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Wang, Zhan. "IMPACT OF MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 2 (MRP2/ABCC2) AND 3 (MRP3/ABCC3) ON THE PHARMACOKINETICS OF METHOTREXATE." Diss., Temple University Libraries, 2012. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/179025.
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Pharmaceutical Sciences<br>Ph.D.<br>This dissertation presents an investigation of the impact of Multidrug Resistance-associated Protein 2/ATP-binding cassette superfamily C member 2 (Mrp2/Abcc2) and 3 (Mrp3/Abcc3) on the pharmacokinetics (PKs) of methotrexate (MTX) using gene knockout murine models. MTX is a substrate for numerous human ATP-binding cassette (ABC) efflux transporters, yet the impact of these transporters on the pharmacokinetics of MTX over a large dose range has not been examined. To investigate the effects of two transporters, Abcc2 (Mrp2) and Abcc3 (Mrp3), involved in MTX hepatobiliary disposition in vivo, MTX plasma, urine and feces concentrations were analyzed after 10, 50, and 200 mg/kg intravenous (IV) doses to groups of wild type (WT), Abcc2-/- and Abcc3-/- mice. The absence of Abcc2 caused a decrease in total clearance of MTX relative to WT mice at all dose levels yet was accompanied by compensatory increases in renal excretion and metabolism to 7-hydroxymethotrexate (7OH-MTX). In Abcc3-/- mice total clearance was elevated at the two lower dose levels that was attributed to stimulation of biliary excretion and confirmed by elevated fecal excretion; however at the high 200 mg/kg dose clearance was severely retarded and could be attributed to hepatotoxicity as conversion to 7OH-MTX was diminished. We also sought to characterize the effects of Abcc2 and Abcc3, on the PKs of MTX after oral dosing. Plasma, urine, and fecal concentrations of MTX were measured after 10, 50, and 200 mg/kg oral doses to cohorts of WT, Abcc2-/- and Abcc3-/- mice mouse strains. The absence of Abcc2 caused an approximate 2-fold increase in system exposure and a slight increase in oral bioavailability of MTX relative to WT mice at all dose levels. These elevations were accompanied by compensatory increases in conversion to 7OH-MTX, and based on AUC7OH-MTX/AUCMTX (area under the curve ratio of metabolite and parent drug) that ranged from 3% to 9% in WT mice increased to a range of 16% to 26% in Abcc2-/- mice. Renal excretion of unchanged MTX was unaltered in the Abcc2-/- strain; fraction urinary excretion (fr) ranged from about 4% to 11% in WT mice, whereas in Abcc2-/- mice fr ranged from about 7% to 23%. Abcc3-/- mice exhibited more than a 2-fold decrease in Cmax and significant reductions in AUCMTX when compared to WT mice at all dose levels. There were no compensatory increases in either metabolism or in renal and biliary excretion, which suggests future studies for investigating a potential unknown mechanism. Regardless of the mouse strain, increases in the MTX dose were not accompanied by proportional increases in AUCMTX. The PKs of MTX in different mouse strains was successfully modeled by a nonlinear semi-mechanistic 3-compartmental conditional model incorporating key efflux transporters. The model employed population-based analysis and conditional transport terms to well capture the nonlinear properties of MTX systemic disposition for a wide dose range of 10 - 200 mg/kg in WT and knockout strains. The model correlates the mechanistic nature of the nonlinear phenomenon with the key efflux transporters effects on MTX PKs and provides insight for preclinical therapeutic study design. Overall, the information obtained in this investigation underscores the significance of efflux transporters, Abcc2 and Abcc3, for they significantly influence the pharmacokinetics of MTX and their impact can be reflected by a nonlinear semi-mechanistic 3-compartmental conditional model. The studies also provide implication in the preclinical therapeutic study design and insights on the source of inter-patient variability as well as on the combination drug regimens to maximize drug activity yet without toxicity.<br>Temple University--Theses
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PESSINA, SARA. "The multidrug-resistance transporter Abcc3 protects NK cells from chemotherapy in a murine model of malignant glioma." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2015. http://hdl.handle.net/10281/94457.
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Il glioblastoma (GBM) è la forma più frequente ed aggressiva dei tumori cerebrali. Le opzioni terapeutiche convenzionali sono attualmente rappresentate da resezione chirurgica della massa tumorale seguita da radioterapia e chemioterapia con temozolomide (TMZ). Nonostante l’uso di strategie terapeutiche aggressive, la prognosi complessiva resta infausta.
L’immunoterapia, descritta nel 2013 “breakthrough dell’anno” da Science, è il principale avanzamento nel GBM. Di particolare interesse è la valutazione degli effetti della chemioterapia in combinazione con l’immunoterapia. La chemioterapia, storicamente considerata immunosoppressiva, può avere effetti stimolatori sul sistema immunitario. In uno studio clinico attualmente attivo presso il nostro istituto, pazienti con prima diagnosi di GBM in seguito a intervento chirurgico e dopo leucaferesi ricevono un trattamento standard di radioterapia e chemioterapia con temozolomide (RT-TMZ) e TMZ come adiuvante in combinazione con vaccinazioni con cellule dendritiche. Una caratterizzazione del sistema immunitario è condotta su sangue periferico dei pazienti con particolare attenzione alla risposta effettrice citotossica. L’aumento della risposta delle cellule NK ma non dei linfociti T CD8+ è al momento correlato significativamente con una prolungata sopravvivenza. Per cercare di comprendere un potenziale effetto diretto della TMZ sulle cellule immuni abbiamo sfruttato un modello murino di glioma maligno focalizzandoci sulla caratterizzazione dei meccanismi molecolari indotti dalla TMZ sui linfociti.
Nel nostro studio, topi con glioma GL261 sono stati trattati con cinque iniezioni intraperitoneali di TMZ 9 giorni dopo l'impianto intracranico del tumore. La TMZ ha indotto una rapida e reversibile linfopenia di linfociti T CD8+. Al contrario, la frequenza delle cellule NK è aumentata rapidamente già dopo la seconda somministrazione del farmaco. Le analisi del profilo di espressione genica sui linfociti del sangue periferico ha rivelato un’up-regolazione di Abcc3, trasportatore associato a farmacoresistenza, nelle NK ma non nei linfociti T CD8+ durante il trattamento. Abcc3 si è rivelato funzionalmente attivo e necessario per la sopravvivenza delle cellule NK. Infatti solo le cellule NK non esprimenti Abcc3 sono sensibili alla TMZ e per questo più inclini ad entrare in apoptosi. L’inattivazione farmacologica di Abcc3 ha inoltre indotto un aumento significativo di apoptosi confermando il suo ruolo cruciale nella resistenza delle cellule NK alla TMZ. Durante il trattamento l’attivazione di Akt, proteina chiave per la sopravvivenza, è stata individuata solo in cellule NK esprimenti Abcc3 e non nei linfociti T CD8+, i quali hanno mostrato un significativo aumento di apoptosi.
La resistenza delle cellule NK è associata ad un aumento della loro capacità migratoria con conseguente maggior infiltrato nei gliomi dei topi trattati con TMZ. Le cellule NK inoltre infiltrano il tumore precocemente determinando un aumento persistente delle molecole citotossiche quali IFN-γ, granzimi e perforina. Abbiamo inoltre evidenziato che la profonda modulazione del microambiente tumorale indotta dalla TMZ fornisce la condizione ottimale per l'infiltrazione e l’attività citotossica delle cellule NK. La citotossicità delle cellule NK nel sangue, valutata come produzione di IFN-γ e capacità litica delle cellule GL261, aumenta significativamente.
I nostri dati mostrano, per la prima volta, che Abcc3 è cruciale nel conferire alle cellule NK resistenza alla chemioterapia. La TMZ inoltre è in grado di promuovere l’attivazione di meccanismi responsabili della sopravvivenza delle cellule NK e della loro risposta anti-tumorale. Queste osservazioni hanno una importante ripercussione clinica e potrebbero avere implicazioni per i pazienti affetti da GBM e trattati con chemio-immunoterapia.<br>Glioblastoma (GBM) is the most common and aggressive form of malignant brain tumors. The current standard treatments for GBM patients still consist of surgical resection of the tumor mass followed by radiotherapy and chemotherapy with temozolomide (TMZ). In spite of therapeutic progresses, the patient prognosis is poor and the recurrence very frequent. There is an urgent need of novel therapeutic strategies in order to prevent or realistically to delay the recurrence.
Cancer immunotherapy, the scientific breakthrough of year 2013 by Science, is the main progress in cancer therapy. A growing amount of preclinical and clinical studies unravels the possibility to potentiate the immune system against GBM. A number of data show that several anticancer agents, including classical chemotherapeutic compounds previously viewed as immunosuppressive, are able to enforce tumor specific immune responses when in combination with immunotherapy. In a clinical trial currently active at our institute, patients with first diagnosis of GBM after surgery and leukapheresis receive standard treatment with radio-chemotherapy with temozolomide (RT-TMZ) and TMZ as adjuvant during DC vaccines. Peripheral blood lymphocytes (PBLs) are analyzed by flow cytometry to characterize immune response with special interest to CD8+ T lymphocytes and Natural Killer (NK) cells, which are responsible of effector response. A significant increase and activation of peripheral blood NK cells, but not CD8+ T cells, correlates significantly with a prolonged survival of patients.
In order to evaluate a potential direct effect of TMZ on immune system, we focused our study on the molecular mechanisms induced by TMZ on immune cells in a murine model of malignant glioma.
We treated GL261 glioma-bearing mice with five intraperitoneal injections of TMZ 9 days after intracranial tumor implantation. TMZ induced a rapid and reversible decrease of CD8+ T cell frequency. Otherwise, trafficking and homing of NK cells rapidly increased after the second TMZ administration. Gene expression profiling on PBLs revealed an up-regulation of the multidrug-resistance protein Abcc3 in NK cells, but not in CD8+T cells, from TMZ-treated compared to mice treated with vehicle as control. We found that Abcc3 is functionally active during chemotherapy treatment and intrinsically required for NK cell survival. Only Abcc3 negative NK cells are more prone to undergo apoptosis. The pharmacological inactivation of Abcc3 induced a significant increase of apoptosis in NK cells demonstrating its crucial role in inducing NK cell resistance to TMZ. Akt activation, key of survival pathways, was found only in NK cells that express Abcc3 and not detected in CD8+ T cells that showed a remarkable increase in apoptosis during TMZ treatment.
Moreover, the resistance of NK cells to TMZ was accompanied by increased migration and homing into the brain at early time points. NK cells infiltrate the tumor mass early leading to an increase and persistent expression of cytotoxic signals including IFN-γ, granzymes and perforin. Additionally, the profound modulation of glioma microenvironment induced by TMZ provided the optimal condition for NK cell infiltration and cytotoxic function. Cytotoxicity, evaluated as IFN-γ production and specific lytic activity against GL261 cells by peripheral NK cells, significantly increased compared to control mice.
Our data showed, for the first time, that Abcc3 expression confers NK cell resistance to chemotherapy. Furthermore, TMZ influenced NK cell functions promoting mechanism involved in cell survival and in the specific anti-tumor response. These observations have clinical implications for GBM patients treated with chemo-immunotherapy.
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Zehnpfennig, Britta. "Modellsysteme für humanes ABCC3 : Funktionelle Rekonstitution und Charakterisierung in Proteoliposomen und Aufbau biosensorischer Oberflächen /." Münster, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000252269.
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Chan, Yuen Man. "Functional analysis of single nucleotide polymorphisms in the proximal promoter regions of the multidrug transporter genes MRP1/ABCC1 and MRP4/ABCC4." Thesis, Kingston, Ont. : [s.n.], 2007. http://hdl.handle.net/1974/730.
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Thajam, Deirdre. "The role of multidrug resistance proteins in determining fetal susceptibility to drugs of misuse." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-multidrug-resistance-proteins-in-determining-fetal-susceptibility-to-drugs-of-misuse(85fef852-5e19-4700-950e-753d85fad88c).html.
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Background: Negative outcomes from fetal exposure to maternal dug use include Neonatal Abstinence Syndrome (NAS) and altered development, the unpredictability of which suggests a biological element as yet not accounted for. The manner in which the human placenta protects the fetus from xenobiotics such as drugs of misuse is not completely characterised. However, Adenosine Triphosphate Binding Cassette (ABC) transporters in placentae have demonstrated their ability to efflux xenobiotics away from the fetal vascular compartment leading to lower concentrations than in the maternal compartment and some commonly used drugs have been shown to be substrates for these proteins, e.g. methadone. It is suggested that polymorphisms in the genes that encode these transporter proteins may alter their expression and/or function. Hypothesis- Polymorphisms (SNPs) in the ABC transporters ABCB1, ABCG2, ABCC1 and ABCC2 change protein expression and/or function leading to increased fetal exposure demonstrated by increased signs of NAS and/or altered development. Objectives: To determine if genotype alters protein expression and whether there is a relationship between the level of placental multidrug resistance protein P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP), Multidrug Resistance Associated Proteins (MRP1 and MRP2) expression and neonatal and/or developmental outcomes. Methods: Drug using women were recruited. In the immediate postnatal period placental tissue, cord blood and maternal hair samples were taken. Hair was analysed to determine drug use in the preceding 3 months, immunoblotting determined the level of P-gp, BCRP, MRP1 and MRP2 protein expression. Sequenom MassExtend Array produced genotypes from DNA obtained from cord blood. Infants were assessed for NAS at birth, 3 days and 3 weeks. At 8 months and 1 year development was assessed using the Griffiths Mental Development Scales. Plink was used to determine statistically significant associations between genotype and outcome phenotypes. Results- The level of fetal drug exposure did not predict the need for pharmacological treatment for NAS. 32 polymorphisms with significant associations to outcome measures were identified: 4 SNPs significantly altered protein expression, (3 for P-gp and 1 for MRP1). 41 SNPs were associated with changes across 4 of the 5 GMDS subscales. Discussion: No clear relationship between MDRP protein expression and neonatal outcome was noted. However, fetal genotype did influence the expression of P-gp and MRP1 and genotype across all four proteins was associated with significant changes in the measures of infant development. This was a small study and as such generation of susceptible haplotypes was not possible. However the data generated do support the concept. Further larger and longer term prospective studies, building on the experience reported in this thesis, are necessary to generate more data in order to identify haplotypes leading to increased fetal susceptibility to drug exposure.
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Meyer, zu Schwabedissen Henriette Elisabeth Ulrike. "Expression und Lokalisation der Eliminationstransporter ABCB1, ABCG2, ABCC2 und ABCC5 in Plazenta Einfluss von Gestationsalter, genetischen Polymorphismen und zellulärer Differenzierung ; Proteomanalyse zur Charakterisierung der In-vitro-Differenzierung isolierter Trophoblasten /." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972753427.
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Zhang, Anja Ziwen. "Sumoylierung und Targeting von ABCA3." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-146702.
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Huppmann, Marceline. "Lungenmechanische Charakterisierung von heterozygoten ABCA3-Knockout-Mäusen." Diss., lmu, 2011. http://nbn-resolving.de/urn:nbn:de:bvb:19-133099.
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Lächelt, Sandra [Verfasser]. "Funktionelle Analyse von ABCC2-Haplotypen / Sandra Lächelt." Kiel : Universitätsbibliothek Kiel, 2009. http://d-nb.info/1019869933/34.
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Rodrigues, Lucas Campos de Sá. "Estudo da expressão dos genes de resistência a múltiplas drogas ABCB1, ABCC1 e ABCG2, em cães com linfoma multicêntrico, submetidos a três diferentes protocolos de tratamento antineoplásico." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/10/10136/tde-08102012-141346/.
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Um dos principais desafios no tratamento quimioterápico em seres humanos e animais é a resistência que as células neoplásicas apresentam, sendo esse mecanismo responsável por falhas no tratamento e recidivas da doença. A resistência pode ser intrínseca ou adquirida e ocorre em função da expressão de transportadores de membrana ABC, como a glicoproteína P (ABCB1/MDR), proteínas de resistência a múltiplas drogas (ABCC1/MRP) e proteína de resistência do câncer de mama (ABCG2/BCRP). O linfoma é a neoplasia hematopoiética mais comum em cães, altamente responsiva à quimioterapia, mas que recidiva durante o tratamento antineoplásico, sendo a resistência das células neoplásicas aos quimioterápicos um fator responsável pela alta taxa de recidiva e óbito dos animais. Neste estudo avaliou-se a expressão de genes relacionados à resistência a múltiplas drogas em cães com linfoma, no diagnóstico e na recidiva da doença, em três diferentes protocolos quimioterápicos utilizados na rotina clínica. A expressão dos genes ABCB1, ABCC1, ACBG2 foi determinada por RT-PCR (PCR em tempo real) em 25 animais naturalmente acometidos pela doença, divididos aleatoriamente em 3 grupos tratados com os protocolos quimioterápicos COP, VCM e Short-Madison, além de um "pool" controle constituído por linfonodos normais de oito animais. A expressão dos genes foi detectada em todas as amostras, tanto de linfonodos normais quanto de animais com linfoma. No diagnóstico da doença, a expressão do gene ABCC1 foi relacionada negativamente com idade (p=0,008) e positivamente com duração da remissão (p=0,027) e sobrevida (p=0,007), entretanto para os genes ABCB1 e ABCG2 não houve diferença estatística significante. Na recidiva, a expressão dos genes não sofreu variação estatística significante em função do tipo e duração da remissão e sobrevida. Não houve variação na expressão dos genes ABCB1, ACBC1 e ABCG2 no momento da recidiva quando comparado ao protocolo quimioterápico utilizado.<br>One of the main challenges of the chemotherapy treatment in human and animals is the resistance of the neoplasic cells, being this mechanism responsible for failures in the treatment and relapse of the disease. The resistance could be intrinsic or acquired and it occurs due to the expression of ABC membrane transporters, such as p-glycoprotein (ABCB1/MDR), resistance protein to multiple drugs (ABCC1/MRP) and resistance protein of breast cancer (ABCG2/BCRP). Lymphoma is the most common hematopoietic cancer disease in dogs, highly responsive to chemotherapy, but relapse during chemotherapy treatment, being the resistance of neoplastic cells to chemotherapy drugs the responsible factor for the high rate of relapse and death of animals. In this study, genes expression related to multiples drugs resistance it was evaluated in dogs with lymphoma, in the diagnosis and in the relapse of the disease in three different chemotherapy protocols used in the clinical routine. The genes expression ABCB1, ABCC1, ACBG2 was determined by RT-PCR (real time PCR) in 25 animals naturally undertaken by the illness, randomly divided into 3 groups treated with the chemotherapy protocols COP, VCM and Short-Madison, besides a "pool" control constituted by normal lymph node of eight animals. The genes expression was detected in all the samples, both in the normal lymph node and in the animals with lymphoma. In the diagnosis of the disease, the gene expression ABCC1 was negatively related with age (p=0,008) and positively with the duration of remission (p=0,027) and survival (p=0,007); however, for ABCB1 and ABCG2 there was no statiscally significant difference. In the relapse, the genes expression had no statiscally significant difference due to the type and duration of remission and survival. There was no variation in the genes expression ABCB1, ACBC1 and ABCG2 in the moment of relapse when compared to the chemotherapy protocol used.
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Bröderdorf, Susanne [Verfasser]. "Regulation des ABC-Transporters MRP4 (ABCC4) / Susanne Bröderdorf." Greifswald : Universitätsbibliothek Greifswald, 2016. http://d-nb.info/1083846779/34.
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Schulte, Daniel. "Molekulare und funktionelle Charakterisierung von Targetingsequenzen im humanen ABCA3-Protein." Diss., lmu, 2008. http://nbn-resolving.de/urn:nbn:de:bvb:19-92875.
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Zang, Sebastian [Verfasser]. "Untersuchungen zur transkriptionellen Regulation des Transporters MRP4 (ABCC4) / Sebastian Zang." Greifswald : Universitätsbibliothek Greifswald, 2015. http://d-nb.info/1079072497/34.
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Höppner, Stefanie [Verfasser], and Matthias [Akademischer Betreuer] Griese. "Funktionelle Analyse des ABCA3 Transporters / Stefanie Höppner ; Betreuer: Matthias Griese." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2020. http://d-nb.info/1206878231/34.
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Nguyen, Kim-Anh. "Synthèse de nouveaux détergents extractants et stabilisants des protéines membranaireset synthèse de dérivés d'aurones comme inhibiteurs d'ABCC2." Thesis, Université Grenoble Alpes (ComUE), 2017. http://www.theses.fr/2017GREAV043/document.
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L’obtention de la structure tridimensionnelle des protéines membranaires (PMs) est cruciale pour la chimie médicinale et la biochimie. Afin de maintenir les PMs en solution, et donc d’éviter leur agrégation, pour les études structurales et fonctionnelles, l’utilisation de détergents est indispensable. Cependant, la conformation des PMs en complexe avec les détergents pourrait être très différente de celle dans la membrane. Nous avons synthétisé une nouvelle famille de détergents, dans lesquels des carboxylates incorporés pourraient générer un réseau de ponts salins avec les acides aminés basiques des PMs, entraînant des interactions plus étroites qui pourraient préserver leur structure native. Les détergents dans lesquels la glycoconjugation a été réalisée par la réaction de cycloaddition d'azide-alkyne (CuAAC) catalysée par le Cu (I) ont montré une capacité remarquable à extraire, à stabiliser et à cristalliser les PMs étudiées. D'autre part, de nouveaux inhibiteurs efficaces d’ABCC2, une PM non cristallisée à ce jour, ont été identifiés par criblage : les 2-indolylméthylènebenzofuranones. De tels composés pourraient être considérés comme des outils pour étudier le rôle d’ABCC2 dans la pharmacocinétique des médicaments<br>Understanding of tridimensional structure of membrane proteins (MPs) is crucial in medicinal chemistry and biochemistry. To maintain them in solution and consequently to prevent them from aggregation for structural and functional studies, utilization of detergents is indispensable. However, the conformation of MPs in complex with detergents could be very different from its membrane-embedded one. We synthetized new family of detergents, in which the incorporated carboxylates could generate a network of salt-bridges with basic-residue-enriched region of MPs, confer tighter interactions which could preserve their structural integrity. The detergents in which the glycoconjugation was achieved by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction showed remarkable capacity to extract, stabilize and crystallize studied PMs. On the other hand, novel inhibitors of ABCC2, a non-crystallized MP to date, were identified by screening: the 2-indolylmethylenebenzofuranones. Such compounds could be considered as useful tools to further investigate the role of ABCC2 in the pharmacokinetics of drugs
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Zhang, Anja Ziwen Verfasser], and Andreas [Akademischer Betreuer] [Holzinger. "Sumoylierung und Targeting von ABCA3 / Anja Ziwen Zhang. Betreuer: Andreas Holzinger." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2012. http://d-nb.info/1026012333/34.
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Zhang, Anja Ziwen [Verfasser], and Andreas [Akademischer Betreuer] Holzinger. "Sumoylierung und Targeting von ABCA3 / Anja Ziwen Zhang. Betreuer: Andreas Holzinger." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2012. http://d-nb.info/1026012333/34.
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Martinelli, Fabio. "The protein related to Pseudoxanthoma Elasticum regulates the purinergic system. New insight on the ABCC6 transporter." Doctoral thesis, Universita degli studi di Salerno, 2019. http://elea.unisa.it:8080/xmlui/handle/10556/4262.
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2017 - 2018<br>ABC (ATP-binding cassette)transporters are the largest superfamily of membrane proteins present in all organisms and they are particularity involved in transport of nutrients and drugs... [edited by Author]<br>XXXI ciclo
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Moraes, Ana Carolina Rabello de. "Estudo da associação de genes e proteínas de resistência a múltiplos fármacos (abcb1/ABCB1, abcc1/ABCC1 e lrp/LRP) com marcadores moleculares em pacientes portadores de leucemias agudas." reponame:Repositório Institucional da UFSC, 2013. https://repositorio.ufsc.br/handle/123456789/107623.
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Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde, Programa de Pós-Graduação em Farmácia, Florianópolis, 2013.<br>Made available in DSpace on 2013-12-06T00:39:31Z (GMT). No. of bitstreams: 1
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Previous issue date: 2013<br>Menos de 45% dos portadores de leucemias agudas (LAs) sobrevivem cinco anos após o diagnóstico. O insucesso no tratamento relaciona-se, principalmente, à resistência à quimioterapia. O mecanismo mais comumente implicado na resistência a múltiplos fármacos (MDR) é a expressão de proteínas de membrana capazes de transportar para fora da célula moléculas citotóxicas, mantendo as concentrações intracelulares de quimioterápicos abaixo das desejadas. O objetivo deste trabalho foi investigar a expressão de abcb1/ABCB1, abcc1/ABCC1 e lrp/LRP como marcadores moleculares de diagnóstico diferencial, estratificação de prognóstico e detecção de doença residual mínima em portadores de LA atendidos pelo Serviço de Oncohematologia do Hospital Universitário da Universidade Federal de Santa Catarina (HU-UFSC). Para tanto, foram coletadas amostras de 75 portadores de LA. A análise da transcrição dos genes mdr foi verificada por RT-PCR semiquantitativo e a expressão das proteínas MDR foi avaliada por citometria de fluxo. Os resultados mostram que nos casos de LA, a expressão de ABCB1 e a atividade da LDH correlacionaram-se positivamente (P=0,001), a presença do marcador CD34 associou-se com a maior transcrição de abcc1 (P=0,006), e a maior transcrição de lrp associou-se com a ausência do marcador CD56 (P=0,029) e com a ausência de transcrição de survivina (P=0,029). Nos portadores de leucemia mieloide aguda (LMA), a transcrição de abcc1 e a idade dos pacientes correlacionaram-se positivamente (P=0,029), a ausência da transcrição de survivina associou-se com a maior transcrição de lrp (P=0,040), e a maior expressão de LRP associou-se com o diagnóstico de LMA (P=0,025). Nos portadores leucemia promielocítica aguda (LPA), as expressões de abcc1 e de LRP correlacionaram-se positivamente com o percentual de blastos leucêmicos ao diagnóstico (P=0,019 e P=0,001, respectivamente), e a expressão de ABCC1 correlacionou-se positivamente com a atividade da LDH (P=0,019). Nos casos de leucemia linfoide aguda (LLA) B, as expressões de ABCB1 e de abcc1 correlacionaram-se positivamente com a atividade da LDH (P=0,007 e P= 0,017, respectivamente), a expressão de ABCC1 correlacionou-se negativamente com a contagem de leucócitos ao diagnóstico (P=0,006), e a expressão de LRP correlacionou-se positivamente com o número de leucócitos ao diagnóstico (P=0,001) e associou-se com a presença da t(9;22)(q34;q11.2) (P=0,012). Nos casos de LLA-T, a transcrição de abcb1 e a contagem de leucócitos correlacionaram-se positivamente (P=0,007). Os pacientes com diagnóstico de LA que não entraram em remissão após a terapia de indução expressaram mais abcb1 do que aqueles que apresentaram remissão completa (P=0,004). Os portadores de LMA que não responderam à terapia de indução expressaram mais abcb1 e ABCC1 do que os que apresentaram remissão (P=0,005 e P=0,017, respectivamente). Além disso, os casos de LMA expressaram menos abcc1 após indução (P=0,016) e os de LPA expressaram mais LRP após a indução (P=0,025). Os resultados mostram que a análise de transcrição dos genes mdr fornece informações de prognóstico diferentes da análise das proteínas MDR. Diante disso, o presente estudo recomenda que no momento do diagnóstico dos portadores de LA seja realizada a avaliação simultânea da expressão dos genes abcb1, abcc1 e lrp e das proteínas ABCB1, ABCC1 e LRP de resistência à quimioterapia.<br><br>Abstract : Less than 45% of patients with acute leukemia (ALs) survive five years after diagnosis. The failure in treatments relate primarily to chemotherapy resistance. The mechanism most commonly implicated in the multidrug resistance (MDR) is the expression of membrane proteins capable of carrying cytotoxic molecules out of the cell, which keeps intracellular concentrations of the chemotherapics below those desired. The aim of this study was to investigate the expression of abcb1/ABCB1, abcc1/ABCC1 and lrp/LRP as molecular markers for differential diagnosis, prognostic stratification and minimal residual disease detection in patients with AL treated by Oncohematology Service do Hospital Universitário da Universidade Federal de Santa Catarina (HU-UFSC). For this purpose, samples were collected from 75 patients with AL. Analysis of mdr genes transcription was assessed by semi-quantitative RT-PCR and MDR proteins expression was evaluated by flow cytometry. The results showed that in AL cases, ABCB1 expression and LDH activity were positively correlated (P=0.001), the presence of CD34 marker was associated with increased abcc1 transcription (P=0.006), and higher LRP expression was associated with the absence of CD56 marker (P=0.029) and with the absence of survivin transcription (P=0.029). In patients with acute myeloid leukemia (AML), the abcc1 transcription and the patients age were positively correlated (P=0.029), the absence of survivin transcription was associated with a bigger lrp transcription (P=0.040), and bigger LRP expression was associated with AML diagnosis (P=0.025). In patients with acute promyelocytic leukemia (APL), abcc1 and LRP expressions were positively correlated with the percentage of blasts at diagnosis (P=0.019 and P=0.001, respectively), and ABCC1 expression was positively correlated with LDH activity (P = 0.019). In B acute lymphoid leukemia (ALL) cases, ABCB1 and abcc1 expressions were positively correlated with LDH activity (P=0.007 and P=0.017, respectively), ABCC1 expression was negatively correlated with the white blood cell count at diagnosis (P=0.006), and LRP expression was positively correlated with the white blood cell count at diagnosis (P=0.001) and with the presence of t(9; 22)(q34; q11.2) (P=0.012). In T-ALL cases, ABCB1 expression and the white blood cell count at diagnosis were positively correlated (P = 0.007). Patients diagnosed with AL who had achieved remission after induction therapy expressed more ABCB1 than those who had had complete remission (P=0.004). The AML patients who have not responded to induction therapy expressed more abcb1 and ABCC1 than those who had achieved remission (P=0.005 and P=0.017, respectively). Additionally, AML cases expressed less abcc1 after induction therapy (P=0.016) and APL cases expressed more LRP after induction (P=0.025). The results showed that mdr genes expression analysis and MDR proteins analysis provide different prognostic informations. Thus, the present study recommends that at the moment of AL patients diagnosis a simultaneous evaluation of mdr genes abcb1, abcc1 and lrp and MDR proteins expression ABCB1, ABCC1 and LRP should be held.
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Materna, Verena Waltraut. "Bedeutung des ABC-Transporters MRP2/cMOAT/ABCC2 bei der Cisplatinresistenz humaner Tumorzellen." Doctoral thesis, [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=96607078X.
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Schindlbeck, Ulrike [Verfasser], and Matthias [Akademischer Betreuer] Griese. "Charakterisierung neuer Missense Mutationen im Lipidtransporter ABCA3 / Ulrike Schindlbeck ; Betreuer: Matthias Griese." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/119981640X/34.
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Schicker, Maresa. "Die Charakterisierung der Funktion des Lipidtransporters ABCA3 in der Milchdrüse (am Mausmodell)." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-172584.
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ABCA3 ist als Phospholipidtransporter der ABC-Transporterfamilie wesentlich an der Synthese von Lungensurfactant beteiligt. Diese wichtige Rolle von ABCA3 in der Lunge ist mittlerweile bekannt und wird weiterhin näher erforscht. Des Weiteren wird ABCA3 auch in anderen Geweben exprimiert, darunter Leber, Niere, Gehirn [Stahlman et al. 2007]. ABCA3 wurde daneben auch in humanem Milchdrüsengewebe entdeckt und stellt in Mammakarzinomen einen Marker für eine gute Prognose dar [Schimanski 2010].
In der murinen Milchdrüse ist die Abca3-Expression molekularbiologisch auf Ebene der mRNA nachgewiesen worden [Hammel 2007]. Des Weiteren ist ABCA3 in immunhistochemischen Färbungen von humaner und muriner Milch darstellbar. Dort ist es auf der Außenseite der Milchfetttröpfchen-Membran lokalisiert [bislang nicht veröffentlichte Daten der eigenen Arbeitsgruppe]. Milchfetttröpfchen werden in Milchdrüsen-Epithelzellen gebildet, indem Lipidtransporter (unter anderem ABC-Transporter der ABCA-Subklasse wie ABCA1 oder ABCA7) Lipide importieren.
In der Milchdrüse ist über den Mechanismus, mit dem ABCA3 an der Milchsekretion beteiligt sein könnte, nicht viel bekannt. Es kann aber analog zu der Rolle in der Lunge davon ausgegangen werden, dass ABCA3 auch in der Milchdrüse Phospholipide transportiert. Phospholipide verfügen über wichtige Eigenschaften in der Milch als Emulgatoren und als protektive Faktoren für das Neugeborene. Es ist nachgewiesen, dass ein Einschnitt in der Phospholipid-Sekretion und eine veränderte Zusammensetzung der Phospholipide in der Milch zu nachteiligen Auswirkungen auf das Neugeborene führen [Isaacs 2005].
Es stellt sich die Frage, ob und inwieweit ABCA3 in der Brustdrüse an der Milchbildung und – sekretion beteiligt ist.
Dazu wurde ein Mausmodell mit spezifischer Deletion des ABCA3 Gens in der Milchdrüse generiert. Eine Mauslinie mit Cre-Expression unter dem während der Laktation spezifisch im Mammagewebe aktiven Lactoglobulin-Promotor wurde mit einer Mauslinie gekreuzt, welche im ABCA3-Gen LoxP Stellen enthielt. Es kommt zur Cre-getriggerten Deletion von ABCA3 im Mammagewebe. Das andere Allel wurde durch Einkreuzen einer klassischen Knockout-Linie gänzlich inaktiviert. Die Genotypisierung erfolgte mittels PCR. Zur quantitativen Bestimmung der Expression von Abca3 im Mammagewebe wurde die Methode der quantitativen RT-PCR angewendet.
Der Melkvorgang erfolgte mittels einer eigens konzipierten Melkvorrichtung. Diese beinhaltet eine Flüssigkeitsfalle, wodurch ein besseres Handling beim Melkvorgang erreicht wurde. So konnte unter anderem eine höhere Milchmenge pro Maus gewonnen werden mit weniger technisch bedingten Schwankungen. Die Milchproben an Tag 5, 10 und 15 der Laktation wurden massenspektrometrisch auf den Gehalt der einzelnen Phospholipide analysiert.
Es ergab sich eine Reduktion des Abca3-Gens im Milchdrüsengewebe der gefloxten Mäuse von 95% im Vergleich zum Wildtyp. Die Analyse der Phospholipide zeigte eine Verminderung von Phosphatidylethanolamin, Phosphatidylserin und Phosphatidylcholin, während innerhalb der Phosphatidylcholin-Spezies kurzkettige Moleküle (PC30:0, PC32:0) signifikant vermindert waren. Die Milchmenge der ABCA3 defizienten Linie an Tag 15 der Laktation war signifikant vermindert im Vergleich zur Wildtyp Gruppe (p = 0,005).
Der Nachweis von ABCA3 in Milchfetttröpfchen und die Verminderung der Milchmenge bei dessen Fehlen weist auf eine Rolle dieses Transporters für die Milchsekretion hin. Da Phospholipide nur einen geringen Anteil der Milchfette darstellen, aber vor allem in der Membran der Milchfetttröpfchen enthalten sind, könnte ABCA3 möglicherweise durch Bereitstellung von Phospholipiden für die Bildung der Membran von Milchfetttröpfchen an der Milchbildung beteiligt sein. Am Höhepunkt der Laktation kann das Phospholipid-Defizit in den Milchfetttröpfchen nicht meht kompensiert werden und die Milchmenge nimmt durch die verminderte Bildung von Milchfetttröpfchen signifikant ab. Dabei ändert sich die Gesamtzusammensetzung der Milch nur unbedeutend, da jeweils das gesamte Organell „Milchfetttröpfchen“ mitsamt Inhalt fehlt. Dies muss im Rahmen dieser Studie allerdings hypothetisch bleiben.
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Muhrez, Kienana. "La métabolomique urinaire permet-elle d'identifier des biomarqueurs visant à optimiser l'utilisation des médicaments anticancéreux ?" Thesis, Tours, 2017. http://www.theses.fr/2017TOUR3303/document.
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Le MTX est un agent anticancéreux utilisé à hautes doses pour le traitement des hémopathies malignes et de certaines tumeurs solides. Il présente une importante variabilité pharmacocinétique (PK) traduite par des surexpositions à l'origine de toxicités très sévères, surtout lors d'une administration à haute dose. Les retards d'élimination du MTX surviennent encore de manière inattendue et il n'existe à ce jour aucun biomarqueur qui permette un diagnostic précoce du risque de surexposition. Nos travaux ont focalisé sur les déterminants de l'élimination rénale du MTX, et en particulier le rôle du transporteur MRP2/ABCC2 dans ce processus. Ce travail s'inscrit donc (1) dans la recherche de biomarqueurs métabolomiques urinaires prédictifs de la PK du MTX et (2) dans l'identification de substrats endogènes de MRP2 parmi un panel de 217 acides organiques urinaires analysés par chromatographie gazeuse couplée à la spectrométrie de masse. Nos analyses ont abouti à un profil de 28 anions organiques endogènes, prédictifs de la CL MTX. L'outil était en revanche mal adapté à la prédiction des retards d'élimination. Pour la 2eme partie, nos résultats tendent à montrer que 8 métabolites urinaires sont des bio-marqueurs potentiels de l'activité de MRP2. Leur utilisation en clinique nécessite encore des études confirmatoires<br>MTX is an anticancer agent used at high doses for the treatment of malignant haemopathies and some solid tumors. It presents an important pharmacokinetic variability (PK), manifested by overexposures causing very severe toxicities, especially when administered at high doses. Delayed elimination of MTX still occurs unexpectedly and there is currently no biomarker that allows early diagnosis of the risk of overexposure. Our work focused on the determinants of renal elimination of MTX, and particularly on the role of MRP2 / ABCC2 in this process. This work is therefore devoted to (1) the search for metabolomic biomarkers predictive of MTX PK and (2) the identification of endogenous substrates of MRP2, from a panel of 217 urinary organic acids analyzed by gas chromatography-mass spectrometry. Our analyses resulted in a profile of 28 endogenous organic anions, predictive of CL MTX. The tool was, on the other hand, poorly adapted to the prediction of delayed elimination. For the second part, our results tend to show that 8 urinary metabolites are potential biomarkers of MRP2 activity. Their clinical use still requires confirmatory studies
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Weichert, Nina. "Some ABCA3 mutations elevate ER stress and initiate apoptosis of lung epithelial cells." Diss., lmu, 2011. http://nbn-resolving.de/urn:nbn:de:bvb:19-137380.
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Ibold, Bettina [Verfasser]. "Untersuchung der Auswirkungen einer Abcc6-Defizienz auf die Cholesterinhomöostase im Mausmodell / Bettina Ibold." Bielefeld : Universitätsbibliothek Bielefeld, 2018. http://d-nb.info/1169825222/34.
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Sowa, Ann-Kathrin [Verfasser]. "Funktionelle Untersuchung des Gens Abcc6 und seines Einflusses auf Verkalkungsprozesse / Ann-Kathrin Sowa." Lübeck : Zentrale Hochschulbibliothek Lübeck, 2014. http://d-nb.info/1058135449/34.
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Huppmann, Marceline [Verfasser], and Andreas W. [Akademischer Betreuer] Flemmer. "Lungenmechanische Charakterisierung von heterozygoten ABCA3-Knockout-Mäusen / Marceline Huppmann. Betreuer: Andreas W. Flemmer." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2011. http://d-nb.info/1015169775/34.
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Haenisch, Sierk [Verfasser]. "Funktionelle Bedeutung genetischer Polymorphismen der Membrantransporter ABCB1 und ABCC2 im Nierenzellkarzinomgewebe / Sierk Haenisch." Kiel : Universitätsbibliothek Kiel, 2008. http://d-nb.info/1019622679/34.
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Leimanis, Mara Laura. "Characterization of ABC transporters in both mammalian cells (ABCG2, ABCC2)and «plasmodium falciparum (Pgh1)»." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=21962.
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In the first part of the thesis two ABC transporters in mammalian cells are explored. Initially, the expression of members of the ABC family of transporters in erythrocytes was measured. It was found that ABCG2 (also known as the breast cancer resistance protein, BCRP, the mitoxantrone resistance protein, and ABC placenta) was expressed in mature human erythrocytes. This work concentrated on characterizing the oligomerization of ABCG2 in membrane extracts from tumour cells and human erythrocytes. Given the ability of ABCG2 to transport protoporphyrin IX or heme, these findings may shed some light on the normal function of erythrocytes. The second chapter of the thesis attempts to elucidate the drug binding characteristics of ABCC2 (MRP2). A radiolabelled photoreactive analogue of LTC4 (IAALTC4) was synthesized and used to carry out photoaffinity labelling experiments; a technique used to predict drug binding to a target protein. LTC4 is an endogenous substrate of ABCC2 since previous reports have shown LTC4 transport by ABCC2. Our binding studies revealed specific photoaffinity labelling of IAALTC4 to ABCC2 transfected cells. This work shows for the first time the direct binding of LTC4 to ABCC2, and further expands on the current biochemical knowledge of ABCC2. The long-standing drug of choice to treat malaria, chloroquine (CQ), is no longer effective due to increasing drug resistance. The lack of both new drug development and a clear understanding of the mechanism(s) of drug resistance have made achieving the global initiative to halve the malaria burden by the year 2010 more problematic; this aim now requires alternative methods of treatment to CQ. Therefore, the second main objective of this thesis was to address the growing problem of malaria drug resistance by exploring alternative therapies and a potential modulator of CQ resistance. In the third chapter, modulators of MRP1-mediated resistance were explored in chloroquine-sensitive and -resista<br>Dans la première partie de la thèse, deux transporteurs ABC ont été explorés. Initialement, nous avons fait l'analyse des protéines ABC (ATP-binding cassette) dans le globules rouges, en examinant leur niveau d'expression au niveau de leur membrane. Nous avons observé que ABCG2 aussi appelé : "breast cancer resistant protein,-BCRP", "mitoxantrone resistant protein", et "ABC placental", était exprimé dans les globules rouges matures. Ce travaille s'est concentré sur la caractérisation de l'oligomérization de ABCG2 dans la membrane des cellules cancéreuses et dans les globules rouges humaines. Nous savons déjà que ABCG2 transporte la protoporphyrin IX ou hème, alors nous souhaitons que ces résultats ajoutent à la connaissance de la fonction normale des globules rouges. Dans le deuxième chapitre, nous avons exploré les caractéristiques de liaison de ABCC2 (MRP2) avec les substrats. En utilisant un analogue photoréactif de LTC4 (IAALTC4) marqué pour faire des études de photoaffinités, une technique fut utilisée pour prédire la liaison d'un composé sur une protéine. La LTC4 est un substrat naturel (endogène) de ABCC2 et des résultats établis antérieurement ont montré le transport de LTC4 par ABCC2. Nos études de liaisons en photoaffinité demontrent spécifiquement que IAALTC4 trace les cellules transfectées avec ABCC2. Ces résultats montrent pour la première fois, la liaison de LTC4 à ABCC2, tout en nous apportant plus d'information biochimique sur ABCC2. La Chloroquine (CQ) est l'agent chimiothérapeutique le plus rèpandu pour combattre et traiter la malaria; toutefois son efficacité est en constante décroissance due à une résistance du parasite rependue mondialement. Les organismes mondiaux de santé préconisent l'utilisation de type de traitements visant une réduction de 50% du paludisme pour l'année 2010. Toutefois, le manque de nouvelles molécules et l'absence d'une compréhension claire des mécanismes$
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Kromrey, Marie-Luise [Verfasser]. "Die Funktion des MRP4 (ABCC4)-Transporters in Thrombozyten: Bedeutung von Adaptorproteinen / Marie-Luise Kromrey." Greifswald : Universitätsbibliothek Greifswald, 2016. http://d-nb.info/1098169204/34.
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Kinting, Susanna [Verfasser], and Heinrich [Akademischer Betreuer] Leonhardt. "Functional rescue of mutant ABCA3 by correctors and potentiators / Susanna Kinting ; Betreuer: Heinrich Leonhardt." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1204005281/34.
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Ocelotl, Josue, Jorge Sánchez, Isabel Gómez, Bruce E. Tabashnik, Alejandra Bravo, and Mario Soberón. "ABCC2 is associated with Bacillus thuringiensis Cry1Ac toxin oligomerization and membrane insertion in diamondback moth." NATURE PUBLISHING GROUP, 2017. http://hdl.handle.net/10150/627167.
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Cry1A insecticidal toxins bind sequentially to different larval gut proteins facilitating oligomerization, membrane insertion and pore formation. Cry1Ac interaction with cadherin triggers oligomerization. However, a mutation in an ABC transporter gene (ABCC2) is linked to Cry1Ac resistance in Plutella xylostella. Cry1AcMod, engineered to lack helix alpha-1, was able to form oligomers without cadherinbinding and effectively countered Cry1Ac resistance linked to ABCC2. Here we analyzed Cry1Ac and Cry1AcMod binding and oligomerization by western blots using brush border membrane vesicles (BBMV) from a strain of P. xylostella susceptible to Cry1Ac (Geneva 88) and a strain with resistance to Cry1Ac (NO-QAGE) linked to an ABCC2 mutation. Resistance correlated with lack of specific binding and reduced oligomerization of Cry1Ac in BBMV from NO-QAGE. In contrast, Cry1AcMod bound specifically and still formed oligomers in BBMV from both strains. We compared association of pre-formed Cry1Ac oligomer, obtained by incubating Cry1Ac toxin with a Manduca sexta cadherin fragment, with BBMV from both strains. Our results show that pre-formed oligomers associate more efficiently with BBMV from Geneva 88 than with BBMV from NO-QAGE, indicating that the ABCC2 mutation also affects the association of Cry1Ac oligomer with the membrane. These data indicate, for the first time, that ABCC2 facilitates Cry1Ac oligomerization and oligomer membrane insertion in P. xylostella.
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Zhang, Wei. "LOSS OF MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 1 (MRP1/ABCC1) POTENTIATES DOXORUBICIN-INDUCED CARDIOTOXICITY IN MICE." UKnowledge, 2015. http://uknowledge.uky.edu/toxicology_etds/12.
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Doxorubicin (DOX) is a broad-spectrum and effective chemotherapeutic agent, but its use in oncologic practice is limited by dose-dependent cumulative cardiotoxicity. DOX-induced cardiotoxicity is in large part due to its ability to cause oxidative stress. Multidrug resistance associated protein 1 (MRP1/ABCC1) is a member of the ATP-binding cassette (ABC) transporter superfamily. By effluxing a wide variety of endogenous and exogenous substrates, Mrp1 plays important physiological roles in multiple tissues and also protects normal tissues against toxicants. However, the role of MRP1 in heart is largely unknown.
The role of Mrp1 in DOX-induced cardiotoxicity was investigated in Mrp1 null (Mrp1-/-) and their C57BL (WT) littermates. Chronic DOX caused body weight loss and hemotoxicity, and these adverse effects were significantly exacerbated in Mrp1-/- vs WT mice. Importantly, loss of Mrp1 potentiated DOX-induced cardiotoxicity, presenting as worsened cardiac function and more cellular apoptosis in DOX treated Mrp1-/- mice. Mrp1 also protected neonatal mouse cardiomyocytes (CM) and cardiac fibroblasts (CF) culture against DOX cytotoxicity in vitro. This was demonstrated by the decreased cell survival, more apoptosis and more DNA damage in DOX treated Mrp1-/- vs WT cells.
In addition, the effects of deletion of Mrp1 was studied on glutathione (GSH)/glutathione disulfide (GSSG) homeostasis, glutathione conjugate of 4-hydroxy-2-nonenal (GS-HNE) accumulation, protein oxidative damage and expression of antioxidant enzymes. Loss of Mrp1 led to significantly higher GSH and GSSG basal levels in heart. Following DOX treatment, Mrp1-/- CM and CF showed increased GSH and GSSG levels vs WT cells. Meanwhile, DOX increased expression of the GSH synthesis enzymes in Mrp1-/- but not WT cells. Thus, increased GSH synthesis may contribute to the further increase in the GSH pool in DOX-treated Mrp1-/- cells. DOX induced comparable increases of GS-HNE concentration in WT and Mrp1-/- mice hearts. Finally, expression of extracellular superoxide dismutase (ECSOD/SOD3) was significantly lower in Mrp1-/- vs. WT CM treated with either saline or DOX.
In summary, this study is the first to document a protective role of Mrp1 in DOX-induced cardiotoxicity. It gives critical information regarding the potential adverse sequelae of introduction of MRP1 inhibitors as adjuncts to clinical chemotherapy of multidrug resistant tumors.
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Nessa, A. "Understanding the molecular basis of Congenital Hyperinsulinism due to autosomal dominant ABCC8 and KCNJ11 mutations." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1443884/.
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Background: Congenital Hyperinsulinism (CHI) is a rare heterogeneous disease characterised by unregulated insulin secretion. A prominent feature of CHI is severe hypoglycaemia which presents during the neonatal period. Immediate medical attention is required to prevent permanent neurological damage. The ABCC8 and KCNJ11 genes encode for the proteins SUR1 and Kir6.2 respectively. Four SUR1 and four Kir6.2 subunits assemble into a single ATP-sensitive potassium channel (KATP), which plays a pivotal role in regulating insulin secretion from pancreatic β-cells. The most common cause of CHI is due to recessive inactivating mutations in ABCC8/KCNJ11, which can lead to defects in KATP channel biogenesis, assembly and regulation. Dominant mutations in ABCC8/KCNJ11 causing medically unresponsive CHI have been reported, but the molecular mechanisms are not clear. Aim: To understand the molecular basis of medically unresponsive CHI due to dominant ABCC8 and KCNJ11 mutations. Patients: We studied 11 patients with diazoxide unresponsive CHI who required a near total pancreatectomy and 2 patients with diazoxide responsive CHI. DNA sequencing revealed dominant inactivating heterozygous missense mutations (9 ABCC8 and 1 KCNJ11). This includes three novel, and seven previously reported mutations. Methods: The mutations were created in plasmid constructs containing the WT cDNA sequence for ABCC8/KCNJ11 using site directed mutagenesis. These constructs were individually transfected into HEK293 cells for a series of functional studies. Confocal microscopy was used to determine the subcellular location of mutant KATP channels, by co-transfecting with pDs-Red2-ER (endoplasmic reticulum marker) and Kir6.2-GFP. Radioactive Rubidium (86Rb+) was used to measure the efflux of Potassium (K+) under stimulated conditions in intact cells. Electrophysiological techniques were also applied to measure the whole-cell and single channel currents. KATP channel activators, inhibitors and metabolic inhibition were used in the functional experiments. Results: The confocal analysis has demonstrated that the NBD2 mutations are not retained in the endoplasmic reticulum (ER), which is indicative of membrane expression. The transmembrane domain (TMD) mutations however are relatively retained in the ER which suggests there is a trafficking defect. D1506E is the most severe SUR1 NBD2 mutation which has been studied extensively. Homologous expression of D1506E under whole-cell patch-clamp, has revealed that there is only -2.88 ± 1 pA/pF of current in the cell in the presence of 100µM diazoxide. The single channel data shows a current response of only 4.5 ± 1.8% in the presence of 1mM ADP. Heterozygous expression of D1506E is suggestive of a strong dominant negative effect on WT SUR1 subunits. Mutations in the TMD however appear to be more responsive to channel activators such as diazoxide and metabolic inhibition, although there is relatively lower expression at the membrane. The A113V is a SUR1 TMD0 mutant which also shows that 52 ± 5% of the channel is retained in the ER. However the channel shows some activation to MgADP (83.5 ± 7.3%). Conclusions: The mechanism underlying medically unresponsive CHI caused by dominant mutations in NBD2, appears to be due the KATP channels inability to respond to channel agonists such as diazoxide. Mutations in NBD2 are likely to abolish the channels sensitivity to MgADP. The TMD0 mutations studied are paternal mutations causing diffuse disease; however the functional data suggests that there may be other unknown mechanisms involved in causing the disease.
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Wittmann, Thomas [Verfasser], and Dominik [Akademischer Betreuer] Hartl. "Categorization and classification of different ABCA3 variants causing interstitial lung disease / Thomas Wittmann ; Betreuer: Dominik Hartl." Tübingen : Universitätsbibliothek Tübingen, 2016. http://d-nb.info/1198120967/34.
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Pouliot, Benoît. "Abc3, un transporteur vacuolaire exprimé en carence de fer chez la levure à fission." Mémoire, Université de Sherbrooke, 2010. http://savoirs.usherbrooke.ca/handle/11143/4028.
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De nombreux processus métaboliques nécessitent la présence de fer en tant que cofacteur. Paradoxalement, la surabondance en fer peut contribuer à la formation de dérivés oxygénés hautement réactifs qui sont toxiques pour la cellule. Ceci fait en sorte que sa concentration intracellulaire doit être finement régulée. Chez la levure à fission, Schizosaccharomyces pombe, plusieurs mécanismes participent à l'établissement de l'homéostasie du fer. Parmi ces mécanismes, on y retrouve des protéines de transport du fer à la surface cellulaire, ainsi que d'autres responsables de la séquestration de l'ion à l'intérieur de la vacuole. Un rôle pour la vacuole consiste à emmagasiner le fer afin de détoxifier la cellule s'il est trop abondant. Du même coup, la vacuole sert de réservoir qui pourra redonner le fer plus tard à la cellule si cette dernière croît en condition de rareté pour cet élément. La voie par laquelle le fer peut ressortir de la vacuole n'a cependant pas encore été identifiée. L'objectif de cette étude est d'identifier le transporteur responsable du relâchement du fer de la vacuole vers le compartiment cytosolique. Nos recherches ont permis d'identifier un candidat, un transporteur transmembranaire de type ABC (ATP binding cassette) nommé Abc3, dont l'expression augmente de 16.9 fois en carence de fer selon des études comparatives par biopuces à ADN. Tout d'abord, l'étude de la régulation du gène abc3[indice supérieur +] a été effectuée selon la présence ou non de fer dans le milieu de culture. L'expression du gène abc3[indice supérieur +] a été comparée avec d'autres gènes codant pour d'autres protéines de la même famille. Seul le gène abc3[indice supérieur +] a montré une expression variant selon le statut en fer. Il est réprimé en présence de fer et activé en carence de ce dernier. Par la suite, des éléments en cis du promoteur abc3[indice supérieur +] pouvant être responsables de la régulation selon le statut en fer ont été analysés. Parmi ces derniers, nous avons démontré que seul l'élément de régulation le plus près du cadre de lecture est fonctionnel permettant la répression du gène abc3[indice supérieur +] en présence de fer. Un essai fonctionnel permettant de montrer l'importance de la protéine Abc3 a été mis au point. Ainsi, une souche nulle pour le gène abc3[indice supérieur +] montre une perte de croissance en présence de cérulénine, un antibiotique qui inhibe la biosynthèse des acides gras. La souche abc3[delta] mutante est également sensible à la présence du chélateur de fer, le 2,2-dipyridyl (Dip), lorsque le système de transport de surface constitué de Fio1 et de Fip1 est inactivé. Une protéine Abc3 portant une étiquette fluorescente exprimée sous le contrôle du promoteur endogène abc3[indice supérieur +] a permis de localiser la protéine Abc3-GFP au niveau des vacuoles en carence de fer. Des analyses de profils transcriptionnels ont indiqué que l'expression forcée du gène abc3[indice supérieur +] en présence de fer active le répresseur Fep1. La surexpression du transporteur Abc3 libérerait plus de fer de la vacuole ce qui aurait pour effet d'activer Fep1, résultant en la répression de la transcription des gènes impliqués dans l'acquisition du fer à la surface cellulaire. Les résultats obtenus sur Abc3 suggèrent fortement que cette protéine pourrait être impliquée dans l'exportation du fer de la vacuole vers le cytoplasme de la levure lorsque cette dernière croît en carence de fer.
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Schicker, Maresa [Verfasser], and Andreas [Akademischer Betreuer] Holzinger. "Die Charakterisierung der Funktion des Lipidtransporters ABCA3 in der Milchdrüse (am Mausmodell) / Maresa Schicker. Betreuer: Andreas Holzinger." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1058076922/34.
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Qiu, Ruolun. "ABCC2 (cMOAT) : role in 4-hydroxycyclophosphamide elimination from the liver and survival of high dose cyclophosphamide regimens /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/7962.
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Li, Yang [Verfasser], and Matthias [Akademischer Betreuer] Griese. "Probe the transport function of ABCA3 by metabolic labelling of choline phospholipids / Yang Li ; Betreuer: Matthias Griese." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2020. http://d-nb.info/1221699148/34.
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Rimington, Tracy L. "Expression, purification and characterisation of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) in Saccharomyces cerevisiae." Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/expression-purification-and-characterisation-of-the-cystic-fibrosis-transmembrane-conductance-regulator-cftr-in-saccharomyces-cerevisiae(5c8c606b-8925-4627-91dc-67a896b9f286).html.
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Mutations in the eukaryotic integral membrane protein Cystic Fibrosis Transmembrane conductance Regulator (CFTR) cause the hereditary disease cystic fibrosis (CF). CFTR functions as an ion channel at the surface of epithelial cells and regulates the movement of chloride ions and water across the plasma membrane. CFTR is difficult to express and purify in heterologous systems due to its propensity to form insoluble aggregates and its susceptibility to degradation. Obtaining good yields of highly purified CFTR has proven problematic and contributes to our limited understanding of the structure and function of the protein. The most prevalent disease causing mutation, F508del, results in misfolded CFTR which is particularly unstable and is quickly targeted for degradation by the host system and is prevented from being trafficked to the plasma membrane. There are limited treatment options for patients with the F508del mutation and it is therefore of significant interest within CF research. New methods and assays are required to identify potential compounds which could correct the F508del mutation. This thesis investigates the use of Saccharomyces cerevisiae to express and purify codon optimised recombinant CFTR. The use of a green fluorescent protein (GFP) tag enabled quick and simple detection of CFTR in whole cells and after extraction from the plasma membrane. By optimising the culture conditions for CFTR expression and detergent solubilisation conditions, relatively high yields of full-length protein were obtained. When used as a chemical chaperone at the time of inducing CFTR expression, glycerol increased yields of full-length protein. Degradation of CFTR could be limited by inducing expression at an optimal cell density and by harvesting cells within a specific time window. CFTR was extracted by solubilisation in the mild detergent dodecyl-β-D-maltopyranoside (DDM) in the presence of up to 1 M NaCl with up to ~87% efficiency in some cases. Using a gene optimisation strategy in which additional purification tags and a yeast Kozak-like sequence were added, the human CFTR (hCFTR) protein was expressed and purified. Fluorescence microscopy revealed CFTR localisation at the periphery of yeast cells. Immunoaffinity chromatography facilitated by the GFP tag at the C terminus of CFTR produced protein of up to 95% purity. An assessment of the thermal stability of this highly purified CFTR using a fluorescent probe binding assay revealed a denaturation midpoint (Tm) of ~43 degC. The ability of this assay to determine the stability of CFTR is encouraging and there is the potential to further develop it in a high-throughput manner to identify compounds which stabilise the F508del protein and which may hold the key to developing new treatments for CF.
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Gschwendtner, Stefanie [Verfasser], and Matthias [Akademischer Betreuer] Griese. "Der Surfactant-Lipidtransporter ABCA3 wird in LAMP3-positiven Vesikeln N-terminal proteolytisch gespalten / Stefanie Gschwendtner ; Betreuer: Matthias Griese." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/1184793964/34.
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Kauschke, René [Verfasser]. "Bedeutung des Transportproteins Mrp2 (ABCC2) für Veränderungen der renalen Hämodynamik bei der Cyclosporin A-induzierten Transplantatnephrotoxizität / Rene Kauschke." Greifswald : Universitätsbibliothek Greifswald, 2013. http://d-nb.info/103880017X/34.
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Weichert, Nina [Verfasser], and Matthias [Akademischer Betreuer] Griese. "Some ABCA3 mutations elevate ER stress and initiate apoptosis of lung epithelial cells / Nina Weichert. Betreuer: Matthias Griese." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2011. http://d-nb.info/1018615423/34.
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Heiden, Lu [Verfasser], and Andreas [Akademischer Betreuer] Holzinger. "Charakterisierung der Funktion des Lipidtransporters ABCA3 im Milchdrüsen- und Lebergewebe am heterozygoten Mausmodell / Lu Heiden ; Betreuer: Andreas Holzinger." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2020. http://d-nb.info/1209472465/34.
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Chantemargue, Benjamin. "In silico investigation of xenobiotic interactions with lipid bilayers and ABC membrane transporters, the case of ABCC4/MRP4." Thesis, Limoges, 2018. http://www.theses.fr/2018LIMO0077/document.
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L’appréhension des mécanismes d’action biologiques des protéines membranaires nécessite de comprendre les interactions des xénobiotiques avec ces protéines et avec les membranes lipidiques. Les méthodes expérimentales sont parfois coûteuses et ne permettent d’obtenir que des informations partielles sur les interactions xénobiotiques-membrane-protéine. La modélisation moléculaire est une sérieuse alternative. Les simulations de dynamique moléculaire et de dynamique biaisées ont ouvert de nombreuses perspectives en permettant de décrire ces interactions moléculaires à l’échelle atomique. Grâce à des simulations de dynamique moléculaire, nous avons été capables de construire un modèle de transporteur humain ABC : ABCC4/MRP4. Cette protéine a été choisie pour sa présence dans le rein, notamment, et son importance clinique. Nous avons évalué l’influence du cholestérol sur cette protéine. L’étude de domaines spécifiques et l’impact d’un polymorphisme a été reliée à l’activité de transport de cette protéine. Nous avons également étudié l’interaction de xénobiotiques avec ce transporteur humain. Le cycle de transport des transporteurs ABC a été examiné afin de comprendre leur fonctionnement. L’incorporation de cholestérol a montré un impact significatif sur la protéine humaine ABCC4/MRP4 et sur les xénobiotiques étudiés. L’importance de domaines constituant la protéine ABCC4/MRP4 ainsi que l’importance de résidus individuels a clairement été prouvée. Nous avons également pu observer des intermédiaires du cycle de transport d’un transporteur ABC conjointement avec des changements structuraux<br>Understanding the biological mechanisms of action of membrane proteins requires the comprehension of the interactions of xenobiotics with these proteins and with lipid membranes. Experimental methods are often demanding and only partially respond to xenobiotic-membrane-protein interactions. In silico molecular modeling is a serious alternative to tackle these issues. Molecular dynamics (MD) and biased dynamics simulations have opened many perspectives by providing an atomistic description of these intermolecular interactions. Using MD simulations, we built a model of the human ABC ABCC4/MRP4 transporter. We explored the influence of cholesterol on this protein as well as the impact of a polymorphism known to shut down the transport activity of this protein. We also studied the interaction of xenobiotics with this human transporter. The transport cycle of the ABC transporters was investigated in an attempt to better understand how it works.Interactions between lipid membranes and xenobiotics were explored by examining their ability to incorporate lipid membranes. Lipid mixtures with cholesterol showed a significant impact on the human protein ABCC4/MRP4 and on the xenobiotics studied. The importance of regions, domains constituting the ABCC4/MRP4 protein as well as the importance of specific residues has been clearly demonstrated. We also observed intermediates in the transport cycle of an ABC transporter in conjunction with structural changes occurring during this cycle
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Ziri, Taissir. "Identification et caractérisation des orthologues du transporteur ABC humain ABBCC10 chez Catharanthus roseus et Arabidopsis thaliana." Thesis, Tours, 2014. http://www.theses.fr/2014TOUR4007/document.
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Les transporteurs ABC sont les membres d'une superfamille de protéines qui utilisent l'hydrolyse de l'ATP pour déplacer une large gamme de substrats au travers des membranes biologiques. Les membres de la sous famille ABCC sont généralement caractérisés par un domaine transmembranaire supplémentaire en région N-terminal (TMD0). Dans cette étude, nous avons analysé deux gènes ABCC de plantes : CrABCC1 de Catharanthus roseus et AtABCC13 son orthologue chez Arabidopsis thaliana. L'analyse phylogénétique répartit les ABCC de plantes dans 3 clades distinctes. Les clades I et II sont spécifiques aux plantes tandis que le clade III est le seul associant des ABCC humains et de plantes. Le criblage de la base de données a permis d'identifier 16 séquences ABCC chez Catharanthus roseus parmi lesquelles 2 appartiennent à CrABCC<br>ABC transporters are members of a large superfamily of proteins that utilize ATP hydrolysis to translocate a wide range of substrate across biological membranes. Members of C. subfamily (ABCC) are generally structurally characterized by an additional (N-Terminal) transmembrane domain (TMD0). In this study the analysed two plant ABCC : CrABCC1 from Catharanthus roseus and AtABCC13, it's ortholog in Arabidopsis thaliana. Phylogenetic analysis of plant ABCCs separates their protein sequences over three distinct clusters : I and II are plant specific whereas cluster III is the only gathering humain and plant ABCCs. Screening of plant database allowed us to identify 16 different ABCCs sequences in Catharanthus roseus
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Sassi, Yassine. "Rôle des transporteurs MRP sur la fonction des myocytes cardiaques et vasculaires via la régulation des nucléotides cycliques : implications physiopathologiques et pharmacologiques." Paris 6, 2009. http://www.theses.fr/2009PA066224.
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L’AMPc et le GMPc jouent un rôle important dans de multiples processus biologiques. De récentes études ont montré qu’un membre de la famille des Multidrug Resistance associated-Protein (MRP4) est capable de transporter ces nucléotides cycliques hors de la cellule. Mes travaux de thèse ont permis de montrer que que l’inhibition de l’expression de MRP4, par des siRNA, augmente les taux intracellulaires des nucléotides cycliques et ceci a pour conséquence une diminution de la prolifération des CML humaines in vitro ainsi que du développement de la néointima de carotides de rats in vivo. Une deuxième étude nous a permis de montrer que l’inhibition de MRP4 induit l’activité de la PKA dans le cardiomyocyte qui module alors l’activité de plusieurs acteurs du couplage excitation-contraction. Les souris déficientes en MRP4 développent une hypertrophie modérée avec l’âge et le système AMPc-dépendant est exacerbée chez ces animaux. En conclusion, notre travail est la première démonstration que l’efflux des nucléotides cycliques par MRP4 permet de réguler le taux d’AMPc et en conséquence la fonction des cellules cardiaques et vasculaires.
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Stefan, Katja [Verfasser]. "Etablierung und Anwendung unterschiedlicher kolorimetrischer Detektionsmethoden zur Aktivitätsbestimmung von Modulatoren der ABC-Transporter ABCB1, ABCC1 und ABCG2 / Katja Stefan." Bonn : Universitäts- und Landesbibliothek Bonn, 2020. http://d-nb.info/1221668986/34.
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Inamahoro, Anny. "The expression of ABC transporter in colorectal cancer : A study about ABCC5 and ABCC11 gene expression in colorectal cancer." Thesis, Högskolan i Skövde, Institutionen för hälsovetenskaper, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-19064.
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Introduction. Stage III colorectal cancer is treated with adjuvant chemotherapy based on 5-fluorouracil and leucovorin. Drug resistance to anticancer treatment might be due to adenosine triphosphate binding cassette transporter family members.Aim. The aim of study was to analyze the expression of two ABC transporters, known as ABCC5 and ABCC11, in tumor tissue obtained from stage III colorectal cancer patients and to correlate the results to clinical data including disease-free survival. Patients and Methods. The expression of ABCC5 and ABCC11 was analyzed in 488 patients out of which 225 were treated with 5-fluorouracil in combination with leucovorin whereas 263 did not receive any chemotherapy. Gene expression was determined using real time qPCR and related to clinical variables. Results. ABCC5 expression was associated with age (r =0.34, P =0.0001) and tumor location (P = 0.0001). ABCC5 expression was not associated with disease-free survival in both groups of treated (P=0.22) and untreated patients (P=0.83). ABCC11 was not associated with disease-free survival in the group of treated patients(P=0.35). Low expression of ABCC11 was significantly associated with a longer disease-free survival of untreated patients (P=0.01). Since the P-value was significant, a further analysis called cox regression multivariate analysis was performed in search of an interaction between the expression of ABCC11 and other covariates. Cox regression multivariate analysis showed that the expression of ABCC11 was an independent marker for disease-free survival in untreated patients [HR 0.67 (range 0.49-0.93), P=0.015]. Conclusions. None of the two analyzed genes predicted disease-free survival of patients treated with 5-fluorouracil.
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Schmitt, Sven Marcel [Verfasser]. "Purines and 9-deazapurines as Modulators of Multidrug Resistance-associated Protein 1 (MRP1/ABCC1)-mediated Transport / Sven Marcel Schmitt." Bonn : Universitäts- und Landesbibliothek Bonn, 2017. http://d-nb.info/1149154101/34.
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