Dissertations / Theses: 'ABCC10'

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VALERIANO, Josué Jeyzon de Lima Soares. "Polimorfismos genéticos associados a efeitos adversos neuropsiquiátricos em pacientes HIV positivos submetidos à terapia com Efavirenz." Universidade Federal de Pernambuco, 2016. https://repositorio.ufpe.br/handle/123456789/17907.

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A Terapia Antirretroviral Altamente Ativa (HAART) foi uma revolução que mudou drasticamente a evolução da infecção pelo HIV, transformando uma doença fatal em uma doença crônica. Efavirenz é um antirretroviral muito eficaz, mundialmente prescrito, presente no tratamento de primeira linha HAART, mas que apresenta uma alta frequência de efeitos neuropsiquiátricos que afetam a adesão ao tratamento, prejudicam a saúde e a qualidade de vida dos pacientes. Neste sentido, este estudo visa identificar polimorfismos genéticos associados à ocorrência de efeitos neuropsiquiátricos relatados no tratamento com Efavirenz em doses padrão. Através da análise retrospectiva dos prontuários dos 162 pacientes HIV positivos que utilizavam Efavirenz, 82 (50,6%) apresentaram efeitos adversos neuropsiquiátricos relacionados, dentre os quais: tonturas, cefaleia, insônia e depressão se mostraram os mais frequentes. Foi demonstrado que o uso da Zidovudina combinado ao Efavirenz, ao invés de Tenofovir (HR: 2,7; p-valor: 0,04), e o sexo feminino (HR: 3,5; p-valor: 0,05) aumentam o risco de tonturas e depressão, respectivamente, ao longo do tempo. Dez sete genes (CYP2B6, ABCB1, ABCC1, ABCC2, ABCC10, NR1I 2p oeli mNoRr1fiIs3m) ofosr eamm analisados. Apenas o polimorfismo no gene ABCC10 (rs2125739), alelo C, foi associado à ocorrência de efeitos adversos neuropsiquiátricos no tratamento com Efavirenz (OR: 2,6; p-valor: 0,03). Análises por regressão logística ajustada para variáveis demográficas, clínicas e genéticas, esta última relacionada ao aumento nas concentrações plasmáticas do Efavirenz, mostraram que os genótipos CT ou CC no rs2125739 estavam ainda mais associados com um risco elevado (OR: 5,1; p-valor: 0,007). Os resultados poderão contribuir para minimizar os riscos de eofceotrivrêidnacdiae ,d eid eefnetiitfoicsa nndeou roppasciqieuniátetrsi cossu sncae ptetírvaepiisa ceo mau Exiflaiavnirdeon z,n am aensteconldhoa sudaa HAART combinada.
Highly Active Antiretroviral Therapy (HAART) was a revolution that changed the HIV dynamic infection, turning a fatal disease into a chronic one. Efavirenz is a very efficient globally prescribed antiretroviral, present in first line of HAART treatment, but which presents a high frequency of neuropsychiatric adverse effects that affect treatment adherence, damaging the patients’ health and their quality of life. Thus, this study aims to identify genetic polymorphism associated with the occurrence of neuropsychiatric adverse effects in HIV-positive patients submitted to Efavirenz therapy in standard oral doses. Through retrospective analysis of medical records of 162 of these patients, 82 (50,6%) had neuropsychiatric adverse effects related, such as: dizziness, headache, depression and insomnia. Survival analysis demonstrated that the combined use of Efavirenz with Zidovudine instead of Tenofovir increases the dizziness risk (HR: 2.7; p value: 0.04), as well as female sex increases the depression risk (HR: 3.5; p-value: 0.05), both polymorphisms in seven genes (CYP2B6, ABCB1, ABCC1, AB CoCve2r, tAimBeC. CT1e0n, NR1I2 and NR1I3) were genotyped. Only a polymorphism on ABCC10 gene (rs2125739) was associated (C allele) with the neuropsychiatric adverse effects occurrence in treatment with Efavirenz (OR 2.6; p value: 0.03). Logistic regression analysis, adjusted to demographic, clinical and genetic variables related to increased plasma concentrations of Efavirenz, showed that the CT or CC genotypes at rs2125739 were even more significantly associated to a higher risk of neuropsychiatric effects (OR 5.1; p -value: 0.007). The results may help to minimize the neuropsychiatric effects risk in therapy with Efavirenz maintaining its effectiveness by identifying susceptible patients and assisting in the choice of combin ed HAART.

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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.
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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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.
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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.

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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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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Matsuda, Akihiro. "(24S)-Hydroxycholesterol efflux from neuronal cells by ABC proteins." Kyoto University, 2014. http://hdl.handle.net/2433/185211.

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Kyoto University (京都大学)
0048
新制・課程博士
博士(農学)
甲第17986号
農博第2033号
新制||農||1019(附属図書館)
学位論文||H26||N4811(農学部図書室)
80830
京都大学大学院農学研究科応用生命科学専攻
(主査)教授植田和光, 教授植田充美, 教授三芳秀人
学位規則第4条第1項該当

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Shanmugarajah, Kalpana [Verfasser], and Karl-Erich [Gutachter] Jaeger. "Characterization of ABCG30 and ABCG1 from Arabidopsis thaliana / Kalpana Shanmugarajah ; Gutachter: Karl-Erich Jaeger." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2019. http://d-nb.info/1180023625/34.

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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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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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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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Gerloff, Thomas. "Die Bedeutung der ABC-Transportsysteme ABCB1 und Abcb11 in der Arzneimitteltherapie und bei cholestatischen Lebererkrankungen." Doctoral thesis, [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972571264.

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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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Brüggmann, Nina [Verfasser]. "Untersuchungen zum ABCA1-/ABCG1-vermittelten Cholesterin-Efflux in humanen Kontroll- und Tangierfibroblasten / Nina Brüggmann." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2021. http://d-nb.info/1228861153/34.

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Monzel, Judith Verena [Verfasser]. "Regulation der Cholesteroltransporter ABCA1 und ABCG1 im Kontext der Doxorubicin-induzierten Kardiotoxizität / Judith Verena Monzel." Greifswald : Universitätsbibliothek Greifswald, 2017. http://d-nb.info/1143131673/34.

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Zago, Vanessa Helena de Souza 1984. "Estudo molecular dos genes ABCA1, ABCG1, ABCG5, ABCG8 e SCARB1 em amostra populacional brasileira assintomática." [s.n.], 2015. http://repositorio.unicamp.br/jspui/handle/REPOSIP/312594.

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Orientadores: Eliana Cotta de Faria, Helena Coutinho Franco de Oliveira, Daniel Zanetti Scherrer
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Dado o importante papel desempenhado pelos transportadores ATP binding cassete A1 (ABCA1), G1 (ABCG1), G5 (ABCG5), G8 (ABCG8) e pelo scavenger receptor class B type I (SR-BI) para a homeostase corpórea de colesterol e desenvolvimento da aterosclerose, este trabalho se propôs a: (i) investigar a relação dos polimorfismos rs2275543 (ABCA1), rs1893590 (ABCG1), rs6720173 (ABCG5), rs6544718 (ABCG8) e rs5888 (SCARB1) com gênero, idade e índice de massa corpórea (IMC) e suas interações sobre variáveis clínicas e bioquímicas (n=654); (ii) determinar a repercussão destes polimorfismos sobre os parâmetros estudados na população total e de forma gênero-específica (n=590) e (iii) avaliar se os miRNAs hsa-miR-33a e hsa-miR-128a são diferencialmente expressos em um subgrupo da população (n=51) e averiguar sua associação com as concentrações plasmáticas do colesterol da lipoproteína de alta densidade (HDL-C), aterosclerose subclínica e expressão de ABCA1, ABCG1 e SCARB1. Para tanto, foram selecionados voluntários normolipidêmicos e assintomáticos, de ambos os gêneros, com idade entre 20 e 75 anos. Dados clínicos e antropométricos foram obtidos, assim como sangue venoso periférico para as determinações bioquímicas e extração de DNA e RNA. O subgrupo de 51 voluntários foi classificado de acordo com HDL-C (mg/dL) em hipoalfalipoproteinêmicos (hipo, HDL-C?39), hiperalfalipoproteinêmicos (hiper, HDL-C?68) e controles (CTL, HDL-C?40<68) e determinadas a espessura íntimo-medial das artérias carótidas e proteínas relacionadas ao metabolismo de HDL. Determinamos que o rs1893590 interage com a idade e o IMC, modulando as concentrações de HDL-C, bem como o tamanho e volume da partícula, sugerindo que este pode modificar seu metabolismo e composição. Nas análises comparativas o rs2275543 apresentou efeitos diferentes, porém benéficos para ambos os gêneros; adicionalmente, o rs6720173 determinou um fenótipo lipoproteico proaterogênico no gênero masculino, enquanto as variantes rs5888 e rs6544718 repercutiram sobre marcadores de adiposidade no gênero feminino. A análise dos cinco polimorfismos nesta população fornece evidências de que estes atuam em diferentes vias do metabolismo lipoproteico, e tem na maioria dos casos características gênero-específicas. Adicionalmente, a avaliação da expressão de hsa-miR-33a, hsa-miR-128a, ABCA1, ABCG1 e SCARB1 revelou que os indivíduos hiper apresentam um aumento da expressão de ABCA1 e ABCG1 em relação ao grupo CTL, somado a uma redução de 72% na expressão do hsa-miR-33a; em conjunto, estes resultados indicam um potencial papel regulatório deste miRNA em indivíduos assintomáticos, possivelmente contribuindo para o aumento do efluxo e do transporte reverso de colesterol
Abstract: Given the important role played by ATP binding cassete transporters A1 (ABCA1), G1 (ABCG1), G5 (ABCG5), G8 (ABCG8) and by scavenger receptor class B type I (SR-BI) on body cholesterol homeostasis and atherosclerosis development, this study proposes to: (i) investigate the relationship of polymorphisms rs2275543 (ABCA1), rs1893590 (ABCG1), rs6720173 (ABCG5), rs6544718 (ABCG8) e rs5888 (SCARB1) with gender, age and body mass index (BMI) and its interactions with clinical and biochemical variables (n=654); (ii) determine the effects of these polymorphisms on the studied parameters in the total population and in a gender-specific manner (n=590) and (iii) evaluate if miRNAs hsa-miR-33a e hsa-miR-128a are differentially expressed in a subgroup of the population (n=51) and verify its association with plasma levels of high-density lipoprotein cholesterol (HDL-C), subclinical atherosclerosis plus ABCA1, ABCG1 and SCARB1 expression. Thus, normolipidemic and asymptomatic volunteers from both genders, with ages ranging from 20 to 75 years were selected. Clinical and anthropometric data were obtained, as well as peripheral venous blood for biochemical determinations plus DNA and RNA extraction. The subgroup of 51 individuals was classified according HDL-C (mg/dL) in hypoalphalipoproteinemics (hypo, HDL-C?39), hyperalphalipoproteinemics (hyper, HDL-C?68) and controls (CTL, HDL-C?40<68); then, were determinated the carotid intima-media thickness and proteins related to HDL metabolism. The polymorphism rs1893590 interacts with age and BMI, modulating HDL-C levels as well as the particle size and volume, suggesting its role on HDL metabolism and composition. Comparative analysis demonstrated that rs2275543 has different, but beneficial repercussions in both genders; furthermore, rs6720173 determines a pro-atherogenic lipoprotein profile in males, while the variants rs5888 and rs6544718 affect positively adiposity markers in females. The analyses of the five studied polymorphism in this population provide evidences of its role in several pathways of lipoproteins metabolism, in most cases in a gender-specific manner. Moreover, the ABCA1, ABCG1, SCARB1, hsa-miR-33a and hsa-miR-128a expression analysis revealed that hyper group presents a significant increase of ABCA1 and ABCG1 expression in relation to the control group; additionally, hsa-miR-33a decreased by 72%. Together, these results indicate a potential regulatory role of this miRNA in asymptomatic individuals, probably contributing to increased cholesterol efflux and reverse cholesterol transport
Doutorado
Ciencias Biomedicas
Doutora em Ciências Médicas

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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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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
Ph.D.
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.
Temple University--Theses

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Moraes, Ana Carolina Rabello de. "Importância da investigação de proteínas de resistência ABCB1, ABCC1 e LRP e da proteína antiapoptótica Bcl-2 no diagnóstico e no prognóstico de leucemias agudas." reponame:Repositório Institucional da UFSC, 2012. http://repositorio.ufsc.br/xmlui/handle/123456789/93790.

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Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde, Programa de Pós-Graduação em Farmácia, Florianópolis, 2010
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A resistência a múltiplas drogas é uma das maiores causas para a falha do tratamento das leucemias agudas (LA). A resistência adquirida ou intrínseca a múltiplas drogas (MDR) depende de muitas variáveis biológicas e é principalmente caracterizada pela resistência cruzada a uma ampla variedade de fármacos não relacionados estrutural e funcionalmente. Vários mecanismos podem estar envolvidos no fenômeno MDR, como o mecanismo de efluxo de drogas através da membrana plasmática e as alterações nos mecanismos que regulam a morte celular por apoptose. Assim, o objetivo desse trabalho foi analisar o perfil de expressão das proteínas relacionadas à resistência a múltiplas drogas (ABCB1, ABCC1 e LRP) e à apoptose (Bcl-2) em células blásticas de pacientes com leucemia aguda (LA), ao diagnóstico, atendidos pelo Serviço de Hematologia do Hospital Universitário da Universidade Federal de Santa Catarina (HU-UFSC) e pelo Serviço de Oncologia do Hospital Infantil Joana de Gusmão (HI-Florianópolis) no período de Janeiro de 2008 a Dezembro de 2009. Para tanto, as células blásticas dos adultos e crianças com LA foram separadas por gradiente de densidade com Ficoll-Hypaque e a expressão dos genes e das proteínas de resistência foram avaliadas por RT-PCR semiquantitativo e citometria de fluxo, respectivamente. A média da expressão relativa de todas as amostras foi utilizada como ponto de corte para superexpressão. Tanto os pacientes adultos quanto as crianças apresentam uma ampla variedade de expressão para as proteínas estudadas. Os pacientes adultos com LA apresentaram correlação significativa entre a expressão dos genes abcb1 e lrp e a expressão das proteínas ABCB1 e ABCC1, ABCB1 e Bcl-2, e ABCC1 e Bcl-2 e nos pacientes pediátricos com LA não houve correlação significativa entre os níveis de expressão de dos genes e proteínas estudados. Nos pacientes adultos com LA, houve correlação positiva entre a expressão do gene abcb1 e a idade dos pacientes, e a concentração de LDH, enquanto nos pacientes pediátricos com LA, houve correlação positiva entre a expressão do gene abcc1 e a expressão de CD34, entre a expressão da proteína LRP e a idade, e entre a expressão da proteína ABCB1 e a leucometria ao diagnóstico. Esses resultados sugerem que a análise da expressão gênica de abcb1 está mais relacionada com um pior prognóstico nos pacientes adultos com LA, enquanto que nos pacientes com LA infantil, é a expressão conjunta das proteínas ABCB1, ABCC1 e LRP que parece estar relacionada com um pior prognóstico. Além disso, os resultados também indicam que a determinação do perfil de expressão da ABCB1, ABCC1 e LRP pelo método do RT-PCR semiquantitativo é mais significativa nos casos de LA em adultos e a determinação do perfil de expressão dessas proteínas por citometria de fluxo é mais significativa nas LAs em crianças

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Sahrhage, Tim Oliver [Verfasser], and Marc [Akademischer Betreuer] Freichel. "Verteilung der ATP-binding-cassette Transporter ABCG1, ABCG2, ABCB9 und ABCE1 in murinem Hodengewebe / Tim Oliver Sahrhage. Betreuer: Marc Freichel." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2014. http://d-nb.info/1053725469/34.

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Kowalski, Petra. "Modulation unterschiedlicher Formen der Multidrug-Resistenz mittels eines Multitargetmultiribozymes." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2006. http://dx.doi.org/10.18452/15511.

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Tumorzellen entwickeln häufig Resistenzen gegen verschiedene strukturell und funktionell unabhängige Zytostatika, was als Multidrug-Resistenz (MDR) bezeichnet wird und die Hauptursache für das Scheitern einer Chemotherapie ist. Mit Hilfe von in vitro-Untersuchungen wurden erhöhte Genexpressionen der ABC-Transporter MDR1, MRP2 und BCRP als maßgebliche Resistenzfaktoren identifiziert, wie z.B. in den Magenkarzinomzellinien EPG85-257RDB (MDR1) und EPG85-257RNOV (BCRP) sowie in der Ovarialkarzinomzellinie A2780RCIS (MRP2). Ziel der Arbeit war die Entwicklung eines auf Ribozym-Technologie basierenden Therapieansatzes, welcher die Expressionen der oben genannten ABC-Transporter simultan inhibiert und dessen Anwendung zur Reversion der zellulären MDR führt. Dazu wurde ein Multitargetmultiribozym (MTMR) entwickelt, das aus in trans-aktiven Ribozymen besteht, die gegen die ABC-Transporter mRNAs gerichtet sind sowie aus in cis-spaltenden Ribozymen und aus Spacer-RNA-Sequenzen. Durch autokatalytische Spaltung in cis konnten die in trans-aktiven Ribozyme aus dem Gesamt-MTMR freigesetzt werden. Die Analyse der kinetischen Parameter des MTMRs ergab, daß die autokatalytisch entstandenen MTMR-Fragmente ihre Substrat-RNAs im Vergleich zu den korrespondierenden Monoribozymen ohne Einbuße an Effizienz spalten können. Darüber hinaus wurde die MTMR-Sequenz stabil in den drei eingangs genannten MDR-Zellinien exprimiert, was in einer signifikanten Reduktion der jeweiligen Ziel-mRNAs (97 % MDR1-, 80 % BCRP-, 96 % MRP2-mRNA) und der entsprechenden Proteine resultierte. Die Multidrug-Resistenz konnte aufgrund der MTMR-Expression um 70% (A2780RCIS), 95% (257RNOV), 100% (257RDB) und die Zytostatikumsakkumulation um 90% (257RNOV-Zellen) sowie 100% (257RDB-Zellen) revertiert werden. Das MTMR stellt erstmalig ein RNA-Konstrukt dar, welches in der Lage ist, simultan mehrere unabhängige Gene funktionell auszuschalten. Es besitzt daher ein großes Potential für zukünftige gentherapeutische Ansätze.
Cancer cells are often insensible against structurally and functionally unrelated drugs that is known as multiple drug resistance (MDR) and the main cause for treatment failure. Overexpression of the ABC-transporters P-gp (ABCB1), MRP2 (ABCC2), and BCRP (ABCG2) is associated with MDR in several cancer cell lines, e.g. in the stomach carcinoma cell lines EPG85-257RDB (P-gp), EPG85-257RNOV (BCRP), and in the ovarian carcinoma cell line A2780RCIS (MRP2). We aimed the development of a novel hammerhead ribozyme-based therapeutic approach capable of simultaneous silencing of the prementioned ABC-transporters, and consequently of reversing MDR phenotypes. We designed a so-called multitarget multiribozyme (MTMR) consisting of trans-acting hammerhead ribozymes directed against the MDR1, MRP2, and BCRP transcripts, of MDR1 homologous spacer sequences, and of cis-acting ribozymes against the spacer sequences. Autocatalytic cleavage in cis excised the full-length MTMR, and released trans-acting hammerhead ribozymes. We also evaluated the catalytic features of the MTMR using large RNA target molecules. Comparison of the kinetic values of the autocatalytically derived MTMR fragments with those of corresponding mono-ribozymes demonstrated an MTMR-mediated substrate cleavage without distinct loss in catalytic efficiency. Moreover, the MTMR was stably expressed in the prementioned multidrug-resistant cancer cell lines, and decreased the targeted transcripts about 97% (MDR1), 80% (MRP2), and 96% (BCRP) as well as the corresponding protein levels, respectively. Cellular MDR could be reverted about 70% (A2780RCIS), 95% (257RNOV), and 100% (257RDB). Additionally, the MTMR reversed mitoxantrone accumulation entirely, and daunorubicin accumulation about 90% in stomach carcinoma cells, respectively. Taken together, the MTMRs capability of simultaneous silencing of multiple genes provides an effective instrument to knockdown genes of interest.

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Teixeira, Mayza Dalcin. "Estudo da associação de polimorfismos dos genes FTO, ABCA1, ABCA7 e ABCG1 com marcadores de obesidade e perfil lipídico em mulheres obesas." reponame:Repositório Institucional da UFPR, 2017. http://hdl.handle.net/1884/47563.

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Orientadora : Profª. Drª. Lupe Furtado-Alle
Coorientadora : Drª Luciane Viater Tureck
Dissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Genética. Defesa: Curitiba, 31/03/2017
Inclui referências : f. 85-88
Resumo: A maioria dos casos de obesidade e de dislipidemias possui origem complexa, pois é resultante da interação entre fatores genéticos e ambientais. Diversos genes têm sido relacionados com a susceptibilidade a estas doenças, incluindo variantes alélicas dos genes FTO, ABCA1, ABCA7 e ABCG1. Desse modo, o objetivo deste trabalho foi verificar se há influência de polimorfismos de nucleotídeo único (SNPs) destes genes em variáveis relacionadas à obesidade e ao perfil lipídico em mulheres obesas e avaliar o efeito destes SNPs na mudança destas variáveis em resposta a uma dieta de restrição calórica. Para isso, foi coletado sangue de 211 mulheres obesas para análises bioquímicas (níveis de triglicerídeos - TG, colesterol total - CT, HDL-c, LDL-c e VLDL) e genotípicas, além de medidas antropométricas (índice de massa corporal - IMC, circunferência da cintura - CC, e circunferência abdominal - CA), antes e depois de uma dieta com redução de 600Kcal por dia. As amostras foram genotipadas por ensaio de discriminação alélica TaqMan® e posteriormente foram feitas análises estatísticas. Como resultado, as mulheres portadoras do alelo A do SNP rs9939609 (FTO) apresentaram uma menor redução de CA e maior redução dos níveis de HDL-c em resposta à dieta. As portadoras do alelo A do SNP rs1800977 (ABCA1) perderam menos IMC após a intervenção do que as não portadoras. As portadoras do genótipo TT do SNP rs2230806 (ABCA1) reduziram mais seus níveis de CT em resposta a dieta do que as portadoras do genótipo GG. Além disso, o alelo T foi mais frequente que o alelo C no grupo de mulheres com níveis de HDL-c maiores e níveis de LDL-c menores. As portadoras do genótipo GG do SNP rs2279796 (ABCA7) apresentaram níveis de CT e LDL-c maiores. Além disso, o alelo G foi mais frequente no grupo de mulheres com nível de CT e LDL-c maiores. Na resposta a intervenção dietética, as portadoras do genótipo GG aumentaram os níveis de TG e VLDL. As portadoras do alelo G do SNP rs692383 (ABCG1) apresentaram IMC maior, menor redução da CA em resposta a dieta e, em contrapartida, níveis de TG e VLDL menores e uma redução menor nos níveis de HDL-c. As portadoras do alelo A do SNP rs3827225 (ABCG1) tiveram uma maior redução de CA que as não portadoras, porém apresentaram um aumento maior nos níveis de LDL-c após a intervenção dietética. Esses resultados são indicativos de que possivelmente o alelo T do SNP rs2230806 (ABCA1) está associado com o efeito de proteção contra doenças cardiovasculares, pelos seus efeitos nos níveis de lipídeos séricos. Outrossim, o alelo G do SNP rs2279796 (ABCA7) pode estar conferindo um risco para doenças cardiovasculares, assim como o alelo A do SNP rs9939609 (FTO) sobre uma maior dificuldade em reduzir a CA e pela maior perda de HDL-c. Palavras-chave: Obesidade. Mulheres obesas. Intervenção dietética. Perfil lipídico. Gene FTO. Transportadores ABC. Estudo de associação.
Abstract: Obesity and dyslipidemias, in the majority of cases, have complex origin, as they result from the interaction between genetic and environmental factors. Many genes have been related to the susceptibility for these diseases, including FTO, ABCA1, ABCA7 and ABCG1 gene variants. Thus, the aim of this study was to verify if single nucleotide polymorphisms (SNPs) of these genes influence variables related to obesity and lipid profile in obese women and evaluate the effect of these SNPs in the variation of the variables in response to a calorie restriction diet. Thereunto, blood of 211 obese women was collected for biochemical (triglycerides - TG, total cholesterol - TC, HDL-c, LDL-c and VLDL levels) and genotypic analyses, besides anthropometric measures (body mass index - BMI, waist circumference - WC and abdominal circumference - AC), before and after a dietetic intervention with reduction of 600kcal per day. The samples were genotyped by allelic discrimination assay TaqMan® and analyzed statistically. As result, women carrying rs9939609 SNP (FTO) allele A had a lower AC reduction and a greater reduction of HDL-c levels in response to diet. A allele carriers of rs1800977 SNP (ABCA1) lost less BMI after intervention than non-carriers. TT genotype carriers of rs2230806 SNP (ABCA1) reduced more their TC levels than GG genotype carriers in response to diet. In addition, the T allele was more frequent than C allele in the group of women with higher HDL-c levels and lower LDL-c levels. GG genotype carriers of rs2279796 SNP (ABCA7) had higher TC and LDL-c levels. In addition, the G allele was more frequent in the group of women with higher TC and LDL-c levels. In response to dietary intervention, GG genotype carriers increased TG and VLDL levels. G allele carriers of rs692383 SNP (ABCG1) had higher BMI and lower AC reduction in response to diet but, on the other hand, lower TG and VLDL levels and a lower reduction in HDL-c levels. A allele carriers of SNP rs3827225 SNP (ABCG1) had a greater reduction in AC than non-carriers, but they had a higher increase in LDL-c levels after dietary intervention. These results are indicative that possibly T allele of rs2230806 SNP (ABCA1) is associated with the protective effect against cardiovascular diseases by their effects on serum lipid levels. In addition, the G allele of rs2279796 SNP (ABCA7) possibly is conferring a risk for cardiovascular diseases, as well as the A allele of rs9939609 SNP (FTO) on a greater difficulty in reducing AC and the greater loss of HDL-c. Keywords: Obesity. Obese women. Dietetic intervention. Lipid profile. FTO gene. ABC transporters. Association study.

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Rajpopat, Shefali. "Harlequin ichthyosis and ABCA12." Thesis, Queen Mary, University of London, 2012. http://qmro.qmul.ac.uk/xmlui/handle/123456789/3159.

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Harlequin ichthyosis (HI), a rare severe form of congenital ichthyosis is caused by recessive mutations in the ABCA12 gene. At birth, affected neonates have widespread, grossly thickened skin, separated by deep red fissures, bilateral ectropion, eclabium and a rudimentary nose and ears. Previously, most babies died shortly after birth but with improved neonatal care and the early introduction of oral retinoids, there is now a cohort of HI survivors. ABCA12 mutation analysis was performed and bi-allelic mutations were identified in 14 out of 17 cases, 9 of which were novel. In one consanguineous case, reverse transcriptase PCR on a parental skin biopsy and copy number analysis were used to identify a multiple exon deletion, when standard techniques failed. A previous study showed that in ABCA12 deficiency, epidermal differentiation is dysregulated. Staining of skin biopsies with RXR-α and PPAR-δ showed that both of these nuclear hormone receptors are up-regulated in the spinous and granular cell layers of HI skin compared to normal skin while ABCA1 is down regulated in the basal layer. The largest review to date of the outcomes of babies born with HI was performed. A retrospective clinical questionnaire was completed for 45 patients worldwide. Survivors’ ages ranged from 10 months to 25 years with an overall survival rate of 55.6%. Death usually occurred in the first 3 months and was attributed to sepsis and/or respiratory failure in 75% if cases. The early introduction of oral retinoids may improve survival as 83% of those treated survived, whereas 76% who were not given retinoids died. Recurrent skin infections in infancy affected one third. Problems maintaining weight affected 44%. Three children developed an inflammatory arthritis and developmental delay was reported in 32%. Mutation analysis revealed that 52% of survivors had compound heterozygous mutations whereas all deaths were associated with homozygous mutations.

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Karcher, Annette. "Struktur von ABCE1." Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-72198.

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Nascimento, Gabrielle Araújo do. "Avaliação do efeito de polimorfismos nos genes FTO, ABCA1, ABCA7 e ABCG1 sobre indicadores de obesidade e dislipidemias em crianças e adolescentes submetidos a treinamentos físico." reponame:Repositório Institucional da UFPR, 2017. http://hdl.handle.net/1884/47393.

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Orientadora : Profª Drª Luciane Viater Tureck
Coorientadora : Profª Drª Lupe Furtado Alle
Dissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Genética. Defesa: Curitiba, 27/03/2017
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Resumo: A obesidade e as dislipidemias geralmente estão associadas, e na maior parte dos casos possuem origem complexa, sendo decorrentes da interação entre os fatores ambientais e fatores genéticos. Dentre os fatores genéticos já conhecidos encontram-se genes relacionados ao metabolismo, como o gene FTO (Fat Mass and Obesity Associated) e os genes dos transportadores ABC. Polimorfismos de nucleotídeo único (SNPs) no gene FTO foram associados com o ganho de peso, enquanto os transportadores ABC estão relacionados com o efluxo de colesterol, e, nesse trabalho, foram analisados SNPs dos genes ABCA1, ABCA7 e ABCG1. Visto isso, o objetivo desse estudo é avaliar se há influência de polimorfismos nesses genes sobre variáveis antropométricas (índice de massa corporal ajustado para idade e sexo (IMC escore-Z), circunferência abdominal (CA), circunferência da cintura (CC), gordura corporal (GC) e massa magra (MM)) e bioquímicas (glicose em jejum, glicose 120, insulina em jejum, insulina 120, HOMA-IR (do inglês homeostasis model assessment of insulin resistance), QUICKI (do inglês quantitative insulin sensitivity check index) e perfil lipídico) de 557 crianças e adolescentes (eutróficos, sobrepeso e obesos) estudantes de escolas de Curitiba (PR), além de verificar o efeito de tais polimorfismos nas mudanças desses marcadores em resposta a um programa de exercícios físicos. A genotipagem foi realizada por ensaio de discriminação alélica. As análises estatísticas realizadas foram contagem direta dos genótipos, cálculo de frequência alélica, comparação de médias (teste T e teste Mann Whitney), análise de regressão múltipla e predição de risco. Todos os SNPs analisados promoveram variação significativa em alguma das variáveis analisadas. Com relação ao gene FTO, o alelo A do SNP rs9939609 foi associado a um aumento da insulina e HOMA-IR, e diminuição de QUICKI. Em relação aos genes dos transportadores ABC, o alelo C do SNP rs1800977 (ABCA1) foi associado a aumento no IMC escore-Z, CA, GC, insulina 120 e redução em QUICKI; o alelo A do SNP rs2230806 (ABCA1) foi associado a aumento no IMC escore-Z, CA e redução em %MM; o alelo C do SNP rs2279796 (ABCA7) foi associado à maior IMC escore-Z; o SNP rs692383 (ABCG1) foi associado à maior IMC escore-Z, CA, HDL-C, glicose, insulina e HOMA-IR e o alelo G do SNP rs3827225 (ABCG1) foi associado à maior VLDL-C e glicose. Com relação ao efeito na resposta aos exercícios físicos, os genes FTO, ABCA7 e ABCG1 não apresentaram interação, enquanto o alelo C do SNP rs1800977 (ABCA1) foi associado à maior redução de IMC escore-Z e maior aumento de QUICKI em resposta ao exercício e o alelo A do SNP rs2230806 (ABCA1) foi associado à maior ganho de MM. Nesse trabalho nós verificamos os efeitos dos polimorfismos analisados em variáveis relacionadas ao metabolismo (adiposidade, metabolismo da glicose e de lipídeos), sendo que alguns desses polimorfismos também interagiram com os programas de exercícios físicos aplicados. Os resultados obtidos corroboram e abrem novas perspectivas de estudo quanto ao papel da interação entre fatores ambientais e genéticos na prevenção e tratamento de patologias complexas, como a obesidade e as dislipidemias, no sentido de tornar tais medidas cada vez mais individualizadas. Palavras chave: Obesidade, dislipidemias, exercício físico, FTO, ABCA1, ABCA7, ABCG1, rs9939609, rs1800977, rs2230806, rs2279796, rs692383, rs3827225.
Abstract: Obesity and dyslipidemias are usually associated, and in most cases have complex origin, resulting from interaction between environmental and genetic factors. Among these already know genetic factors there are genes related to metabolism, such as FTO (Fat Mass and Obesity Associated) and the ABC transporters genes. Single nucleotide polymorphisms (SNPs) in FTO gene are associated to weight gain, while ABC transporters are related to cholesterol efflux, and SNPs in ABCA1, ABCA7 and ABCG1 genes were analyzed in this work. The objective of this study is to evaluate the influence of polymorphisms in these genes on anthropometric (body mass index adjusted for age and sex (BMI Z-score), abdominal circumference (AC), waist circumference (WC), fat mass (FM) and lean body mass (LBM)) and biochemical variables (fasting glucose, glucose 120, fasting insulin, insulin 120, HOMA-IR (homeostasis model assessment of insulin resistance), QUICKI (quantitative insulin sensitivity check index) and lipid profile) of 557 children and adolescents (normal weight, overweight and obese) in Curitiba (PR), and verify these polymorphisms effects in the changes of these markers in response to a physical exercise program. Genotyping was carried out by allelic discrimination assay. The statistical analyzes made were direct counting of genotypes, allelic frequency calculation, comparison of means (T test and Mann-Whitney test), multiple regression analysis and risk prediction. All the analyzed SNPs promoted significant variation in some of the variables. Regarding FTO gene, the rs9939609 SNP A-allele was associated to higher insulin and HOMA-IR, and reduced QUICKI. In relation to the ABC transporter genes, SNP rs1800977 C-allele (ABCA1) was associated to higher BMI-Z score, AC, FM and insulin 120 increase and QUICKI reduction; SNP rs2230806 (ABCA1) A-allele was associated to higher BMI-Z score and AC and %LBM reduction; SNP rs2279796 (ABCA7) C-allele was associated to higher BMI Z-score; SNP rs692383 (ABCG1) was associated to higher BMI Z-score, AC, HDL-C, glucose, insulin and HOMA-IR, and SNP rs3827225 (ABCG1) G-allele was associated to higher VLDL-C and glucose. Regarding the effect on physical exercise response, FTO, ABCA7 and ABCG1 genes did not shown interaction, whereas rs1800977 (ABCAI) C-allele was associated to higher reduction of BMI Z-score and increase in QUICKI in response to physical exercise and rs2230806 SNP (ABCA1) A-allele was associated to higher gain of LBM. In this study, we verified the effects of the polymorphisms analyzed on variables related to metabolism (adiposity, glucose metabolism and lipid metabolism), and some of these polymorphisms also interacted with the applied physical exercise programs. The results obtained corroborate and open new perspectives on the role of the interaction between environmental and genetic factors in the prevention and treatment of complex pathologies, such as obesity and dyslipidemias, in order to make these measures more individualized. Key-words: Obesity, dyslipidemia, physical exercise, FTO, ABCA1, ABCA7, ABCG1, rs9939609, rs1800977, rs2230806, rs2279796, rs692383, rs3827225.

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Sims, Lynn. "Biochemical Studies of ABCE1." Doctoral diss., University of Central Florida, 2012. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/5501.

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The growth and survival of all cells require functional ribosomes that are capable of protein synthesis. The disruption of the steps required for the function of ribosomes represents a potential future target for pharmacological anti-cancer therapy. ABCE1 is an essential Fe-S protein involved in ribosomal function and is vital for protein synthesis and cell survival. Thus, ABCE1 is potentially a great therapeutic target for cancer treatment. Previously, cell biological, genetic, and structural studies uncovered the general importance of ABCE1, although the exact function of the Fe-S clusters was previously unclear, only a simple structural role was suggested. Additionally, due to the essential nature of ABCE1, its function in ribosome biogenesis, ribosome recycling, and the presence of Fe-S within ABCE1, the protein has been hypothesized to be a target for oxidative degradation by ROS and critically impact cellular function. In an effort to better understand the function of ABCE1 and its associated Fe-S cofactors, the goal of this research was to achieve a better biochemical understanding of the Fe-S clusters of ABCE1. The kinetics of the ATPase activity for the Pyrococcus abyssi ABCE1 (PabABCE1) was studied using both apo- (without reconstituted Fe-S clusters) and holo- (with full complement of Fe-S clusters reconstituted post-purification) forms, and is shown to be jointly regulated by the status of Fe-S clusters and Mg2+. Typically, ATPases require Mg2+, as is true for PabABCE1, but Mg2+ also acts as a unusual negative allosteric effector that modulates ATP affinity of PabABCE1. Comparative kinetic analysis of Mg2+ inhibition shows differences in the degree of allosteric regulation between the apo- and holo-PabABCE1 where the apparent Km for ATP of apo-PabABCE1 increases >30 fold from ~30 [micro]M to over 1 mM when in the presence of physiologically relevant concentrations of Mg2+. This effect would significantly convert the ATPase activity of PabABCE1 from being independent of cellular energy charge to being dependent on energy charge with cellular [Mg2+]. The effect of ROS on the Fe-S clusters within ABCE1 from Saccharomyces cerevisiae was studied by in vivo 55Fe labeling. A dose and time dependent depletion of ABCE1 bound 55Fe after exposure to H2O2 was discovered, suggesting the progressive degradation of Fe-S clusters under oxidative stress conditions. Furthermore, our experiments show growth recovery, upon removal of the H2O2, reaching a growth rate close to that of untreated cells after ~8 hrs. Additionally, a corresponding increase (~88% recovery) in the ABCE1 bound 55Fe (Fe-S) was demonstrated. Observations presented in this work demonstrate that the majority of growth inhibition, induced by oxidative stress, can be explained by a comparable decrease in ABCE1 bound 55Fe and likely loss of ABCE1 activity that is necessary for normal ribosomal activity. The regulatory roles of the Fe-S clusters with ABCE1 provide the cell a way to modulate the activity of ABCE1 and effectively regulate translation based on both cellular energy charge and the redox state of the cell. Intricate overlapping effects by both [Mg2+] and the status of Fe-S clusters regulate ABCE1's ATPase activity and suggest a regulatory mechanism, where under oxidative stress conditions, the translational activity of ABCE1 can be inhibited by oxidative degradation of the Fe-S clusters. These findings uncover the regulatory function of the Fe-S clusters with ABCE1, providing important clues needed for the development of pharmacological agents toward ABCE1 targeted anti-cancer therapy.
Ph.D.
Doctorate
Biology
Sciences
Biomedical Sciences

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Delhorme, Jean-Baptiste. "Etude des mécanismes de chimiorésistance dans les cancers digestifs : impact de CDX2 et des transporteurs ABC." Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAJ119.

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La chimiorésistance est un enjeu majeur dans la prise en charge des patients atteints de cancers digestifs et peut se manifester par l’efflux de molécules cytotoxiques via la surexpression des transporteurs ABC. Le facteur de transcription CDX2 est un régulateur important de l’identité intestinale et agit comme gène suppresseur de tumeur dans le côlon. Il pourrait être impliqué dans des phénomènes de chimiorésistance des cancers colorectaux (CCR) car le transporteur MDR1/ABCB1 correspond à un de ses gènes cibles. Nous avons confirmé le rôle de CDX2 dans la chimiorésistance des CCR. Nous avons montré par une approche translationnelle, que la surexpression de CDX2 était impliquée dans la résistance au 5-fluorouracile (5-FU) dans les CCR. Le transporteur du 5-FU ABCC11 a été identifié comme gène cible de CDX2 dont l’activité contribue à la résistance au 5-FU des cellules cancéreuses coliques. L’expression d’ABCC11 corrèle avec celle de CDX2 dans les CCR humains mais également avec celle de la DYPD, enzyme impliquée dans le catabolisme du 5-FU. Cette étude montre pour la première fois que CDX2 contribue à la chimiorésistance au 5-FU en impliquant des mécanismes régulant son métabolisme
Chemoresistance represents a major drawback in digestive cancers’ management and may be achieved particularly through active efflux of the drug through overexpression of ABC transporters The transcription factor CDX2 is a master regulator of intestinal identity that acts as a tumor suppressor in the colon and may be important for drug resistance in colorectal cancer (CRC) as MDR1/ABCB1 was recently identified as one of its target genes. Here, we confirmed the role of CDX2 in the chemoresistance of CRC. We showed through a translational approach that CDX2 overexpression is implicated in 5-fluorouracil (5-FU) chemoresistance in CRC and described the molecular mechanisms implicated in this finding. We identified the 5-FU transporter ABCC11 as a new transcriptional target of CDX2 whose activity contributes to the 5-FU-chemoresistance of colon cancer cells. Remarkably, CDX2 expression correlates with the expression of ABCC11 in human colon tumors, but also with the one of the DPYD, enzyme involved in the 5-FU break down. Thus, our study links for the first time CDX2 to the 5-FU metabolism and provides a molecular mechanism for its impact on 5-FU-based chemotherapy

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Do, Tuan Minh. "Intégrité de la barrière hémato-encéphalique et transport du peptide bêta-amyloïde dans la maladie d'Alzheimer." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA114839.

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Récemment, des études menées chez des patients atteints de la maladie d’Alzheimer (MA) suggèrent un rôle important de la clairance cérébrale des peptides bêta-amyloïde (Abeta) dans la physiopathologie de la MA. Les échanges de peptide Abeta entre le cerveau et le sang peuvent se faire à travers la barrière hémato-encéphalique (BHE). De nombreux transporteurs sont exprimés au niveau de la BHE, telles les protéines ABC (ATP-Binding Casette) et SLC (Solute Carriers). Il a été montré que l’influx du peptide Abeta à travers la BHE était partiellement médié par le récepteur RAGE (Receptor for Advanced Glycation End products) et son efflux par le récepteur LRP-1 (Low density lipoprotein receptor-related protein 1). De plus, l’implication de transporteurs ABC/SLC dans le passage cérébral du peptide Abeta a été suggérée. Il paraît donc important de caractériser les transporteurs ABC et/ou SLC impliqués dans le transport du peptide Abeta à travers la BHE. D’autre part, l’on peut se demander si, dans le cadre de la MA, la BHE subit des modifications, en termes d’étanchéité, d’expression de transporteurs, de mécanismes de transport, et si, dans ce cas, il y a une modification du transport du peptide Abeta à travers la BHE altérée. Nous avons d’abord montré que des transporteurs ABC et SLC étaient respectivement impliqués dans l’efflux et l’influx des peptides Abeta à travers la BHE. Concernant l’efflux, outre l’Abcb1, nous avons montré qu’Abcg2 et Abcg4 étaient impliquées dans la clairance cérébrale des peptides Abeta. Concernant l’influx, nous avons montré qu’Oatp1a4 pourrait jouer un rôle important dans la pénétration cérébrale des peptides Abeta. De plus, Abca1, principal transporteur ABC impliqué dans le transport du cholestérol, régule indirectement les taux cérébraux d’Abeta. En particulier, nous avons identifié la L-thyroxine et la rosuvastatine comme de puissants inhibiteurs respectifs de l’efflux et de l’influx cérébral d’Abeta. L’ensemble de ces transporteurs d’influx et d’efflux fixe ainsi la clairance cérébrale des peptides Abeta à travers la BHE. Or ces transporteurs sont régulés chez les souris 3xTg-AD (modèle de souris triple transgénique pour la MA exprimant à la fois les pathologies amyloïde et tau), dans des phases précoces et/ou tardives de la MA. Précocement, l’expression de Rage et d’Abca1 sont fortement augmentées au niveau de la BHE chez les souris 3xTg-AD. L’augmentation de Rage dès l’âge de 3 mois laisse supposer une augmentation très précoce de l’influx du peptide Abeta à travers la BHE. Mais cet influx semble être contre-balancé par l’augmentation concomitante d’Abcg4. Quant à Abca1, ne transportant pas directement le peptide Abeta, le rôle de son augmentation graduelle au cours du développement de la MA reste à déterminer. L’ensemble de ces régulations n’étant pas suffisantes pour empêcher l’accumulation cérébrale d’Abeta, des régulations plus tardives semblent se mettre en place, avec notamment l’augmentation de l’expression d’Abcb1 et d’Abcg2, et la diminution d’Oatp1a4. Ces mécanismes semblent donc correspondre à des phénomènes compensatoires ayant pour objectif d’augmenter la clairance cérébrale d’Abeta. Enfin, nous avons montré que l’intégrité physique de la BHE n’était pas altérée chez ces souris 3xTg-AD âgées de 3 à 18 mois. De plus, nos résultats ont montré que le volume vasculaire était diminué de manière précoce, notamment au niveau de l’hippocampe, chez les souris 3xTg-AD par rapport à leurs contrôles. Ce phénomène n’a pas été retrouvé chez les souris APP/PS1 n’exprimant que la pathologie amyloïde. Ces résultats suggèrent un rôle causal et précoce de la protéine tau hyperphosphorylée dans la pathologie de la MA. En conclusion, nos résultats soulignent l’importance de la BHE dans la physiopathologie de la MA. Ce travail de thèse ouvre des perspectives thérapeutiques, mais aussi des pistes pour la compréhension des mécanismes conduisant à une régulation de ces systèmes de transport dans la MA
Recent studies in Alzheimer's disease (AD) patients have suggested an important role of cerebral clearance of Abeta peptide in the pathogenesis of AD. The blood-brain barrier (BBB) represents a major pathway for exchanges of Abeta between the brain and the peripheral circulation. Many transporters are expressed at the BBB, such as the ABC (ATP-Binding Casette) and SLC (Solute Carriers) proteins. It has been shown that the influx of Abeta peptide across the BBB was partially mediated by the receptor RAGE (Receptor for Advanced Glycation End products) and its efflux by the LRP-1 receptor (low density lipoprotein receptor-related protein 1). On the other hand, the involvement of ABC/SLC transporters in the brain efflux/influx of Abeta peptide has been suggested. It was therefore important to characterize the ABC/SLC transporters involved in the transport of Abeta peptide across the BBB. In addition, the disorders of the BBB have always been suggested in neurodegenerative diseases. The question is whether, in the context of AD, the BBB undergoes changes in terms of integrity, expression of transporters, transport mechanisms, and if, in this case, there is a change in the transport of Abeta peptide across the impaired BBB. We first showed that the BBB regulated the exchange of blood-brain Abeta peptides. Thus, the involvement of efflux (ABCG2 and ABCG4) and influx (Oatp1a4) transporters allows this equilibrium of Abeta peptides between the blood and the brain parenchyma. In addition, ABCA1, the main ABC transporter involved in cholesterol transport, regulates indirectly the brain levels of Abeta. We also identified the L-thyroxine and rosuvastatin as potent inhibitors of the efflux and influx transport of brain Abeta, respectively. All these influx and efflux transporters could control the transport of Abeta peptide across the BBB. However, these transporters are regulated in 3xTg-AD mice (triple transgenic mouse model for AD expressing both amyloid and tau pathologies) in the early and/or late stages of AD. Early, the expression of Abca1 and Rage are strongly increased at the BBB in 3xTg-AD mice. The high expression levels of Rage at the age of 3 months suggest an early increase in the influx transport of Abeta peptide across the BBB. But this increase seems to be compensated by the concomitant increase of Abcg4. As Abca1 does not directly mediate the transport of Abeta peptide, the role of its gradual increase in the development of AD remains to be determined. As all these regulations are not sufficient to prevent the accumulation of cerebral Abeta, the late regulations seem to develop, including increased expression of Abcb1 and Abcg2, and decreased expression of Oatp1a4. These mechanisms seem to correspond to compensatory phenomena with the objective to increase the cerebral clearance of Abeta. Finally, we have shown that the physical integrity of the BBB was not altered in 3xTg-AD mice aging from 3 to18 months. In addition, our results showed that the cerebral vascular volume was reduced early, especially in the hippocampus of 3xTg-AD mice compared to their age-matched controls. This phenomenon was not found in APP/PS1 mice expressing only the amyloid pathology. These results suggest a causal and early role of hyperphosphorylated tau in AD pathology.In conclusion, our results show the importance of the BBB and particularly of Abcg2, Abcg4 and Oatp1a4 transporters in the pathophysiology of AD. Knowledge of these transporters not only opens up therapeutic or prophylactic purposes, but also leads to the further understanding of the regulation mechanisms of these transport systems in AD

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Calderón, Toledo Susana Vanessa. "Asociación de polimorfismos de los genes ABCB1 y ABCC2 con la epilepsia refractaria en pacientes del Hospital Nacional Edgardo Rebagliati Martins de mayo de 2016 a junio de 2017." Bachelor's thesis, Universidad Nacional Mayor de San Marcos, 2018. https://hdl.handle.net/20.500.12672/10007.

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Determina si existe asociación entre los polimorfismos C3435T del gen ABCB1 y -24C>T del gen ABCC2 con la epilepsia refractaria o farmacorresistente en pacientes del Hospital Nacional Edgardo Rebagliati Martins (HNERM) durante el periodo de mayo 2016 a junio 2017, en este estudio participaron 22 pacientes con epilepsia refractaria y ocho pacientes con epilepsia farmacorrespondedora. Para ello, se tomaron muestras de sangre venosa para extraer el ADN genómico y se amplificaron las regiones que contenían los polimorfismos C3435T del gen ABCB1 y -24C>T del gen ABCC2 mediante la reacción en cadena de la polimerasa. Los polimorfismos de los genes ABCB1 y ABCC2 fueron detectados en el amplificado mediante restricción enzimática con Mbo I y secuenciación, respectivamente. La información clínica se obtuvo de las historias clínicas y se contrastó con una encuesta que se le realizada a cada paciente. El polimorfismo C3435T del gen ABCB1 en pacientes epilépticos refractarios se observó en 11 individuos, dos homocigotos (CC) y nueve heterocigotos (CT), con frecuencias alélicas de C=0.705 y T=0.295. El polimorfismo -24C>T del gen ABCC2 en pacientes refractarios se determinó en un paciente heterocigoto (CT), con frecuencias alélicas de C=977 y T=0.023. En cuanto a la información clínica, se observaron epilepsias de tipo focal y generalizada con etiología estructural, genética, infecciosa y desconocida, de inicio de crisis ya sea focal o generalizada en el grupo de pacientes refractarios estudiados. La epilepsia focalizada de etiología estructural fue la que presentó mayor prevalencia entre los pacientes epilépticos refractarios estudiados. Por otro lado, no se observó asociación significativa entre el alelo T de los polimorfismos C3435T del gen ABCB1 y - 24C>T del gen ABCC2 con la epilepsia refractaria (p>0.05).
Tesis

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Pedersen, Jenny M. "ATP-Binding-Cassette Transporters in Biliary Efflux and Drug-Induced Liver Injury." Doctoral thesis, Uppsala universitet, Institutionen för farmaci, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-205355.

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Membrane transport proteins are known to influence the absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs. At the onset of this thesis work, only a few structure-activity models, in general describing P-glycoprotein (Pgp/ABCB1) interactions, were developed using small datasets with little structural diversity. In this thesis, drug-transport protein interactions were explored using large, diverse datasets representing the chemical space of orally administered registered drugs. Focus was set on the ATP-binding cassette (ABC) transport proteins expressed in the canalicular membrane of human hepatocytes. The inhibition of the ABC transport proteins multidrug-resistance associated protein 2 (MRP2/ABCC2) and bile salt export pump (BSEP/ABCB11) was experimentally investigated using membrane vesicles from cells overexpressing the investigated proteins and sandwich cultured human hepatocytes (SCHH). Several previously unknown inhibitors were identified for both of the proteins and predictive in silico models were developed. Furthermore, a clear association between BSEP inhibition and clinically reported drug induced liver injuries (DILI) was identified. For the first time, an in silico model that described combined inhibition of Pgp, MRP2 and breast cancer resistance protein (BCRP/ABCG2) was developed using a large, structurally diverse dataset. Lipophilic weak bases were more often found to be general ABC inhibitors in comparison to other drugs. In early drug discovery, in silico models can be used as predictive filters in the drug candidate selection process and membrane vesicles as a first experimental screening tool to investigate protein interactions. In summary, the present work has led to an increased understanding of molecular properties important in ABC inhibition as well as the potential influence of ABC proteins in adverse drug reactions. A number of previously unknown ABC inhibitors were identified and predictive computational models were developed.

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Kang, Martin Hubert. "Post-transcriptional regulation of ABCA1." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/43655.

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Epidemiological studies consistently demonstrate an inverse relationship between HDL levels and cardiovascular disease (CVD), independent of LDL and triglyceride levels. Due to the crucial role ABCA1 plays in HDL biogenesis, increasing ABCA1 expression is considered an attractive strategy to increase plasma HDL levels. In this thesis we attempt to identify novel post-transcriptional and post-translational mechanisms that regulate ABCA1 expression and/or function. Prior to translation, ABCA1 protein expression is regulated by non-coding RNA molecules known as microRNAs which bind and inhibit translation of mature mRNA transcripts in the cytoplasm. In this study we used bioinformatic prediction programs to identify potential microRNA regulators of ABCA1. Using reporter constructs, protein expression analysis by immunoblotting, and cholesterol efflux assays, we validated microRNA-145 as a novel repressor of ABCA1 translation. The inhibition of endogenous microRNA-145 in HepG2 cells increases both ABCA1 protein levels and cholesterol efflux activity. The inhibition of this microRNA in the liver is a potential strategy to increase HDL levels. Following translation, numerous post-translational modifications and protein-protein interactions are required for the ABCA1 protein to function properly. In this study we identified palmitoylation as a novel post-translational modifier of ABCA1. The majority of ABCA1-mediated cholesterol efflux and HDL biogenesis occurs at the cell surface. We show that palmitoylation is a crucial lipid addition for proper ABCA1 plasma membrane localization. We also identify a number of enzymes that mediate the incorporation of radio-labeled palmitate onto ABCA1, and demonstrate that the overexpression of the palmitoyl transferase enzyme DHHC8 increases ABCA1 palmitoylation and cholesterol efflux activity. The increase of ABCA1 palmitoylation in the liver is a novel strategy to increase HDL levels. In this thesis, we have contributed to the understanding of ABCA1 biology by the identification of two novel regulators of ABCA1 expression and/or function.

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30

Wolbergs, Daniel [Verfasser]. "Quantifizierung der ABCB1-mRNA in Lymphozytensubpopulationen : die Rolle genetischer Polymorphismen im ABCB1-Gen / Daniel Wolbergs." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2015. http://d-nb.info/1066645078/34.

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Chambenoit, Olivier. "ABCA1 et l'homéostasie du cholestérol cellulaire." Aix-Marseille 2, 2003. http://www.theses.fr/2003AIX22023.

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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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Lächelt, Sandra [Verfasser]. "Funktionelle Analyse von ABCC2-Haplotypen / Sandra Lächelt." Kiel : Universitätsbibliothek Kiel, 2009. http://d-nb.info/1019869933/34.

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34

Funazo, Tomoko. "Acquired Resistance to Alectinib in ALK-Rearranged Lung Cancer Due to ABCC11/MRP8 Overexpression in a Clinically Paired Resistance Model." Kyoto University, 2020. http://hdl.handle.net/2433/258997.

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Knight, Helen Miranda. "Candidate gene studies in psychiatric illness." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/6508.

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Schizophrenia, bipolar disorder and major depression are common, heritable neuropsychiatric conditions and yet the source of the inherited risk remains largely unknown. This thesis focuses on two complementary strategies for identifying and characterising the genetic component of these illnesses: homozygosity mapping in consanguineous pedigrees, and genetic and neurobiological investigations of candidate genes identified by the analysis of structural chromosomal abnormalities carried by patients with psychiatric diagnoses. In a family of a cousin marriage, five of six offspring presented with a rare combination of schizophrenia, sensori-neural hearing impairment and epilepsy. Two loci were located on chromosomes 22q13 and 2p24-25 where a series of markers were homozygous by descent (HBD). Five further HBD loci were identified in a second, related family where four of five offspring had hearing loss. However, there was no overlap of the HBD intervals in the two families, and sequencing coding regions of candidate genes failed to identify causative mutations. A second study investigated the candidate gene ABCA13 identified at a breakpoint region on chromosome 7 in a patient with schizophrenia who carried a complex chromosomal rearrangement. Re-sequencing exons encoding the highly conserved functional domains identified eight potentially pathogenic, rare coding variants. Case control association studies involving cohorts of schizophrenia, bipolar disorder and major depression revealed significant associations of these variants with all three clinical phenotypes, and follow-up in relatives displayed familial inheritance patterns. Disruption of ABCA13, expressed in human hippocampus and frontal cortex, implicates aberrant lipid biology as a pathological pathway in mental illness. A third study focused on GRIK4, a candidate gene previously reported disrupted in a patient with schizophrenia who carried a chromosome abnormality. A deletion in the 3’UTR of GRIK4, encoding the kainate receptor subunit KA1, was identified as a protective factor for bipolar disorder. Using post mortem human brain tissue from control subjects, KA1 protein expression patterns were characterized in the hippocampal formation, amygdala, frontal cortex and cerebellum. KA1 expression was found significantly increased in subjects with the protective allele, supporting the hypothesis that reduced glutamatergic neurotransmission is a risk factor in major psychiatric illnesses. Together, these novel discoveries define aspects of the genetic contribution to mental illness, implicate specific dysfunctional processes and suggest new directions for research in the quest to find rationally based treatments and preventative strategies for some of the most common and disabling psychiatric disorders.

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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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Nagao, Kojiro. "Mechanism of high-density lipoprotein formation by ABCA1." Kyoto University, 2010. http://hdl.handle.net/2433/120486.

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Kyoto University (京都大学)
0048
新制・課程博士
博士(農学)
甲第15443号
農博第1828号
新制||農||981(附属図書館)
学位論文||H22||N4542(農学部図書室)
27921
京都大学大学院農学研究科応用生命科学専攻
(主査)教授植田和光, 教授間藤徹, 教授阪井康能
学位規則第4条第1項該当

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Othman, Ramadhan T. "ABCB1 and MGMT mediated drug resistance in medulloblastoma." Thesis, University of Nottingham, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.718995.

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Background: Medulloblastoma (MB) is the most common malignant paediatric brain tumour. Recurrence and progression of disease occurs in a substantial number of patients with current multimodal treatment. Drug resistance is a major obstacle to successful chemotherapy treatment of MB. Chemotherapeutic drugs must remain in the tumour cell long enough to damage DNA and this damage must not be accurately repaired. The expression of multidrug efflux transporter ABCB1 and DNA repair protein 06-methylguanine-DNA-methyltransferase (MGMT) might be involved in chemotherapeutic drug resistance. In this study, I investigated the correlation of ABCB1 expression with clinicopathological features in MB patients. Additionally, I evaluated expression and function of ABCB1 and MGMT as putative drug resistance mechanisms in a panel of MB cell lines. Material and Methods: Immunohistochemistry analysis of patient tissue microarrays was used to assess ABCB1 expression in paediatric MB. Expression of ABCB1 and MGMT was assessed by quantitative reverse transcription polymerase chain reaction, western blotting and flow cytometry in MB cell lines. Clonogenic- assays were used to assess cell survival in response to chemotherapeutics. Wound healing-assay was used to assess MB cell migration in vitro. Results: ABCB1 expression was expressed in 43 % (112/260) of tumours, showed significant association with high-risk (P= 0.035) patients and metastatic disease (P= 0.04). In cell line analysis, inhibition of ABCB1 using vardenafil or verapamil resulted in a significant increase in sensitivity to etoposide (ABCB1 substrate) in ABCB1-expressing MB cell lines (P< 0.0001). In the presence of verapamil or vardenafil. the capacity of MED1 cells (high ABCB1-expressing cell line) to migrate in vitro was significantly inhibited (P< 0.01). Sensitivity to temozolomide (TMZ) was MGMT-dependent, but two novel imidazotetrazine derivatives (N-3 sulfoxide and N-3 propargyl) demonstrated a significantly higher cytotoxicity compared to TMZ that was independent of MGMT and base excision repair. Conclusion: Data from this study indicate that ABCB1 is clinically associated with high-risk MB and MB cell invasion/metastasis. Thus, inhibition of ABCB1 by vardenafil may represent a valid approach in high-risk MB patients. In addition imidazotetrazine analogues of TMZ are promising clinical approaches to overcome resistance to alkylating drugs in MB tumours expressing MGMT.

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Jeannesson, Elise. "Analyse génétique et transcriptomique du transporteur ABCB1 en physiopathologie cardiovasculaire." Thesis, Nancy 1, 2008. http://www.theses.fr/2008NAN10130/document.

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ABCB1 est une protéine impliquée dans le transport des médicaments mais aussi probablement du cholestérol. Des phénomènes de résistance médicamenteuse sont associés à ses polymorphismes et à des modulations de son expression via le facteur PXR. Notre objectif était de réaliser une analyse génomique et transcriptomique d’ABCB1 basée sur ces hypothèses : 1) les variants d’ABCB1 expliquent-ils une part de la variabilité des taux de lipides et de lipoprotéines plasmatiques ? 2) le profil d’expression d’ABCB1 dans les cellules mononuclées du sang périphérique (PBMCs) constitue-t-il un biomarqueur cardiovasculaire nouveau ? Nous avons déterminé la prévalence de polymorphismes d’ABCB1 chez 371 sujets de la cohorte STANISLAS. Nous montrons que ces variants modulent les concentrations en lipides des sujets sains. Des associations significatives avec les lipides sont aussi notées chez des sujets à haut risque cardiovasculaire. Nous observons qu’une majorité d’enzymes du métabolisme des xénobiotes et de facteurs de transcription sont exprimés dans les PBMCs de sujets sains. Nous montrons par RTPCR qu’ABCB1 et PXR sont exprimés dans les PBMCs de 83 sujets de la cohorte. Enfin, il n’y a pas d’association entre l’expression d’ABCB1 dans les PBMCs et le taux de lipides plasmatiques chez le sujet sain. En conclusion, les polymorphismes d’ABCB1 peuvent moduler le taux de lipides et d’apolipoprotéines. Nous ne pouvons toutefois pas proposer l’expression d’ABCB1 dans les PBMCs comme biomarqueur du risque cardiovasculaire. Il serait intéressant de reproduire cette étude chez des sujets à risque cardiovasculaire élevé ou d’utiliser un modèle in vitro permettant d’induire l’expression d’ABCB1
ABCB1 is an ubiquitously expressed membrane transporter. Resistance to drugs is associated with genetic variations of its gene and with modulation of its expression through the PXR transcription factor. Given that ABCB1 could also transport cholesterol, our goal was to conduct a genomic and transcriptomic analysis of ABCB1 based on the following hypotheses: 1) ABCB1 variants would partly explain plasma lipid and apolipoprotein concentrations, and 2) ABCB1 expression profile in PBMCs would be a new, and easily available, cardiovascular biomarker. We have determined frequency of ABCB1 variants in 371 subjects from the STANISLAS cohort. We have shown in these healthy people that ABCB1 variants modulate lipid concentrations, sometimes in a sex-dependant manner. Significant associations were also observed in subjects with a high cardiovascular risk. In addition, DNA microarray analysis showed that most of the xenobiotic metabolizing enzymes and transcription factors are constitutively expressed in PBMCs of healthy subjects. ABCB1 and PXR were measured by quantitative RT-PCR in 83 subjects from the STANISLAS cohort. They are both expressed in PBMCs but their expressions do not correlate. Finally, there is no association between ABCB1, or PXR, expression in PBMCs and lipid plasma concentrations in healthy subjects. To conclude, ABCB1 variants would modulate lipid and apolipoprotein concentrations. However, from our results, we cannot propose ABCB1 expression in PBMCs as a biomarker of cardiovascular risk. It would be of interest to reproduce this study in PBMCs of people at high cardiovascular risk or in an in vitro model of PBMCs with induction studies of ABCB1 expression

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RUBBI, LIUDMILLA. "Etude fonctionnelle de la proteine abc10, sous-unite commune aux trois arn polymerases de la levure saccharomyces cerevisiae." Paris 11, 1999. http://www.theses.fr/1999PA112189.

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Chez saccharomyces cerevisiae, les trois arn polymerases, (i, ii et iii), sont constituees chacune de deux grandes sous-unites, homologues aux sous-unites ' et de l'enzyme bacterienne, associees a de plus petits polypeptides. Parmi ceux-ci, cinq abc27, abc23, abc14. 5, abc10 et abc10, sont communs aux trois formes d'enzyme et sont strictement indispensables a la viabilite cellulaire. Ce travail porte sur l'etude fonctionnelle de l'une de ces sous-unites communes, la proteine abc10. Tous les homologues eucaryotiques d'abc10 ainsi qu'un homologue archebacterien putatif, possedent deux regions conservees : un motif de liaison au zinc et une region c-terminale riche en acides amines basiques. Par une analyse mutationnelle, nous avons isole plusieurs mutants conditionnels qui nous ont permis de montrer l'importance de ces deux regions. Parmi ces mutants, deux ont ete retenus afin d'etudier in vivo leur activite transcriptionnelle. L'un d'entre eux, possedant des substitutions dans la region c-terminale, presente un defaut plus specifique dans la synthese des transcrits de l'arn polymerase iii. L'analyse biochimique de ce mutant a montre que cette forme mutagenisee d'abc10 entraine un defaut dans l'assemblage de l'enzyme sans affecter sa stabilite ou son activite catalytique. L'etude genetique des mutants conditionnels par suppression extragenique et par la methode du double-hybride a revele que la deuxieme plus grande sous-unite de chaque arn polymerase est le principal partenaire proteique d'abc10 au sein des trois enzymes. L'interaction d'abc10 avec ces sous-unites pourrait representer l'etape limitante dans le processus d'assemblage des arn polymerases puisque nous avons observe que abc10 est la seule sous-unite pour laquelle le dosage du gene limite le taux de croissance cellulaire.

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Tandia, Mahamadou. "INTERACTIONS ENTRE THERAPIES CIBLEES ANTI-ANGIOGÉNIQUES (BEVACIZUMAB, SORAFÉNIB) ET TRANSPORTEURS D’EFFLUX." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS424/document.

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Le traitement des cancers constitue un problème de santé publique et repose entre autres sur la chirurgie, la radiothérapie, la chimiothérapie, l’hormonothérapie et les thérapies ciblées. Les progrès médicaux récents ont permis l’amélioration de la survie sans progression des patients atteints de cancer, ainsi que de la survie globale. Parmi les nouvelles stratégies thérapeutiques, le blocage de l’angiogenèse fait l’objet de nombreux essais cliniques.Cependant, l’intervention de transporteurs membranaires (influx et / ou efflux), joue un rôle important sur le plan pharmacocinétique, pharmacogénétique et dans la résistance aux médicaments anticancéreux.Nous avons observé chez des patients atteints de CHC une grande variabilité des paramètres pharmacocinétiques du sorafénib (inhibiteur de tyrosine kinase, anti-angiogénique et substrat de la P-gp et de la BCRP) et une tendance à une meilleure réponse clinique dans le groupe hétérozygote, ABCB1 3435 CT, ABCG2 34 GA, ABCG2 1143CT et ABCG2 421CA par rapport aux groupes homozygotes (type sauvage et mutant) avec une association significative aux concentrations plasmatiques normalisées aux poids.Nos travaux ont montré in vitro qu’un prétraitement avec des médicaments anti-angiogéniques tels que le bévacizumab et le sorafénib entrainait une réversion de la résistance à la doxorubicine (substrat de la P-gp) dans un modèle de cellules IGR OV1-DXR (résistantes à la doxorubicine et surexprimant la P-gp) par modulation de la fonctionnalité de la P-glycoprotéine. Cette réversion a été objectivée par l’augmentation significative des concentrations intracellulaires de la doxorubicine dans les cellules IGR OV1-DXR.In vivo chez la souris xénogreffée de cancer colorectal humain, un prétraitement par le bévacizumab a entrainé une augmentation significative des concentrations plasmatiques du SN38 (métabolite actif de l’irinotécan et substrat de la P-gp), de même que de l'AUC et de la Cmax plasmatique de l'irinotécan (susbtrat de la P-gp) après administration orale de l’irinotecan. Une augmentation significative de l'AUC plasmatique du sorafénib après un prétraitement par le bévacizumab a été également observée sur le même modèle expérimental.La connaissance et l’utilisation de la modulation d’activité des transporteurs d’efflux par les thérapies ciblées anti-angiogéniques seraient intéressantes à transposer en thérapeutique cancéreuse pour l’augmentation de la réponse clinique et pour la réversion de la résistance des cellules tumorales et endothéliales surexprimant les transporteurs d’efflux en particulier la P-gp
Treatment of cancers is a public health problem and based on surgery, radiotherapy, chemotherapy, hormone therapy and targeted therapies. Recent medical advances allowed progression-free survival of cancer patients, and even their overall survival. Among the new therapeutic strategies, blocking of angiogenesis was the subject of several clinical trials.Intervention of membrane transporters (influx and / or efflux) plays an important pharmacokinetic and pharmacogenetic role in anticancer drugs resistance.We observed in patients with HCC, a great pharmacokinetics parameters variability of sorafenib (tyrosine kinase inhibitor, anti-angiogenic drug and P-gp and BCRP substrat) and a tendency to a better clinical response in the ABCB1 3435 CT, ABCG2 34 GA, ABCG2 1143CT and ABCG2 421CA heterozygous group than in the homozygous group (wild type and mutant).Our work showns in vitro that pretreatment with anti-angiogenic drugs such as bevacizumab and sorafenib resulted in a resistance reversion to doxorubicin (P-gp substrate) in an IGROV1 – DXR cells (resistant to doxorubicin and P-gp overexpressing cells) by modulating the functionality of P-glycoprotein. This reversion is measured by the significant increase in intracellular doxorubicin concentrations in IGR OV1-DXR cells.In vivo in human colorectal cancer xenograft mice, bevacizumab pretreatment led to a significant increase in plasma concentrations of SN38 (active metabolite of irinotecan and P-gp substrate), as well as plasma AUC and Cmax of irinotecan (P-gp substrate) after oral administration of irinotecan. Similarly, a significant increase in plasma AUC of sorafenib after bevacizumab pretreatment was observed on the same experimental model.Knowledge and use of activity modulation of efflux pumps by anti-angiogenic targeted therapies would be interesting to translate into cancer therapy for increased clinic response and resistance reversion of the tumor and endothelial cells overexpressing efflux transporters, particularly P-gp

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Wilcox, Sara Morgen. "The function of ABCF1 in immunity and mouse development." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/31026.

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ABCF1 is an ABC (ATP binding cassette) transporter protein that lacks trans-membrane domains. Gene expression of ABCF1 has been shown to increase upon tumour necrosis factor alpha (TNFα) stimulation [1]. This is significant as TNFα is a pro-inflammatory cytokine produced by macrophages and T cells and has a number of functions in the immune response [2]. ABCF1 is thought to function in translational initiation by interacting with the eukaryotic initiation factor 2 (eIF2) [3]. We have determined that ABCF1 is an essential gene in development by the generation and characterization of mice that have a gene trap insertion in the ABCF1 gene, which terminates the expression of the ATP binding cassettes. Homozygous ABCF1 knock-out (ABCF1-/-) mice are embryonic lethal at 3.5 days post coitus (dpc) while heterozygous ABCF1 knock-out (ABCF1+/-) mice appear to be developmentally normal. This thesis utilizes the ABCF1 gene trapped mouse model which contains a β-geo (β-galactosidase /neomycin) reporter gene in the ABCF1 gene to examine the endogenous ABCF1 promoter expression. This allows us to concurrently observe the activity of the ABCF1 promoter in all tissues through sectioning and X-Gal staining. This analysis provides further insight into the physiological function of ABCF1 by identifying the tissues and cell types that have the highest levels of promoter activity. Interestingly, ABCF1 appeared to be expressed in the marginal zone of the spleen and areas surrounding the lymphoid follicles. Macrophages, which were isolated from spleens of ABCF1+/- mice, were found to be hyper-responsive to stimulation by TLR ligands, particularly LPS, while macrophages derived from the bone marrow were found to be hypo-responsive. When challenged with LPS, ABCF1+/- mice produced altered cytokine production compared to their wild-type controls. Upon challenge with Listeria monocytogenes, ABCF1+/- mice succumbed to infection sooner than their ABCF1+/+ littermates. Taken together, these data indicate that ABCF1 is necessary for survival and development and likely has a role in the regulation of cytokines. Thus ABCF1 may play a significant role in regulating inflammation and pathogen induced “cytokine storm”.

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Nandi, Shilpi. "The involvement of membrane vesiculation in ABCA1 mediated efflux." Thesis, University of Ottawa (Canada), 2007. http://hdl.handle.net/10393/27897.

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The mechanism of ATP binding cassette transporter A1 (ABCA1) mediated cholesterol efflux is presently unclear. Cells expressing ABCA1 reported to display distinctive membrane-protrusion-like morphology and apoA1 was also seen to bind to those structures. We hypothesized that cholesterol efflux may be in part originated from membrane shedding through membrane vesiculation and therefore may rely on relatively flexible plasma membrane. We tested several reagents known to modulate membrane fluidity and found that cholesterol efflux is indeed inversely correlated with membrane rigidity. Additionally, using differential ultracentrifugation, we provide evidence that, during ABCA1 mediated cholesterol efflux, cells produce a significant quantity of apoA1 free membrane vesicles along with apoA1 containing lipoproteins. This process can be inhibited by rigidifying the plasma membrane. We therefore conclude that flexibility of plasma membrane is necessary for ABCA1 mediated cholesterol efflux and speculate that ABCA1 and apoA1 work together to secrete membrane vesicles during efflux.

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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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Lieb, Soeren [Verfasser]. "Untersuchung der murinen Lith1 Kandidatengene ABCB11 und LXRA beim humanen Gallensteinleiden / Soeren Lieb." Kiel : Universitätsbibliothek Kiel, 2009. http://d-nb.info/1019868546/34.

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Raas, Quentin. "Inactivation génique des transporteurs ABC peroxysomaux ABCD1 et ABCD2 dans les cellules microgliales BV-2 : étude de la physiopathogenèse de l’adrénoleucodystrophie liée à l’X." Thesis, Bourgogne Franche-Comté, 2018. http://www.theses.fr/2018UBFCI011/document.

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L’adrénoleucodystrophie liée à l’X (X-ALD) est une maladie neurodégénérative sévère caractérisée par une accumulation d’acides gras à très longue chaîne (AGTLC), conséquence d’un défaut de β-oxydation peroxysomale. La maladie est associée à l’absence de la protéine ABCD1, transporteur ABC du peroxysome qui, tout comme son homologue le plus proche, ABCD2, participe à l’import des AGTLC-CoA au sein du peroxysome, l’unique site de leur dégradation par β-oxydation. La compréhension des mécanismes physiopathologiques est aujourd’hui limitée par le manque de modèles expérimentaux pertinents, cellulaires ou animaux. Puisque le défaut peroxysomal dans la microglie apparait comme un événement pathogénique majeur, nous avons généré des lignées de cellules microgliales incapable de transporter et/ou β-oxyder les AGTLC au sein du peroxysome. Quatre lignées cellulaires microgliales BV-2 déficientes en ABCD1, ABCD2, ABCD1 et ABCD2 ou ACOX1 (l’enzyme limitante de la β-oxydation peroxysomale) ont ainsi été générées par édition génique par CRISPR-Cas9. Ces cellules déficientes présentent d’importants défauts biochimiques, une accumulation d’AGTLC mais aussi des changements des contenus en acides gras et cholestérol. Les analyses ultrastructurales effectuées démontrent l’existence d’importantes inclusions lipidiques et indiquent également une augmentation du nombre de peroxysomes et mitochondries dans ces cellules. Les profils transcriptomiques signalent des altérations de la plasticité de ces cellules microgliales et de leur capacité de reprogrammation métabolique en réponse à un stimulus inflammatoire. Les fonctions de phagocytose ou de présentation antigénique des cellules microgliales semblent être affectées par le défaut peroxysomal. Enfin, les résultats obtenus à l’aide de ces modèles suggèrent que l’altération du métabolisme lipidique peroxysomal modifie l’organisation des membranes cellulaires. Ces lignées cellulaires apparaissent donc comme des modèles prometteurs, d’un grand intérêt pour la compréhension de la physiopathologie et l’identification de cibles thérapeutiques de cette maladie neurodégénérative complexe
X-linked adrenoleukodystrophy (X-ALD) is a severe neurodegenerative disorder characterized by very-long-chain fatty acid (VLCFA) accumulation resulting from a peroxisomal β-oxidation defect. The disease is caused by mutations in the ABCD1 gene, which encodes for a peroxisomal half ABC transporter predicted, like its closest homologue ABCD2, to participate in the entry of VLCFA-CoA into the peroxisome, the unique site of their β-oxidation. Progress in understanding the physiopathogenesis of X-ALD suffers from the lack of appropriate cell and animal models. Since peroxisomal defects in microglia seem to be a key element of the onset of the disease, we generated four microglial cell lines unable to transport and/or β-oxidize VLCFA into the peroxisome. BV-2 microglial cells were engineered with CRISPR-Cas9 to generate four microglial cell lines deficient in ABCD1, ABCD2, both ABCD1 and ABCD2 or ACOX-1 (the first rate-limiting enzyme of the peroxisomal β-oxidation system). Biochemical defects and lipid content changes associated with VLCFA accumulation but also fatty acids and cholesterol changes were identified in deficient microglia. Ultrastructural investigations confirmed cytosolic lipid inclusions and an increased number of peroxisome and mitochondria. Transcriptomic profiles of deficient microglia are indicative of an impaired plasticity and an impaired capacity to operate the metabolic shift required upon an inflammatory stimulation. Peroxisomal defect is likely to affect phagocytosis and antigen presentation capacity of microglia. Peroxisomal lipid metabolism defect is also suggested to modify cell membranes organization. Altogether, these novel mutant cell lines represent a promising model that should permit identification of new therapeutic targets for this complex neurodegenerative disease

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Jennelle, Lucas Trent. "Contribution of Calnexin to HIV-1 Nef effects on ABCA1." Thesis, The George Washington University, 2013. http://pqdtopen.proquest.com/#viewpdf?dispub=3557581.

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HIV-infected patients are at increased risk of developing atherosclerosis, in part due to an altered HDL profile exacerbated by downmodulation and impairment of ATP-Binding Cassette Transporter A1 (ABCA1) activity by the HIV-1 protein Nef. Nef has been shown to increase delivery of cholesterol to lipid rafts, sites of viral assembly and egress, by inhibition of ABCA1 cholesterol efflux functionality and reduction of ABCA1 protein levels through lysosomal degradation. Important mechanistic details of ABCA1 inactivation and degradation by Nef, and whether these two processes are intimately linked or separable are still to be defined. The studies presented here were designed to identify cellular co-factors for ABCA1-mediated cholesterol efflux that may be targeted by Nef to achieve ABCA1 inactivation. In these studies, a novel cellular factor, the ER-resident lectin chaperone calnexin, was shown to be involved in a physical interaction with ABCA1 that is disrupted by Nef. Nef was found to bind and redistribute calnexin and reduce binding and co-localization of ABCA1 with calnexin. In vitro knockdown of calnexin via RNAi reproduced several previously described biochemical effects of Nef, including redistribution of ABCA1, increased ABCA1 membrane localization, and reduced ABCA1 recycling. Importantly, knockdown of calnexin also resulted in reduced ABCA1-mediated cholesterol efflux, but without the Nef-mediated reduction in ABCA1 protein levels, suggesting that Nef utilizes a bipartite mechanism to inactivate and degrade ABCA1 and that these functions may be separable. Despite the lack of effect of calnexin knockdown on ABCA1 protein levels, interference with the ABCA1-calnexin interaction was critical for Nef-mediated functional impairment of ABCA1. This was shown with a Nef mutant defective in interaction with calnexin which was incapable of preventing ABCA1-calnexin interaction and was also defective in impairing ABCA1-mediated cholesterol efflux activity. Thus, these studies identified a novel mechanism by which HIV-1 Nef impairs functional activity of cholesterol transporter ABCA1 by blocking its interaction with calnexin. Calnexin acts as an ABCA1 functional chaperone, limiting total and cell surface ABCA1 expression while increasing ABCA1-mediated cholesterol efflux. Combined with the demonstration that Nef increases delivery of ABCA1 to lysosomes, these results suggest the Nef-mediated impairment of ABCA1 function involves reduced interaction with calnexin followed by delivery of ABCA1 to lysosomes for degradation.

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Bajuaifer, Nada A. "Translational regulation of ABCB1 gene in acute myeloid leukaemia (AML)." Thesis, University of Nottingham, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.594594.

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Introduction: Multidrug Resistance (MDR) was and remains a major obstacle in the way of successful chemotherapy for cancer patients and especially acute myeloid leukaemia (AML) patients. In AML, MOR mediated by ABCBl over-expression accounts for the majority of MOR cases. The ABCB1 gene encodes a surface protein known as P-glycoprotein (Pgp) which plays a major role in MOR by effluxing drugs out of cells leading to increased relapse rates in AML patients. The regulation of ABCBl and subsequently Pgp is multifactorial and can be altered at many levels. Common regulators of genes expression may play a role in the regulation of this gene such as genetic sequence variation in the form of single nucleotide polymorph isms and short noncoding RNAs known as microRNAs. Results and Discussion: Role of different regulators in the regulation of ABeBl gene was investigated; these were microRNAs and 3'UTR SNP (specifically rs3842). Microarray profiling of 11 AML cell lines and 45 NeRN AMLl4 and AMLl5 trial patients samples showed significant down-regulation of miR-34b and miR-503 in Pgp positive cell lines when compared with Pgp negative cell lines and miR-l48a, miR-45l, miR-659, miR-499-5p, miR-l97 and miR-642 in Pgp positive patient samples when compared with Pgp negative patient samples. This suggests a role of these miRs in MDR in AML. No significant up-regulation was found in the Pgp positive cell lines and patients samples when compared with the Pgp negative group. Functionally, no direct effect of miR-l48a and miR-34b on ASeSl3'UTR constructs and Pgp protein level (for miR-34b) was found but an indirect effect of these miRs on ASeS! still needs to be tested. Second, the role of rs3842 on regulation of ABeBl gene was investigated. rs3842 genotyping of 455 NCRN AMll4 and AML15 trial patients showed comparable distribution to the reported distribution of the genotypes of normal healthy European population. Furthermore, an effect of the rs3842 polymorphism on Pgp protein expression and function (but not at the mRNA level) was seen in the 35% of patients where ASeS! expression is high. Functionally, higher baseline activity of the ASeS! wild type 3'UTR construct was found when compared with the ABeBl variant 3'UTR construct and a further construct mutated by site-directed mutagenesis. On examination of the rs3842 polymorphism and surrounding sequence, it was predicted that miR-374a targets AseSl very close to the SNP. This went to show that miR-374a causes down-regulation of ASCSl 3'UTR activity but only when the wild type rs3842 allele A is expressed. In addition, an effect of miR-374a on Pgp protein expression was found at the protein level but not at the mRNA suggesting a role of miR-374a in the translational regulation of the ABCBl gene. To conclude, the role found of microRNAs (miR-374a) and rs3842 in ABCBl regulation in this work suggests a significant role of the 3'UTR of ABCBl gene in its regulation.

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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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Jeannesson, Elise Siest Gérard Visvikis-Siest Sophie. "Analyse génétique et transcriptomique du transporteur ABCB1 en physiopathologie cardiovasculaire." S. l. : Nancy 1, 2008. http://www.scd.uhp-nancy.fr/docnum/SCD_T_2008_0130_JEANNESSON.pdf.

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Dissertations / Theses on the topic 'ABCC10'

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