for the activation of CaN by CaM. In this work, we explore the nature of the disorder in the RD and its transition to an ordered state, demonstrating that the RD exists in a compact disordered state that undergoes further compaction upon CaM binding. We also demonstrate that a single CaM molecule is responsible for binding to and activating CaN. Finally, we determine that the CaM binding to CaN induces an amphipathic helix (the distal helix) C-terminal to the CaM binding region. The distal helix undergoes a hairpin-like chain reversal in order to interact with the surface of CaM, resulting in the removal of the AID from CaN’s active site. We employ site-directed mutagenesis, size-exclusion chromatography, protein crystallography, circular dichroism spectroscopy, fluorescence anisotropy and correlation spectroscopy, and phosphatase activity assays to investigate the ordering of CaN’s regulatory domain, the stoichiometry of CaN:CaM binding, and the impact of the distal helix on CaM activation of CaN.
5
Erdmann, Frank. "Identifizierung und biochemische Charakterisierung neuer Calcineurin-Inhibitoren." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=967391296.
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Gemke, Ulrike. "Rolle von Calcineurin B bei menschlicher Herzhypertrophie." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2006. http://dx.doi.org/10.18452/15426.
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Herzinsuffizienz mit konsekutivem Herzversagen ist ein zentrales kardiovaskuläres Problem der heutigen Bevölkerung.Ursächlich ist insbesondere eine progrediente Herzhypertrophie. Die Calcium-Calmodulin abhängige Phosphatase Calcineurin (CnR) spielt hierbei in der Pathogenese eine entscheidende Rolle. CnR wird über seine Calciumbindungsstellen an der regulatorischen Untereinheit Calcineurin B (CnB) aktiviert.Um zu untersuchen, inwieweit CnB bei der Hypertrophie verschiedener Ätiologien reguliert wird, wurde in linksventrikulären Myokardbiopsien von Patienten mit Aortenstenose (AS= 14) bzw. aus explantierten Herzen mit Dilatativer Kardiomyopathie (DCM=27) und Koronarer Herzerkrankung (KHK=7) der mRNA-und Proteingehalt von CnB bestimmt und mit der Expression von ANP und BNP korreliert. Als Kontrollgruppe dienten 15 abgelehnte Spenderherzen mit normaler systolischer Funktion und gesunder Morphologie. In den Herzen der Kontroll-, DCM-, und KHK-Gruppen wurde der linksventrikuläre Fibrosegehalt bestimmt. Hierzu wurden eine extern standardisierte Real-Time-PCR-Technik und ein etabliertes Western Blot Verfahren angewandt. Die Ergebnisse werden im Median ± 25%/75%-Perzentile angegeben und mit dem Mann-Whitney-Test bzw. Korrelationsanalysen nach Spearman berechnet. In den Herzen mit DCM zeigte sich eine signifikante Erhöhung der CnB mRNA auf ca. das Dreifache der Kontrollen (293% der Ko, pHeart failure is a central cardiovascular problem for the current population. Cardiac hypertrophy is a central factor. The calcium-Calmodulin dependent phosphatase Calcineurin (CnR) plays a crucial role in the pathogenesis. CnR is activated via its calcium-binding site in the regulatory subunit Calcineurin B (CnB). In order to examine, to what extent CnB is regulated in different aetiologies of hypertrophy, we analysed CnB´s mRNA and protein in left ventricular samples from patients with aortic valve stenosis (AS = 14) and from explanted hearts with dilated (DCM=27) and ischemic (ICM=7) cardiomyopathy and correlated them with the expression of ANP and BNP. As a control, 15 rejected donor hearts with normal systolic function and non-pathologic changed morphology were used. Fibrosis of the left ventricle was determined in three groups: control , DCM and ICM. Therefore, we used an externally standardized real-time PCR and an established Western Blot. Data are given as median ± 25%/75%- percentiles; Mann Whitney test and Spearman´s correlation-analyses were used. CnB mRNA was significantly raised in DCM (293% of control, p
7
Kessen, Ursula. "Biochemische und genetische Untersuchungen zu Calcineurin aus Dictyostelium." [S.l. : s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=95995550X.
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Horn, Fabiana. "A role for calcineurin in Dictyostelium cell development." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294379.
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Namgaladze, Dmitry. "Redox regulation of protein serine threonine phosphatase calcineurin /." [S.l. : s.n.], 2002. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB9977814.
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Marchesan, Elena. "Calcineurin regulates Parkin-translocation to mitochondria and mitophagy." Doctoral thesis, Università degli studi di Padova, 2019. http://hdl.handle.net/11577/3424737.
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The selective removal of dysfunctional mitochondria, named mitophagy, is crucial for the maintenance of cellular homeostasis. This event is initiated by the translocation of the E3 ubiquitin ligase Parkin to intoxicated mitochondria and it requires the kinase PINK1. In a remarkable set of studies it was found that PINK1 operates upstream Parkin in a linear pathway that culminates in the phosphorylation of Parkin, Ubiquitin and Parkin mitochondrial substrates, leading to the ubiquitination of outer mitochondrial membrane proteins. Ubiquitin decorated mitochondria are selectively recruiting autophagy receptors which are required to terminate the organelle via autophagy. In this study we show a previously uncharacterized molecular pathway that correlates the activation of the Ca2+-dependent phosphatase Calcineurin (CaN) to PINK1/Parkin-dependent mitophagy. CaN downregulation or genetic inhibition prevents Parkin translocation to intoxicated mitochondria, and impairs stress-induced mitophagy. Moreover, CaN constitutive activation can trigger Parkin translocation under basal conditions also in the absence of PINK1, but requires PINK1 expression to promote mitophagy.
In summary, we identified CaN as a novel key player in the regulation of Parkin translocation and PINK1/Parkin dependent mitophagy.
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Sieber, Matthias. "Modulatoren des Calcineurin-NFATc-Signalweges in humanen TH-Zellen." Phd thesis, Universität Potsdam, 2010. http://opus.kobv.de/ubp/volltexte/2010/4467/.
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Die Ca2+/Calmodulin-aktivierte Serin/Threonin-Phosphatase Calcineurin ist ein Schlüsselmolekül des T-Zell-Rezeptorabhängigen Signalnetzwerkes. Calcineurin aktiviert die Transkriptionsfaktoren der NFATc-Familie durch Dephosphorylierung und reguliert darüber die Expression wichtiger Zytokine und Oberflächenproteine. Die Aktivität von Calcineurin wird durch zahlreiche endogene Proteine moduliert und ist Angriffspunkt der immunsuppressiven Substanzen Cyclosporin A und FK506.
In dieser Arbeit wurde der alternative niedermolekulare Calcineurin-NFATc-Inhibitor NCI3 hinsichtlich seiner Effekte auf T-Zell-Rezeptor-abhängige Signalwege charakterisiert. Die Ergebnisse zeigen, daß das Pyrazolopyrimidinderivat NCI3 nichttoxisch und zellmembranpermeabel ist. In T-Zell-Rezeptor-stimulierten primären humanen TH-Zellen unterdrückt NCI3 die Proliferation und IL-2-Produktion (IC50-Wert ~4 µM), da die Dephosphorylierung von NFATc und die anschließende nukleäre Translokation gehemmt wird. NCI3 inhibiert die calcineurinabhängige NFAT- und NF-κB-, aber nicht die AP-1-kontrollierte Reprtergenexpression, in mikromolaren Konzentrationen (IC50-Werte 2 bzw. 7 µM). Im Gegensatz zu Cyclosporin A stört NCI3 nicht die Phosphataseaktivität von Calcineurin, sondern interferiert mit der Calcineurin-NFATc-Bindung.
Ein wichtiges endogenes Modulatorprotein für die Calcineurinaktivität ist RCAN1, das vermutlich den Calcineurin-NFATc-Signalweg über einen negativen Rückkopplungsmechanismus reguliert.
Hier wurde gezeigt, daß RCAN1 in humanen TH-Zellen exprimiert wird. Die Spleißvariante RCAN1-1 ist in ruhenden T-Zellen basal exprimiert und wird nicht durch T-Zell-Rezeptor-Stimulierung in seiner Expression verändert. RCAN1-4 dagegen ist in ruhenden Zellen kaum zu detektieren und wird stimulierungsabhängig induziert. Durch die Verwendung Calcineurin-NFATc-spezifischer Inhibitoren wie NCI3 wurde gezeigt, daß die RCAN1-4-Induktion durch diesen Signalweg limitiert ist.
Die in dieser Arbeit gewonnenen Daten und Erkenntnisse tragen dazu bei, das Verständnis der Funktion und Regulation von Calcineurin in T-Zellen zu vertiefen.The Ca2+/calmodulin dependent serine/threonine phosphatase calcineurin is a key molecule in the T cell receptor dependent signalling network. Calcineurin dephosphorylates and thereby activates the transcription factors of the NFATc family that, among others, control the expression of important cytokines and cell surface molecules. The activity of Calcineurin is modulated by several endogenous proteins and is inhibited by the immunosuppressants cyclosporine A and FK506. Here, the novel low molecular weight inhibitor NCI3 was characterized in respect to its effects on T cell receptor dependent signalling. The results of this work show, that the pyrazolopyrimidine derivate NCI3 is nontoxic and permeates the cell membrane. Upon TCR stimulation NCI3 suppresses T cell proliferation and IL-2 production of primary human TH cells with IC50 values of ~4 µM by blocking the dephosphorylation and subsequent nuclear translocation of NFATc. NCI3 conse-quently inhibits calcineurin dependent NFAT- and NF-κB-, but not AP-1-controlled reporter gene expression, in micromolar concentrations (IC50 values 2 and 7 µM, respectively). In opposite to cyclosporine A and FK506, NCI3 does not interfere with the phosphatase activity of calcineurin but rather disturbs the calcineurin-NFATc interaction. A major endogenous modulator of calcineurin is the protein RCAN1, which is supposed to regulate calcineurin-NFATc signalling in a negative feedback loop. The presented data show that RCAN1 is expressed in human TH cells. The splice variant RCAN1-1 is basally expressed in resting T cells, and its expression levels are not changed by T cell receptor stimulation. Expression of RCAN1-4, on the other hand, is nearly undetectable in resting TH cells and is induced upon cell stimulation. By using calcineurin-NFATc specific inhibitors such as NCI3 it could be shown that RCAN1-4 induction is limited by this pathway. This work provides a comprehensive characterization of the novel inhibitor NCI3 and insights into the regulation of calcineurin by RCAN1 in human TH cells.
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Hesselink, Dennis Alexander. "Optimization of calcineurin inhibitor treatment after solid organ transplantation." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2007. http://hdl.handle.net/1765/10510.
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Obasanjo-Blackshire, Mojisola Kofoworola. "The role of calcineurin in myocardial injury and protection." Thesis, King's College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.423178.
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Jensen, Barbara Ann. "The effects of calcineurin inhibitors on epithelial electrolyte transport." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10050573/.
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Calcineurin inhibitor (CNI)-induced hypertension is common after renal transplantation, rendering patients susceptible to cardiovascular and kidney disease, graft failure and death. CNI-induced hypertension occurs as a result of enhanced sodium retention by activation, via phosphorylation, of the renal thiazide-sensitive NaCl cotransporter, NCC (SLC12A3). CNI-treated renal transplant patients also have increased NCC abundance in isolated urinary exosomes. The studies described in this thesis were designed to investigate the effects of CNI treatment on mouse renal and intestinal sodium transport proteins, to determine whether alterations in proteins other than NCC may also contribute towards sodium retention. These changes were compared with those in an established mouse model of metabolic syndrome, comprising hypertension, insulin resistance, obesity and hypercholesterolemia which are also associated with CNI use. The abundance of NCC and phospho-NCC was also investigated in urinary exosomes from patients taking CNIs or with Gitelman syndrome. There was a higher abundance of NCC and pNCC in urinary exosomes from CNI-treated renal transplant patients compared with patients with Gitelman syndrome. Both CNI-treated and metabolic syndrome rodent models displayed a significant increase in pNCC. No differences were observed for intestinal transport proteins with CNI-treatment, however, a lower abundance of PiT1 and SGLT1 in the small intestine was observed with high-fat feeding. Renal NHE3 and ENaC were down-regulated in CNI-treated mice, a response that could be compensatory to the upregulation of pNCC in the DCT. These data provide evidence that CNIs influence a number of renal sodium transport proteins that may contribute towards the development of hypertension following transplantation. These studies suggest an important role for calcineurin in the regulation of blood pressure and sodium transport in the kidney, and its possible involvement in the pathogenesis of hypertension and electrolyte disorders.
15
Politino, Michael. "Calcium- and calmodulin-sensitive interactions of calcineurin with phospholipids /." The Ohio State University, 1989. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487672245903115.
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Li, Shuai. "Targeting the Calcineurin-NFAT Interaction by Solution NMR Spectroscopy." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:14226037.
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The serine/threonine phosphatase calcineurin (Cn) targets the nuclear factors of activated T cells (NFATs) that activate cytokine genes. Calcium influx activates Cn to dephosphorylate multiple serine residues within the ~200 residue NFAT regulatory domain, which triggers joint nuclear translocation of NFAT and Cn. The dephosphorylation process relies on the interaction between Cn and the conserved motifs PxIxIT and LxVP, which are located N- and C-terminal to the phosphorylation sites in NFAT’s regulatory domain. Here, we show that an NFATc1-derived 15-residue peptide segment containing the conserved LxVP motif binds to an epitope on Cn’s catalytic domain (CnA), which overlaps with the previously established PxIxIT binding site on CnA and is distant to the regulatory domain (CnB). Both NFAT motifs partially compete for binding but do not fully displace each other on the CnA epitope, revealing that both segments bind simultaneously to the same epitope on the catalytic domain.
The Cn-NFAT signaling pathway has been well credentialed as a potential target in the treatment of graft transplant rejection, autoimmune diseases and cardiovascular disorders, and is a common target of immunosuppressive drugs cyclosporin A (CsA) and FK506. Although effective in the disruption of Cn phosphatase activity, CsA and FK506 also result in undesired side effects and toxicity, promoting the discovery of alternative inhibitors which can selectively inhibit the Cn-NFAT interaction without altering the functioning of other Cn substrates. Several peptides directly inhibiting NFAT binding to Cn, as well as several small molecule inhibitors of NFAT-Cn association targeting an allosteric site on Cn have been developed previously. However, to-date there have been no reported small molecule inhibitors directed against the PxIxIT-binding site on Cn. Here, we report the fragment-based discovery of several direct-acting small molecule inhibitors targeting the Cn-NFAT interaction, and show that they selectively inhibit NFAT-dephosphorylation and NFAT-mediated gene expression without affecting Cn phosphatase activity against other substrates. We further demonstrate that the binding site for these inhibitors coincides with the core PxIxIT-binding site on Cn. The development of these inhibitors provides a new tool for probing Cn-NFAT signaling, further optimization of which may provide an alternative strategy for immunosuppressive therapy.
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Barrot, Claire-Cécile. "Recherche de Pharmacogènes associés aux effets indésirables des Inhibiteurs de la Calcineurine : développement d'approches bio-informatiques adaptées aux petits échantillons." Thesis, Limoges, 2019. http://www.theses.fr/2019LIMO0079.
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L'efficacité des méthodes de séquençage de nouvelle génération et la réduction de leur coût ont conduit à l'utilisation de nouvelles méthodes, basées sur le concept de l’analyse de big data, appliqué aux données génomiques. Cependant, ces outils nécessitent de très grandes cohorte d’échantillons à analyser, limitées en pharmacogénomique par l’accès aux patients appropriés ainsi que par la logistique complexe des protocoles d’expérimentation animale. La capacité de retirer des résultats fiables et cohérents à partir de petites cohortes reste donc primordiale. Dans le cadre de cette thèse, de nouvelles approches bio-informatiques adaptées aux petites cohortes ont été explorée en recherchant des pharmacogènes associés aux effets indésirables des Inhibiteurs de la CalcineurineEfficiency of new generation sequencing methods and the reduction of their cost have led to use new methods based on big data to analyse genomic data. However, these tools require very large cohorts of samples to be used, whiwh is limited in pharmacogenomics due to access to appropriate patients and complex logistics of animal testing protocols. The ability to obtain reliable and consistent results from small cohorts remains an important challange. As part of this thesis, new bioinformatics approaches adapted to small cohorts were explored by investigation of pharmacogenes related to adverse effects of Calcineurin Inhibitors
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Rooij, Eva van. "Novel insights into the calcineurin/NFAT pathway in cardiac hypertrophy." Maastricht : Maastricht : Universiteit Maastricht ; University Library, Maastricht University [Host], 2004. http://arno.unimaas.nl/show.cgi?fid=7585.
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Kießling, Anja [Verfasser]. "Calcineurin-Inhibitor-freie Immunsuppression – Mycophenolatmofetil-Monotherapie nach Lebertransplantation / Anja Kießling." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2008. http://d-nb.info/1023051389/34.
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Gonde, Christopher. "Incidences of calcineurin-inhibitor adverse events in liver transplant recipients." Thesis, University of Portsmouth, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.516883.
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Reimann, Ricarda. "De novo Calcineurin-Inhibitor-freie Immunsuppression bei Patienten nach Herztransplantation." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-179026.
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Systemische Immunsuppression nach Herztransplantation wurde in den letzten zwanzig Jahren fast ausschließlich unter Zuhilfenahme von Calcineurininhibitoren (CNI) wie Tacrolimus oder Ciclosporin A durchgeführt. Diese Medikamente besitzen jedoch ein erhebliches Nebenwirkungsprofil, und reduzieren insbesondere aufgrund ihrer Nephrotoxizität die Lebensqualität und Lebenserwartung der Patienten.
Mit Proliferations-Signal-Inhibitoren wie Sirolimus und Mycophenolat Mofetil (MMF) stehen jedoch auch Immunsuppressiva zu Verfügung die ein anderes Nebenwirkungsprofil besitzen. Frühere Studien, mit dem Versuch Therapieregime zu ändern, auf Calcineurininhibitoren zu verzichten und ausschließlich auf Sirolimus und MMF zu wechseln, brachten vielversprechende Ergebnisse in Bezug auf Abstoßungsfreiheit und Transplantatvaskulopathie. Die Nierenfunktion konnte durch den Therapiewechsel erhalten werden und eine fortschreitende Nierenschädigung sogar verhindert werden (Fenandez-Valls M.2005). Alle diese bisherigen Untersuchungen basierten jedoch auf Studienprotokollen, die ein spätes Absetzen der Calcineurininhibitoren vorsahen.
In dieser Studie wurden fünfzehn Patienten unmittelbar ab dem Zeitpunkt der orthotopen Herztransplanatation mit einer Calcineurininhibitor freie Immunsuppression behandelt. Als Basis- immunsuppression erhielten die Patienten Sirolimus (Rapamune®, Wyeth Pharma, Münster) mit angestrebtem Plasmaspiegel zwischen 10 und 15ng/ml, MMF (Cellcept®, Roche Pharmaceuticals AG, Basel, Schweiz) mit angestrebtem Talspiegel zwischen 1,5 und 4 µg/ml, sowie Corticosteroide (Prednisolut®, Mibe GmbH, Sandersdorf-Brehna) mit einer Dosis von initial 1mg/kg/Tag auf 0,1mg/kg/Tag ausgeschlichen. Die Patienten wurden über einen Zeitraum von fünf Jahren nachuntersucht. Dabei wurde neben dem Überleben der Patienten unter anderem die Häufigkeit von Abstoßungsreaktionen, Transplantatvaskulopathie, Pumpfunktion des Grafts, Nierenfunktion sowie Lipid und Glucosestoffwechsel beobachtet.
Unsere Studie zeigte, dass de novo Calcineurininhibitor-freie Immunsuppression nach Herztransplantation mit guten klinischen Ergebnissen möglich ist, 14 der 15 in die Studie eingeschlossenen Patienten waren nach fünf Jahren am Leben. Die Anzahl der Abstoßungsreaktionen war jedoch höher als unter konventioneller Immunsupression. In unserer Studie, mit komplett CNI freiem Therapieprotokoll, war nach fünf Jahren lediglich bei 40% der Patienten keine Abstoßungsreaktion aufgetreten.
Im Rahmen der Transplantatvaskulopathie kommt es nach Herztransplantation häufig zu einer Intimaproliferation und so zu einer Einengung der Gefäßdurchmesser. Die TVP stellt langfristig die primäre Ursache für ein Transplantatversagen dar und führt so entweder zum Tode oder zu einer erneuten Transplantation. In unserer Kohorte wurde über einen Beobachtungszeitraum von 5 Jahren keine Transplantatvaskulopathie beobachtet. Die Serumtriglyceridspiegel waren trotz Therapie mittels Statinen erhöht.
Die chronische Nierenschädigung durch Calcineurininhibitoren ist irreversibel und die Nierenfunktion kann sich nur in geringem Maße erholen, wenn diese abgesetzt werden (Ojo AO, 2003). Sowohl MMF als auch Sirolimus haben keine nephrotoxischen Effekte und die Kombination beider verspricht einen Erhalt der Nierenfunktion über lange Zeit. Die Nierenfunktion in unserer Kohorte blieb nicht nur stabil, sondern verbesserte sich sogar leicht in dem Zeitraum der 5-Jahres Untersuchung. In keinem Fall wurde eine Nierenersatztherapie erforderlich. Die Kombination von MMF und Sirolimus mit kompletter Vermeidung von Calcineurininhibitoren scheint die Nierenfunktion zu erhalten und verbessert daher auch das Langzeit - Überleben.
Während die Nephrotoxizität vermieden werden konnte, traten aber häufig andere nachteilige Ereignisse auf. Chirurgische Interventionen aufgrund von Perikardergüssen wurden in 5 Fällen erforderlich. Auch Pleuraergüsse, periphere Ödeme und venöse Thrombosen wurden beobachtet. Zwei Patienten mussten zwischenzeitlich aus der Studie genommen werden, da schwere gastrointestinale Nebenwirkungen auftraten. In drei Fällen wurde eine Konversion zu Calcineurininhibitoren nötig, da verzögerte Wundheilung auftrat, die eventuell auf den antiproliferativen Effekten von Sirolimus auf Fibroblasten beruht.
Beim Vergleich mit Calcineurininhibitor basierter Immunsuppression, sollten uns mehrere Ergebnisse davor warnen, diese Therapie als Standard nach Herztransplantation zu verwenden. Allen voran die Anzahl der Abstoßungsreaktionen. Diese können schwerwiegende Folgen haben und schlimmstenfalls zu irreversiblem Transplantatversagen führen. Für Patienten, die beispielsweise ein beginnendes Nierenversagen haben, ist diese Immunsuppression jedoch ins Auge zu fassen.
Unsere Daten zeigen einen außergewöhnlichen Effekt in Bezug auf das Auftreten der Transplantatvaskulopathie, dem Verlauf der Nierenfunktion und dem Auftreten von Transplantatvaskulopathie, verglichen mit Patienten, die mit Calcineurininhibitoren behandelt wurden. Die Verbesserung der Nierenfunktion für Patienten, mit beginnendem Nierenversagen ist ermutigend, hinsichtlich Erhaltung von Nierenfunktion und damit Lebensqualität nach Herztransplantation
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Bieber, Thomas, Michael Cork, Charles Ellis, Giampiero Girolomoni, Richard Groves, Richard Langley, Thomas Luger, et al. "Consensus Statement on the Safety Profile of Topical Calcineurin Inhibitors." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-135523.
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Krämer, Dana. "Calcineurin : a regulator of neuronal gene expression in the cerebellum." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.615813.
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Bieber, Thomas, Michael Cork, Charles Ellis, Giampiero Girolomoni, Richard Groves, Richard Langley, Thomas Luger, et al. "Consensus Statement on the Safety Profile of Topical Calcineurin Inhibitors." Karger, 2005. https://tud.qucosa.de/id/qucosa%3A27656.
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Rocchetti, Francesca. "Study of calcineurin pro-oncogenic role in acute lymphoblastic leukemia." Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCC166.
Full textAbstract:
Malgré les avancés thérapeutiques, le pronostic des leucémies aiguës lymphoblastiques (LAL) reste mauvais. Notre laboratoire a montré que la calcineurine (Cn) est requise pour le maintien à long terme des LAL-T. Sa délétion est associée à la dérégulation de l'expression de plusieurs gènes, dont TRNP1 et NFIB, qui sont nouveaux dans le contexte des LAL-T. Nous avons montré que la suppression de leur expression a un effet délétère sur les cellules leucémiques de LAL-T in vitro et in vivo. Cn est aussi activée dans les LAL-B BCR-ABL+. Des travaux publiés ont proposé que son inhibition par la cyclosporine A (CsA) sensibilise les cellules leucémiques aux inhibiteurs de BCR-ABL. Nous montrons ici que cette sensibilisation est indépendante de l'inhibition de Cn. En effet, son inactivation génique n'affecte ni le maintien, ni la propagation de ces LAL-B in vivo. In vitro, la CsA sensibilise ces cellules leucémiques aux inhibiteurs de BCR-ABL en présence ou non de Cn. Le pronostic des patients atteints de LAL-B est mauvais lorsqu'ils présentent la délétion du gène codant pour le facteur de transcription Ikaros (IKZF1). Dans un modèle murin de LAL-B combinant BCR-ABL avec la perte d'un allèle de IKZF1 dans le lignage B, now montrons une accélération de l'émergence de la maladie et une dérégulation de gènes préférentiellement exprimés dans les cellules souches/progéniteurs hématopoïétiques précoces. Ceci suggère que la perte d'un allèle de IKZF1 permet la reprogrammation des progéniteurs B, cellules d'origine de ces leucémies, vers un stade plus primitif et indifférencié, augmentant ainsi l'agressivité de la maladieAlthough acute Iymphoblastic leukemia (ALL) cure rates improved in the last decades, outcome for primary resistant and relapsed patients remains poor. Our laboratory showed that calcineurin (Cn) is essential to T-ALL Leukemia Initiating Cells activity. Its deletion is associated with strong anti-leukemic effects and to the deregulation of several genes, including TRNP1 and NFIB, which have never been reported in T-ALL. Here, we demonstrate that silencing of these genes is deleterious to T-ALL cells both in vitro and in vivo, unravelling new actors involved in leukemogenesis. Cn is activated in BCR-ABL+ B-ALL (Ph+ B-ALL) as well and its inhibition by cyclosporin A (CsA) was reported to sensitize leukemic cells to BCR-ABL inhibitors in a mouse model of the disease. We demonstrate here that this sensitization is due to off-target effects of CsA, since Cn genetic deletion did not affect BCR-ABL-induced B-ALL maintenance and propagation in two mouse models of the disease. Moreover, CsA similarly sensitized Cn+ and Cn- leukemic cells to BCR-ABL inhibitors in vitro. The outcome of B-ALL is particularly poor when patients present deletions of IKZF1, the gene encoding the transcription factor Ikaros, which are observed in >800/0 of Ph+ B-ALL cases. Using a mouse model of BCR-ABL-induced B-ALL in which one copy of Ikaros can be specifically deleted in pro-B cells, we observed acceleration of leukemia onset and a stem-cell/early progenitor-like transcriptomic signature. Thus, the loss of one copy of Ikaros allows the reprogramming of the pro/pre-B cell of origin towards a more primitive, undifferentiated state, likely explaining the increased aggressiveness of the disease
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Yin, Lunxiang. "Synthesis of new calcineurin inhibitors via Pd-catalyzed cross coupling reactions." Doctoral thesis, [S.l. : s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=975817868.
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Martínez, Høyer Sergio 1983. "Unraveling the molecular mechanisms involved in RCAN-peptide mediated inhibition of calcineurin-NFAT signaling and its potential as an inhibitor of tumor progressions." Doctoral thesis, Universitat Pompeu Fabra, 2012. http://hdl.handle.net/10803/123913.
Full textAbstract:
The calcineurin-NFATc signaling pathway is involved in many aspects of
the development and function of the immune, neural, skeletal,
cardiovascular and muscular system of vertebrates. Regulators of
Calcineurin (RCAN) proteins constitute a family of endogenous regulators
of calcineurin, which play an important role in the modulation of the
calcineurin-NFATc pathway. Here, we identifiy a novel protein kinase CK2
dependent mechanism by which the CIC motif of RCAN proteins modulate
the final signaling output of the pathway. Moreover, we show that the
functional CIC motif of RCANs responsible for Cn-NFATc regulation is
sufficient to inhibit tumor progression producing a strong anti-angiogenic
phenotype in an orthotopic human breast cancer mouse model. Therefore,
a CIC-derived peptide has potent immunosuppressive and antitumoral
activities by itself. Finally, the results here presented provide important
insights for the rational design of potent and specific NFATc inhibitory
drugs, which could be of use in autoimmune diseases and cancer.La vía de señalización calcineurina-NFATc desempeña diversos roles en el desarrollo y function en el sistema, immune, nervioso, esqueletico, cardiovascular y muscular de veretebrados. Las proteínas RCAN (Regulators of Calcineurin), constitutyen una familia de reguladores endógenos de la calcineurina (Cn) que juegan un papel importante en la modulación de dicha vía. En el presente trabajo, hemos identificado un nuevo mecanismo de regulación, dependiente de la proteína quinasa CK2, por el cual el motivo CIC de las RCAN regula la vía Cn-NFATc. Además, demostramos que el motivo CIC de las RCAN responsable de la regulación de la vía Cn-NFATc, es suficiente para inhibir la progresión tumoral, produciendo un fuerte efecto angiogénico en un modelo ortotópico murino de tumor de mama. Por tanto, un péptido derivado del motivo CIC posee actividad inmunosupresora y antitumoral por sí mismo. Finalmente, este trabajo proporciona nuevos conocimientos que pueden ser de aplicación en el desarrollo racional de nuevos fármacos, especificos y potentes inhibidores de NFATc con posibles aplicaciones en la terapia immunosupresora y del cáncer.
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Li, Qiong. "Factors contributing to the development of cardiac hypertrophy : calcineurin dependent pathway /." [St. Lucia, Qld.], 2006. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe19384.pdf.
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Wilkins, Benjamin Joseph. "Calcineurin-NFAT Signaling in Cardiac Hypertrophy: In Sickness and In Health?" University of Cincinnati / OhioLINK, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1088446389.
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Nguyen, Huong. "Molecular Pathways Involved In Calcineurin Inhibitor Nephrotoxicity In Kidney Allograft Transplants." VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/2545.
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ABSTRACT MOLECULAR MECHANISMS AND GENE SIGNATURES INVOVLED IN CALCINEURIN INHIBITOR NEPHROTOXICITY IN KIDNEY ALLOGRAFT By Huong Le Diem Nguyen, M.S. A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science in Physiology at Virginia Commonwealth University. Virginia Commonwealth University, 2011. Major Director: Valeria Mas, Ph.D. Associate Professor, Department of Surgery and Pathology Director of Molecular Transplant Research Laboratory, Division of Transplant Calcineurin inhibitors (CNI), cyclosporin A and tacrolimus, are potent immunosuppressive agents but induce toxicities causing damages and graft dysfunction, and have been suggested to contribute to late-term loss of graft in kidney transplant recipients. Even though insights on mechanism of CNI nephrotoxicity have been uncovered, prevention and treatment of these toxicities remain a major challenge in the clinical administration of CNI due to low dose-toxicity correlation, difficulty in establishing a differential patho-histological diagnosis, and varying individual susceptibility. We hypothesize that CNI nephrotoxicity follows distinct disease pathways and is characterized by significant gene signatures that differentiate it from other conditions such as acute rejection and chronic allograft dysfunction. Moreover, we postulate that CNI-induced toxicity profiles contribute to the IF/TA signatures. Microarray analysis and gene annotation were done on the study database included of tissues diagnosed with CNI nephrotoxicity (n = 9), interstitial fibrosis/tubular atrophy (IF/TA, n=10), and normal allografts (NA, n = 8). All samples were histologically classified based on the revised Banff ‘07 criteria for renal allograft pathology. Top-scored biological networks in CNI tissues were related to metabolic disease, cellular development, renal necrosis, apoptosis cell-death, immunological disease, inflammatory disease, and many others. Canonical pathway analysis emphasized oxidative stress response mediated by NRF2 and various cell-death signaling pathways including 14-3-3 signaling pathway, p53 signaling pathway, and TGF-β signaling pathway. Profiling of differentially expressed genes was done based on their statistical significance and biological relevance to the unique pathology of CNI nephrotoxicity. Among these, three genes RGS1, CXCR4, and TGIF1 were further quantitatively evaluated using real time-PCR. Between CNI group and normal allograft, t-test results showed only RGS1 gene expression level was statistically significant. Between IF/TA group in normal allograft, both RGS1 and CXCR4 showed statistical significance. The calculated relative fold changes revealed an up-regulated pattern of RGS1 and CXCR4 expression in association with pathological groups (CNI and IF/TA). We did not, however, find any association between the expression of TGIF1 in either CNI group or IF/TA group.
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Oliveria, Seth F. "Localized calcineurin controls L-type Ca²⁺ channel activity and nuclear signaling /." Connect to abstract via ProQuest. Full text is not available online, 2008.
Find full textAbstract:
Thesis (Ph.D. in Neuroscience) -- University of Colorado Denver, 2008.Typescript. Includes bibliographical references (leaves 110-125). Online version available via ProQuest Digital Dissertations.
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Wilkins, Benjamin J. "Calcineurin-NFAT signaling in cardiac hypertrophy in sickness and in health? /." Cincinnati, Ohio : University of Cincinnati, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=ucin1088446389.
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Pane, Roberto. "Rôles de la protéine cardio-protectrice, Carabine, et de ses partenaires nucléaires, MLL3 et CHD8, dans la reprogrammation génique au cours de l’hypertrophie cardiaque." Thesis, Toulouse 3, 2020. http://www.theses.fr/2020TOU30157.
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L'insuffisance cardiaque (IC) est le resultat d'une mauvaise hypertrophie cardiaque (HC), caractérisée par une croissance non mitotique des cardiomyocytes. Le HC est induit par une importante reprogrammation génique, qui voit la ré-expression de certains gènes fœtaux. Récemment, les analyses des marques histoniques ont montré que cette reprogrammation est associée à des changements épigénétiques dans les cardiomyocytes. Cependant, les mécanismes du remodelage de la chromatine impliqués dans l'activation de l'épigénome hypertrophique restent mal connus. Bisserier et al. (2015) ont identifié une nouvelle protéine cardioprotectrice, Carabin. Cette protéine est connue pour inhiber la phosphatase Ca2+/Calmoduline-dépendante, la Calcineurine (CaN), un activateur du HC. Afin de mieux comprendre le mécanisme d'action de Carabin, un criblage double hybride (CDH) d'une bibliothèque d'ADNc ventriculaire gauche a été réalisé. Nous avons identifié 47 interactants putatifs de Carabin, dont 15 étaient impliqués dans la régulation transcriptionnelle et 5 d'entre eux étaient des remodeleurs de chromatine. L’objectif de mes études de doctorat était d'abord de vérifier l'implication de ces remodeleurs de chromatine dans la réponse des cardiomyocytes au stress hypertrophique et de caractériser leur mode d'action lors de l'apparition du HC. Effectivement, trois d'entre eux, l'histone déméthylase JARID1B (Jumonji AT Rich Interactive Domain 1B), l'histone méthyltransférase MLL3 (Mixed-Lineage Leukemia Protein 3) et le remodeleur de chromatine ATP-dépendant CHD8 (Chromodomain-helicase-DNA-binding protein 8) sont surexprimés dans les cœurs insuffisants humains et de souris et ont un effet pro-hypertrophique puissant dans les cardiomyocytes primaires. Cette première partie de mon projet a identifié MLL3, CHD8 et JARID1B comme des nouveaux remodeleurs de la chromatine impliqués dans l'activation du programme de gènes hypertrophiques dans les cardiomyocytes. Dans une deuxième partie, j'ai caractérisé les mécanismes moléculaires régulant l'expression des gènes induit par MLL3 et CHD8 en réponse au stress hypertrophique. J'ai montré que dans les cœurs sains, Carabin et MLL3 forment un complexe macromoléculaire avec CaN et la sérine / thréonine kinase 24 (STK24), qui était present dans le CDH. Dans ce complexe, MLL3 est phosphorylé par STK24. Sous stress hypertrophique, la libération de STK24 et de Carabin du complexe MLL3-CaN entraîne une activation de CaN et une déphosphorylation de MLL3, augmentant son activité d'histone méthyltransférase. De plus, dans ces conditions, j'ai observé une diminution de la liason CHD8-Carabin et une augmentation des interactions CHD8-MLL3. Ces résultats suggèrent que le dépôt de H3K4me1 médié par MLL3 peut être associé à un déplacement des nucléosomes par CHD8. Dans une troisième partie, j'ai étudié l'impact du knock down MLL3 sur l’instauration de l’HC. Pour cela, un virus adéno-associé cardiotrope (AAV9) exprimant trois shRNA ciblant MLL3 a été injecté à des souris soumises à un stress hémodynamique cardiaque par constriction aortique transversale. De façon intéressante, la régulation négative de l'expression de MLL3 a réduit l'hypertrophie cardiaque. J'ai ensuite identifié le programme du gène hypertrophique régulé par MLL3 en utilisant des expériences ChIP-seq réalisées sur la chromatine des cœurs de souris soumises ou non à un stress hémodynamique. En conclusion, CHD8 a donné des résultats très encourageants pour la prévention de l'IC, mais il nécessite une meilleure compréhension de ses implications moléculaires dans la pathologie. En revanche, MLL3, s'est avéré être un élément crucial dans la réponse hypertrophique médiée par CaN agissant directement sur la chromatine. Pour cette raison, le ciblage MLL3 peut représenter une stratégie intéressante pour le développement de nouvelles thérapies pour bloquer la progression du HC en HFMaladaptive cardiac hypertrophy (CH) is a dynamic process that lead to heart failure, a major cause of mortality worldwide. CH is induced by an important gene reprogramming, characterized by the re-expression of some fetal genes. Recently, genome-wide analyses of histone marks indicate that this gene reprogramming is associated with epigenetic changes in cardiomyocytes. However, the mechanisms of chromatin remodeling implicated in the activation of the hypertrophic epigenome are still poorly understood. Our laboratory identified a novel cardioprotective protein named Carabin. This protein inhibits the Ca2+/Calmodulin-dependent phosphatase, Calcineurin (CaN), a well-known and potent activator of CH. To better understand the mechanism of action of Carabin, a yeast two-hybrid screen (Y2HS) of a left human ventricular cDNA library was performed. We identified 47 putative interactants of Carabin, 15 of which were implicated in transcriptional regulation and 5 of them were chromatin remodelers. The aim of my PhD studies was first, to determine the involvement of these chromatin remodelers in cardiomyocyte response to hypertrophic stress and second, to further charactarize their mode of action at the onset of CH.Among the chromatin remodelers that we identified, three of them, the histone demethylase JARID1B (Jumonji AT Rich Interactive Domain 1B), the histone methyl transferase MLL3 (Mixed-Lineage Leukemia Protein 3) and the ATP-dependent chromatin remodeler CHD8 (Chromodomain-helicase-DNA-binding protein 8) were overexpressed in human and mouse failing hearts and displayed potent pro-hypertrophic effect in primary cardiomyocytes. These data took me to identify MLL3, CHD8 and JARID1B as new chromatin remodelers implicated in the activation of the hypertrophic gene program in cardiomyocytes. Then, I characterized the molecular mechanisms of MLL3 and CHD8 regulating gene expression in response to hypertrophic stress. I showed that in basal conditions, Carabin and MLL3 formed a macromolecular complex together with CaN and the Serine/Threonine Kinase 24 (STK24), which was identified in the Carabin targeted-Y2HS. Specifically, I found that MLL3 was phosphorylated by STK24. Under hypertrophic stress, the release of STK24 and Carabin from MLL3-CaN complex led to CaN activation and MLL3 dephosphorylation, thereby increasing MLL3 histone methyltransferase activity. Moreover, in these conditions, I observed a decrease of CHD8-Carabin and an increase of CHD8-MLL3 interactions. These results suggest that MLL3-mediated H3K4me1 deposition may be associated with nucleosome displacement by CHD8.Finally, I studied the impact of MLL3 knock down on cardiac hypertrophy development. For that, I constructed a cardiotropic Adeno-Associated Virus serotype 9 expressing three MLL3-targeting shRNAs that was injected in mice subjected to a cardiac hemodynamic stress induced by transverse aortic constriction (TAC). Interestingly, I found that MLL3 knock-down reduced cardiac hypertrophy. I also identified the hypertrophic gene program regulated by MLL3 using ChIP-seq experiments performed on chromatin extracted from mice hearts subjected or noto TAC. In conclusion, CHD8 has given very encouraging results for HF prevention but it requires a better understanding of its molecular implications in the pathology. In contrast, MLL3, has proven to be a crucial element in the CaN-mediated hypertrophic response directly acting on chromatin. For this reason, MLL3 targeting can represent an interesting strategy for the development of new therapies to slowdown or even block HF progression
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Lopez, Johanna. "The MAKAPbeta Signalosome Is Involved In Cardiac Myocyte Hypertrophy Through The Recruitment Of Calcineurin Abeta: A Study On How Multimolecular Complexes Are Important For The Integration And Fidelity Of Signal Transduction Behind Cellular And Physiological Responses." Scholarly Repository, 2009. http://scholarlyrepository.miami.edu/oa_theses/226.
Full textAbstract:
Myocyte hypertrophy is the major compensatory response of the heart to chronic stress. It is induced by the activation of a network of interdependent, intracellular signaling pathways.1 An important pathway activated during the hypertrophic response is the calcineurin Abeta-NFATc transcription factor pathway.2 Our laboratory has recently discovered that calcineurin Abeta and NFATc transcription factors can associate with the scaffold protein mAKAPbeta.3 mAKAPbeta is a scaffold protein that forms a multimolecular signalosome located to the nuclear envelope of cardiac myocytes. Preliminary data demonstrate that calcineurin Abeta binds to a specific site on mAKAPbeta that lacks any of the consensus calcineurin binding sequences previously described. In this report, it is shown that a peptide, which contains the mAKAPbeta -calcineurin Abeta binding domain, associates with calcineurin Abeta in a calcium/calmodulin dependent manner. In addition, the binding of this mAKAPbeta peptide to calcineurin Abeta has no effect on calcineurin?s phosphatase activity. In fact, calcineurin Abeta bound to this mAKAPbeta peptide is catalytically active and capable of dephosphorylating NFAT. This is novel since other scaffold proteins that associate with calcineurin Abeta have been reported to inhibit its phosphatase activity. Furthermore, in our laboratory it has been shown that mAKAPbeta is required for both the nuclear translocation of NFATc and the induction of myocyte hypertrophy in vitro.4 In this report it is demonstrated that inhibition of calcineurin Abeta association to mAKAPbeta affects NFATc phosphorylation state and attenuates the norepinephrine induced hypertrophic response in primary neonatal cardiac myocytes. This study supports the hypothesis that the formation of multimolecular signaling complexes, like the mAKAPbeta signalosome, is necessary for the integration and fidelity of signal transduction involved in physiological processes like hypertrophy. Although hypertrophy is an adaptive response; it is often accompanied by maladaptive remodeling of the heart that can result in heart failure, a leading cause of death in the United States. Research in the signaling complexes involved in myocyte hypertrophy, like the mAKAPbeta signalosome, may lead to the development of novel treatments for pathologic hypertrophy and heart failure.
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Pouche, Lucie. "Variabilité d'origine génétique et épigénétique de la pharmacodynamie des inhibiteurs de la calcineurine en transplantation rénale." Thesis, Limoges, 2016. http://www.theses.fr/2016LIMO0017/document.
Full textAbstract:
Ce travail de thèse reposait sur l’hypothèse que la variabilité génétique des protéines « cibles » des médicaments immunosuppresseurs de la famille des inhibiteurs de la calcineurine (ICN ; ciclosporine et tacrolimus) pourrait expliquer une partie de la variabilité observée dans leur efficacité et toxicité. Une revue de la littérature nous a permis de lister un panel de variants génétiques au sein de la voie de la calcineurine, considérés comme étant de bons candidats pour des études en transplantation. Ces variants n’ont pas été associés au risque de rejet aigu ou d’infection grave dans une étude incluant 381 patients transplantés rénaux suivis durant un an après la transplantation. La variabilité pharmacodynamique des ICN a ensuite été explorée au travers des régulations épigénétiques. Une analyse de la méthylation de l’ADN après exposition médicamenteuse a été menée sur deux modèles. Premièrement, la lignée cellulaire JURKAT a été utilisée pour développer la méthode d’immunoprécipitation de l’ADN méthylé (MeDIP). Chez des souris traitées par ciclosporine et tacrolimus durant 3 mois, nous avons ensuite isolé les cellules cibles des médicaments, les lymphocytes T CD4 puis, après immunoprécipitation de l’ADN méthylé et analyse par séquençage pangénomique haut débit (MeDIP-seq, séquençeur Ion Proton), nous avons recherché les régions du génome présentant des différences de méthylation induites par le traitement. L’analyse différentielle bio-informatique a été menée à l’aide des outils SAMtools (Li et col., 2009), BEDtools (Quinlan and Hall, 2010), MACS2 (Zhang et col., 2008) et Diffbind (Stark and Brown, 2011 - Bioconductor). Sur l’ensemble du génome, nous n’avons identifié que 24 régions présentant un niveau de méthylation modifié par l’exposition au tacrolimus. Le promoteur du gène Calm2, codant pour l’isoforme 2 de la calmoduline, semble être davantage méthylé chez les souris traitées. Ces résultats préliminaires semblent prometteurs pour la découverte de biomarqueurs épigénétiques de la réponse thérapeutique aux immunosuppresseursInter-individual genetic variation might account for diverse efficacy and toxicity of calcineurin inhibitors (cyclosporin and tacrolimus). In particular, some variants located within genes coding for proteins of the calcineurin pathway can explain part of this variability. In this manuscript, a panel of candidate genes was selected based on bibliographic review and tested in a pharmacogenetics study encompassing 381 renal transplants followed for one year after surgery. None of these candidates was associated with the acute rejection or serious infection risks. Furthermore, the pharmacodynamic variability of these drugs was also investigated, exploring the use of epigenomics profiling as proximal readout of the calcineurin inhibition treatment. In particular, we investigated the impact of drug exposure on DNA methylation in two experimental models. Methylated DNA immunoprecipitation followed by high-throughput sequencing (MeDIP-seq, Ion Proton technology) was deployed in JURKAT cell line, used as in vitro model, and in CD4 T lymphocytes isolated from mice treated with either cyclosporin or tacrolimus for three months. After sequencing, the differentiated methylated regions caused by drug exposure were analyzed. Bioinformatics analyses were performed using SAMtools (Li et al., 2009), BEDtools (Quinlan and Hall, 2010), MACS2 (Zhang et al., 2008) and Diffbind (Stark and Brown, 2011 - Bioconductor). Overall, the genome-wide analysis revealed only 24 regions with a differentiated enrichment in DNA methylation after three month-tacrolimus treatment, indicating a targeted effect of these treatments on a subset of key genes. Of note, CALM2 promoter, coding for the calmodulin isoform 2 protein, showed significant hypermethylation in tacrolimus-treated mice. These preliminary results corroborate the interest in using DNA methylation as promising approach to identify candidate biomarkers for therapeutic drug monitoring in calcineurin inhibitor treatments
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Wuyts, Geert. "Einfluss einer Calcineurin-Inhibitor-freien Immunsuppression auf kardiovaskuläre Risikofaktoren nach einer Nierentransplantation." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972552723.
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Dai, Yang. "Impact of the CYP3A5 polymorphism on the metabolic disposition of calcineurin inhibitors /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/7935.
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PARSONS, STEPHANIE A. "THE ROLE OF CALCINEURIN IN SKELETAL MUSCLE HYPERTROPHY AND FIBER TYPE DIVERSITY." University of Cincinnati / OhioLINK, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1078511890.
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Alghanem, Ahmad. "The role of regulator of calcineurin 1 (RCAN1) signalling in endothelial cells." Thesis, University of Liverpool, 2014. http://livrepository.liverpool.ac.uk/2003343/.
Full textAbstract:
Regulator of calcineurin 1 (RCAN1) has been shown to act as a negative regulator of vascular endothelial growth factor (VEGF)-signalling in endothelial cells. Two isoforms are detectable in cells, RCAN1.1 and RCAN1.4, produced by alternative splicing of the RCAN1 mRNA. In this study it was demonstrated that only RCAN1.4 is induced in human dermal microvascular endothelial cells (HDMECs) in response to VEGF. Using siRNA-mediated gene silencing this work shows that RCAN1 depletion leads to a reduction in VEGFR-2 internalisation following VEGF-A stimulation. RCAN1 depletion also leads to a reduction in cell polarity and cytoskeletal reorganisation in response to VEGF. siRNA-mediated silencing of RCAN1 led to an inhibition of VEGF-A mediated migration of HDMECs. These effects of RCAN1 knockdown appear to be specific to VEGFR-2, as no apparent effect on hepatocyte growth factor receptor (HGFR) internalisation and cytoskeletal reorganisation and migration in response to HGF was observed in HDMECs. Over- expression of RCAN1.4 isoform using adenoviral mediated gene delivery resulted in increased migration of HDMECs in the absence of ligand. This effect was insensitive to the calcineurin inhibitor cyclosporine, indicating that RCAN1.4 was not operating through the classical calcineurin/NFAT pathway to regulate cell migration. Instead, the RCAN1.4 effect was sensitive to a small molecule VEGFR-2 kinase inhibitor, which blocked cell migration. This study also examined the role of phospholipase D (PLD) in endothelial cell function. By utilising siRNA for PLD1 and PLD2 it was shown that both PLD1 and PLD2 are required for VEGF-A mediated proliferation, migration and tubular morphogenesis in HDMECs. Overall, the data presented in this thesis defines a novel role for both RCAN1 and PLD in regulating in endothelial cell function. Both proteins could be potential therapeutic targets to regulate vascular function.
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Martin, Lisa Joy. "FK506, an inhibitor of calcineurin, prevents cadmium-induced testicular toxicity in mice." Diss., Restricted to subscribing institutions, 2007. http://proquest.umi.com/pqdweb?did=1320950781&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Linhart, Thomas. "Untersuchungen zur Funktion, Regulation und Expression des Calcineurin/ NFAT2 Signalweges im Pankreaskarzinom." [S.l. : s.n.], 2007. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-60528.
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Jensen, Tyron DeRay. "Calcineurin is Required for TRPV1-induced LTD of CA1 Stratum Radiatum Interneurons." BYU ScholarsArchive, 2011. https://scholarsarchive.byu.edu/etd/3057.
Full textAbstract:
Learning and memory in the brain are thought to be dependent on synaptic plasticity. In response to sensory input, synapses can be strengthened or weakened, known as long-term potentiation or long-term depression (LTD), respectively. Transient receptor potential vanilloid 1 (TRPV1) has been shown to mediate a novel form of presynaptic LTD in hippocampal interneurons. TRPV1 is currently being heavily studied in the PNS and being targeted by pharmaceuticals for its anti-nociceptive and anti-inflammatory properties. However, much less is known regarding TRPV1 function in the CNS, including the signal mechanism mediating hippocampal LTD despite its obvious importance. Here we performed whole-cell voltage clamp electrophysiology experiments from CA1 hippocampal interneurons to identify this signaling mechanism. Because calcineurin (CaN) is reported to be linked to multiple forms of synaptic plasticity, we hypothesized that TRPV1 activates presynaptic CaN, which is required for this presynaptic LTD. In order to distinguish between presynaptic and postsynaptic CaN activity we added the specific CaN inhibitors cyclosporin A (CsA) or FK-506 to the bath to block CaN activity ubiquitously in the slice, both presynaptically and postsynaptically, and to the internal solution to block CaN only in the postsynaptic neuron. CsA or FK-506 present in the internal solution, blocking only postsynaptic CaN, showed no effect on TRPV1-dependant LTD. Bath application of CsA or FK-506, inhibiting CaN in the presynaptic neuron as well, blocked LTD elicited by both a high frequency stimulation protocol (P < 0.05) and by direct TRPV1 activation with specific agonists resiniferotoxin and capsaicin (P < 0.05). This demonstrates that CsA and FK506 block both high frequency stimulation induced LTD and also TRPV1 specific depression. We are thus able to show that calcineurin is required for this form of presynaptic TRPV1 mediated LTD in the hippocampus. This finding is the first to demonstrate a TRPV1-induced signaling mechanism in CA1 hippocampus.
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O'Donnell, Susan Ellen. "Recognition of calcineurin by the domains of calmodulin: thermodynamic and structural determinants." Diss., University of Iowa, 2009. https://ir.uiowa.edu/etd/866.
Full textAbstract:
Calcineurin (CaN), a heterodimeric Ca2+-calmodulin-dependent Ser/Thr phosphatase, regulates diverse pathways, from stress responses in yeast to T-cell activation and cardiac hypertrophy in humans. Calmodulin (CaM), an essential mediator of calcium–dependent signaling pathways, activates CaN in the presence of calcium by binding to an intrinsically disordered region of the enzyme and altering its conformation. My hydrodynamic studies have determined that CaM participates in a 1:1 complex with the CaM-binding domain of βCaN (CaNp, residues 400–423).
To explore the molecular mechanism of CaM association with CaN, I have used spectroscopic methods to determine the calcium-dependent and domain–specific interactions of CaM with CaNp. These studies revealed that the affinity of CaM1–148 for CaNp was weak in the absence of calcium, and very high (Kd in the nM to pM range) in the presence of calcium. I have demonstrated that CaNp binding to CaM increases the calcium–binding affinity of each domain of CaM1–148 to a similar degree, thereby retaining the property of sequential calcium binding to the domains, with preference for sites in the C–domain. This allows the N–domain to lag in response to an increase in cellular calcium and perhaps contribute to the regulation of CaN in a manner distinct from that of the C–domain.
NMR studies of calcium–saturated CaM1–148 demonstrated that the N–domain of CaM experienced a larger structural perturbation than the C–domain upon binding CaNp. Additional NMR studies revealed that CaNp adopts an anti–parallel orientation when bound to CaM, with the sole aromatic residue of CaNp contacting the N–domain of CaM. This contrasts with many CaM-target complexes in which the sole aromatic residue contacts the C–domain of CaM. Rigorous thermodynamic studies explored how mutations in the calcium-binding sites of mammalian CaM (mCaM) and mutations known to cause disruption of CaM–mediated ion channel regulation in Paramecia (PCaM) affected the allosteric interactions of the domains of CaM in the presence of CaNp. These studies demonstrated separable roles of the domains of CaM in recognition of CaNp. The consequences of a mutation depended upon its location within the complex. Collectively, research presented in this thesis provides insight into the mechanisms whereby the two domains of CaM contribute to recognition of CaN.
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Reimann, Ricarda [Verfasser], and Ingo [Akademischer Betreuer] Kaczmarek. "De novo Calcineurin-Inhibitor-freie Immunsuppression bei Patienten nach Herztransplantation : eine klinische Untersuchung zum Vergleich einer Sirolimus-Therapie zur Calcineurin-Inhibitor basierten Immunsuppression nach Herztransplantation / Ricarda Reimann. Betreuer: Ingo Kaczmarek." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1069743313/34.
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Hattori, Kimihiko, Shinji Hayano, and Hisao Seo. "Expression of ZAKI-4 in Mammalian Cells." Research Institute of Environmental Medicine, Nagoya University, 2003. http://hdl.handle.net/2237/7558.
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Long, Yun Chau. "Skeletal muscle metabolic flexibility: the roles of AMP-activated protein kinase and calcineurin /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-152-4/.
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Erdmann, Frank [Verfasser]. "Die Ca2+- und Calmodulin-regulierte Proteinphosphatase Calcineurin als pharmakologisch bedeutsame Zielstruktur / Frank Erdmann." Halle, 2018. http://d-nb.info/1162134291/34.
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Taylor, John Philip. "Sub-cellular localisation and function of calcineurin B-like proteins in plant cells." Thesis, University of East Anglia, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268512.
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Lam, Yee Hong Brian. "The role of calcium and calcineurin in the regulation of neuronal gene expression." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612396.
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Parsons, Stephanie A. "The role of the calcineurin in skeletal muscle hypertrophy and fiber type diversity." Cincinnati, Ohio : University of Cincinnati, 2003. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=ucin1078511890.
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