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1
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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Tomioka, Maiko. "Expression of ABCA13 in the brain and the effect of neurological disorder-related SNPs on the function." Kyoto University, 2013. http://hdl.handle.net/2433/175051.
Full textAbstract:
Kyoto University (京都大学)0048
新制・課程博士
博士(農学)
甲第17622号
農博第1984号
新制||農||1010(附属図書館)
学位論文||H25||N4743(農学部図書室)
30388
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 阪井 康能
学位規則第4条第1項該当
3
Davids, Muneera. "Single nucleotide polymorphism association studies of ABCA13 and ABHD11 genes and the bioinformatics analysis of the autism candidate genes localized on chromosome 7." University of the Western Cape, 2016. http://hdl.handle.net/11394/4977.
Full textAbstract:
Magister Scientiae - MScAutism, Aspergers Syndrome and Pervasive Developmental Delay-Not Otherwise Specified (PDD-NOS), among others, fall under an umbrella of disorders known as Autism Spectrum Disorder. Twin studies show that autism is a highly heritable disorder. More than 100 genes have been implicated in the aetiology of autism, each of which is involved in numerous biological processes and a variety of molecular interactions. William-Beuren syndrome is a multisystem developmental disorder caused by the deletion of contiguous genes at the 7q11.23 position. The aims of this study were (i) to genotype three SNPs (rs10279013, rs2293484 and rs17060) in the ABHD11 and ABCA13 genes, respectively, using Taqman® SNP Genotyping assays to detect association with autism in three distinct South African (SA) ethnic groups (Black, Caucasian and Mixed), and (ii) to ascertain common pathways or regulating transcription factors for genes on chromosome 7 that may attribute to it being an “autism hotspot”. Chapter 3 objectives were to identify potential candidate genes using STRING analysis and the Gene Cards database. The Taqman® study indicated significant association for SNP rs2293484 in the South African Caucasian group, as well as for the G allele in the South African Mixed group, where p<0.001. STRING analysis yielded 2 new candidate genes, FZD1 and FZD9. It was also found that the Wnt pathway in mammals plays a significant role in both ASDs and cancer, and there is a definite link between genes regulating cancer, and genes implicated in autism. The study provides evidence for not only the association of the investigated SNP in a South African population, but also provides evidence for the co-morbidity of several neurological and psychological disorders such as depression and bipolar disorder with autism.
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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-AlleCoorientadora : 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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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
6
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 TureckCoorientadora : 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
Inclui referências
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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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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Plazzo, Anna Pia. "Influence of ABCA1 and ABCA7 on the lipid microenvironment of the plasma membrane." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2009. http://dx.doi.org/10.18452/15953.
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Der ABC-Transporter ABCA1 ist unmittelbar in die zelluläre Lipidhomeostasie einbezogen, in dem er die Freisetzung von Cholesterol an plasmatische Rezeptoren, wie ApoA-I, vermittelt. Trotz intensiver Untersuchungen ist dieser molekulare Mechanismus nicht verstanden. Verschiedene Studien deuten daraufhin, dass durch die Aktivität von ABCA1 bedingte Veränderungen in der Lipidphase der äußeren Hälfte der Plasmamembran (PM) wichtig für die Freisetzung des Cholesterols sind. In der vorliegenden Arbeit wird die Lipidumgebung von ABCA1 in der PM lebender Säugetierzellen unter Anwendung der Fluoreszenzlebenszeitmikroskopie von fluoreszierenden Lipidsonden untersucht. Es wurde eine breite Verteilung der Fluoreszenzlebenszeiten der Sonden gefunden, die sensitiv gegenüber Veränderungen der lateralen und transversalen Organisation der Lipide ist. Im Einklang mit Studien an riesengroßen unilamellaren Vesikeln und Plasmamembranvesikeln weisen unsere Ergebnisse die Existenz einer größeren Vielfalt submikroskopischer Lipiddomänen auf. Die FLIM-Untersuchungen an ABCA1 exprimierenden HeLa-Zellen weisen eine die Lipidphase destabilisierende Funktion des Transportes aus. Dieses wurde unterstützt durch die Lipidanalyse von Fraktionen der PM. Auf der Basis unserer Untersuchungen und früheren Daten stellen wir die Hypothese auf, dass die Exponierung von Phosphatidylserin (PS) auf der Zelloberfläche ein zentrales Ereignis der ABCA1 bedingten Veränderungen ist. Allerdings zeigen vergleichende Studien an ABCA7 exprimierenden Zellen, dass dies nicht ausreicht, um die ABCA1 verursachten Veränderungen in der Lipidpackung der PM zu erklären. Unsere Ergebnisse beweisen, dass die Fähigkeit von ABCA1, den Cholesterolefflux zu vermitteln, auf durch den Transporter bedingte Veränderungen in der LP der PM zurückzuführen sind, die unabhängig von der Bindung von ApoA-1 sind und dieser vorausgehen. Diese Veränderungen sind notwendig für die Lipidierung von ApoA-1 und der Generierung von HDL-Partikeln.The ABCA1 transporter organizes cellular lipid homeostasis by promoting the release of cholesterol to plasmatic acceptors such as ApoA-I. Despite intensive investigation, the molecular mechanism of such a process has not yet been clarified. In the present study we report on the analysis of the ABCA1 lipid microenvironment at the plasma membrane of living cells, by a novel approach based on fluorescence lifetime imaging microscopy (FLIM). In the plasma membrane of mammalian cells, a broad fluorescence lifetime distribution sensitive to treatments interfering with the membrane lateral and transbilayer organization was found. In agreement with investigations in giant unilamellar vesicles and giant plasma membrane vesicles, our results are consistent with the existence of a large variety of submicroscopic lipid domains. Based on that, FLIM in HeLa cells expressing ABCA1 revealed the destabilizing function of the transporter on the lipid arrangement at the membrane, indicating that lipid packing was a primary target of ABCA1 activity. This was corroborated by the analysis of plasma membrane fractions isolated by density fractionation. On the basis of our analysis and previous data, we speculate that the exposure of phosphatidylserine on the cell surface is a central event for ABCA1-dependent modifications. However, a comparative study of cells expressing ABCA7, the member of the ABCA subfamily with the highest homology to ABCA1, revealed that exposure of PS alone cannot account for the detected effects. Collectively, our data suggest that the ability of ABCA1 to promote cholesterol efflux is independent and precedes its actual binding to ApoA-I. Rather, ABCA1-induced plasma membrane modifications are necessary for the lipidation of ApoA-I and the generation of high density lipoprotein particles.
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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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中塔, 充宏. "ABCタンパク質による脳内脂質輸送の生理的役割." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263711.
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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 ScherrerTese (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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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.Made available in DSpace on 2013-12-06T00:39:31Z (GMT). No. of bitstreams: 1 319055.pdf: 3105190 bytes, checksum: f462b93c678d315794c7ff809ddb0b6c (MD5) Previous issue date: 2013
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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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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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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Zhang, Anja Ziwen. "Sumoylierung und Targeting von ABCA3." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-146702.
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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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Chambenoit, Olivier. "ABCA1 et l'homéostasie du cholestérol cellulaire." Aix-Marseille 2, 2003. http://www.theses.fr/2003AIX22023.
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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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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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Huppmann, Marceline. "Lungenmechanische Charakterisierung von heterozygoten ABCA3-Knockout-Mäusen." Diss., lmu, 2011. http://nbn-resolving.de/urn:nbn:de:bvb:19-133099.
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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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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 MARecent 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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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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Schulte, Daniel. "Molekulare und funktionelle Charakterisierung von Targetingsequenzen im humanen ABCA3-Protein." Diss., lmu, 2008. http://nbn-resolving.de/urn:nbn:de:bvb:19-92875.
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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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Höppner, Stefanie [Verfasser], and Matthias [Akademischer Betreuer] Griese. "Funktionelle Analyse des ABCA3 Transporters / Stefanie Höppner ; Betreuer: Matthias Griese." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2020. http://d-nb.info/1206878231/34.
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Patel, Dipesh C. "Glycaemic influences on the ATP-binding cassette transporter A1 (ABCA1)." Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/6864.
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Increased glucose levels are associated with increased risk of vascular disease. The risk is elevated 2-4 fold in type 2 diabetes and there is a positive relationship between glucose (or HbA1c) levels and vascular disease in the general population. We tested the hypothesis that there is a glycaemia-mediated impairment of reverse cholesterol transport (RCT) by studying an early key step, notably the expression and activity of the ATP binding cassette transporter-A1 (ABCA1). This protein exports cellular cholesterol to apolipoprotein A1 (ApoA-I), thereby forming nascent HDL. In this thesis, it is shown that ABCA1 gene expression in leukocytes in men is reduced in Type 2 diabetes and correlates negatively with circulating HbA1c levels and fasting glucose. This confirms our earlier findings in healthy men. An independent relationship between glycaemia and leukocyte ABCG1 gene expression was not seen. ABCA1 protein concentrations in blood leukocytes were reduced in patients with diabetes. ApoA-I-mediated cholesterol efflux in cultured fibroblasts taken from subjects was studied as a measure of ABCA1 function. This negatively associated with fasting glucose at the time of sampling as well as adiposity. Cellular cholesterol removal was reduced in subjects with diabetes compared with controls. There was a positive relationship between both ABCA1 function and leukocyte protein concentration with circulating HDL cholesterol. These relationships were independent of expression of liver X receptor-α (LXRα) and peroxisome proliferator-activated receptor-γ (PPARγ). These data imply a persistent glycaemia-mediated suppression of an early step in RCT which may contribute to the excess vascular disease observed in such patients. It further proposes impaired cholesterol efflux may contribute to the low circulating HDL cholesterol which is commonly seen in patients with impaired glucose regulation.
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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, 2010Made available in DSpace on 2012-10-25T03:26:24Z (GMT). No. of bitstreams: 1 279884.pdf: 7471394 bytes, checksum: 49ecffa5cacc5208c3b1840fdef5866c (MD5)
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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Karcher, Annette. "Struktur von ABCE1." Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-72198.
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Lee, Jee Yeon. "ABCA1 Increases Extracellular ATP to Mediate Cholesterol Efflux to ApoA-I." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/20519.
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ABCA1 is a key plasma membrane protein required for the efflux of cellular cholesterol to extracellular acceptors, particularly to apoA-I. This process is essential to maintain cholesterol homeostasis in the body. The detailed molecular mechanisms, however, are still insufficiently understood. Also, the molecular identity of ABCA1, i.e. channel, pump or flippase, remains unknown. In this study we analyzed the extracellular ATP levels in the medium of ABCA1-expressing BHK cells and RAW macrophages and compared them to the medium of relevant non-expressing cells. We found that the extracellular ATP concentrations are significantly elevated when cells express ABCA1. Importantly, a dysfunctional ABCA1 mutant (A937V), when expressed similarly as WT-ABCA1, is unable to raise extracellular ATP concentration. This suggests a causal relationship between functional ABCA1 and elevated extracellular ATP. To explore the physiological role of elevated extracellular ATP, we analyzed ABCA1-mediated cholesterol efflux under the conditions where extracellular ATP levels were modulated. We found that increasing extracellular ATP within the physiological range, i.e. < μM, promotes cholesterol efflux to apoA-I. On the other hand, removing extracellular ATP, either by adding apyrase to the medium or by expressing a plasma membrane bound ecto-nucleotidase CD39, abolishes cholesterol efflux to apoA-I. Based on these results we conclude that, through direct or indirect mechanisms, ABCA1 functions to raise ATP levels in the medium. This elevated extracellular ATP is required for ABCA1-mediated cholesterol efflux to apoA-I.
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Kahraman, Emine. "Rolle von ABCA1 auf das HDL-induzierte Recycling von Chylomikronen Bestandteilen /." Hamburg, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000252993.
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Zhang, Anja Ziwen Verfasser], and Andreas [Akademischer Betreuer] [Holzinger. "Sumoylierung und Targeting von ABCA3 / Anja Ziwen Zhang. Betreuer: Andreas Holzinger." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2012. http://d-nb.info/1026012333/34.
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Zhang, Anja Ziwen [Verfasser], and Andreas [Akademischer Betreuer] Holzinger. "Sumoylierung und Targeting von ABCA3 / Anja Ziwen Zhang. Betreuer: Andreas Holzinger." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2012. http://d-nb.info/1026012333/34.
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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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Genvigir, Fabiana Dalla Vecchia. "Estudo da expressão gênica e de polimorfismos do gene ABCA1 em indivíduos sob terapia hipolipemiante." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-17042008-151909/.
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A ATP-binding cassette transporter A1 (ABCA1) é uma proteína transmembrana responsável pelo efluxo celular de colesterol e fosfolipídeos, que é um passo essencial para o transporte reverso do colesterol e para a biogênese da HDL. Polimorfismos do gene ABCA1 foram associados com risco de doença arterial coronariana, variações no perfil lipídico e diferenças na resposta a fármacos hipolipemiantes. Com a finalidade de avaliar os efeitos de polimorfismos do ABCA1 sobre a expressão gênica e a resposta a vastatinas, foram selecionados indivíduos normolipidemicos (NL, n=143) e hipercolesterolêmicos (HC, n=224). A resposta a atorvastatina (10 mg/dia/4 semanas) foi avaliada pelo perfil lipídico sérico em 141 indivíduos do grupo HC (ATORVA). DNA e RNA total foram extraídos de amostras de sangue periférico. Os polimorfismos de nucleotídeo único (SNP) G70943A (R219K), C-14T e C-105T, uma variante nova do ABCA1, foram detectados por PCR-RFLP e confirmados por seqüenciamento de DNA. A expressão de RNAm do ABCA1 em células mononucleares do sangue periférico (CMSP) foi analisada por PCR-duplex e PCR em tempo real, utilizando o gene GAPD como referência endógena. A freqüência do alelo -105T foi 1,4% em NL e 2,0% em HC. O alelo 70943A (genótipos GA+AA) foi associado com maior concentração sérica basal de apoAI (NL), de HDL-c (ATORVA) e com menores concentrações basais de triglicerídeos e VLDL-c e menor índice TG/HDL-c (HC e ATORVA) em comparação com o genótipo 70943GG (p<0,05). O polimorfismo C-105T está em desequilíbrio de ligação com o SNP C-14T (p=0,006). Portadores do alelo -105T (genótipos CT+TT), quando comparados aos portadores do genótipo -105CC, tiveram menores valores basais de triglicerídeos e VLDL-c, maior concentração de HDL-c e menor índice TG/HDL-c nos grupos HC e ATORVA e também maiores concentrações de apoAI e menor índice apoB/apoAI no grupo ATORVA (p<0,05). Nos grupos HC e ATORVA, os portadores do haplótipo -14CT+TT/-105CT+TT tiveram menores valores de triglicerídeos e VLDL-c basais, maiores concentrações de HDL-c e menor índice TG/HDL-c quando comparados aos portadores dos outros haplótipos (p<0,05). A expressão basal do ABCA1 foi menor nos HC que nos NL independentemente da taxa de expressão alta (GM1) ou baixa (GM2). Este efeito foi associado com os SNPs C-14T e G70943A SNPs. Após o tratamento com atorvastatina, a expressão de RNAm foi reduzida nos HC portadores do alelo - 14T em comparação com os portadores de alelo -14C. Esses resultados são sugestivos de que ABCA1 SNPs estão envolvidos na variação do perfil lipídico sérico e na expressão de RNAm em resposta a atorvastatina.The ATP-binding cassette transporter A1 (ABCA1) is a transmembrane protein involved on cholesterol and phospholipid cellular efflux, which is an essential step for the reverse cholesterol transport and HDL biogenesis. Single nucleotide polymorphisms (SNPs) in the ABCA1 gene have been associated with increased risk of coronary heart disease, differences on serum lipid profile and response to lowering-cholesterol drugs. We have evaluated the influence of ABCA1 SNPs on mRNA expression and lipid-lowering response to atorvastatin. Normolipidemic (NL, n=143) hypercholesterolemic (HC, n=224) individuals were enrolled in this study and the response to atorvastatin (10 mg/day/4 weeks) was evaluated in HC individuals (ATORVA, n=141). Blood samples were collected for biochemical analyses, genomic DNA and total RNA extraction. SNPs G70943A (R219K), C-14T and C-105T, a novel variant of ABCA1, were detected by PCR-RFLP and confirmed for DNA sequencing. ABCA1 mRNA expression in peripheral blood mononuclear cells (PBMC) was analysed by PCR-duplex and Real Time PCR, using the GAPD as the endogenous reference. In HC and NL, the frequency of -105T allele was 2.0% and 1.4%, respectively. The 70943A allele (genotypes GA+AA) was associated with higher basal concentrations of apoAI (NL) and HDL-c (ATORVA) and lower triglyceride and VLDL-c and TG/HDL-c ratio (HC and ATORVA) than the 70943GG genotype (p<0.05). We found a linkage disequilibrium between C-14T and C-105T SNPs in HC group (p=0.006). Individuals carrying -105T allele (CT/TT genotypes), when compared with -105CC carriers, had lower basal concentrations of triglyceride and VLDL-c, higher concentration of HDL-c and lower TG/HDL-c ratio in HC and ATORVA groups and also higher concentration of apoAI and lower apoB/apoAI ratio in ATORVA group (p<0.05). In HC and ATORVA, individuals with -14CT+TT/-105CT+TT haplotype had lower basal values of triglyceride and VLDL-c, higher concentration of HDL-c and lower TG/HDL-c ratio than carries of others haplotypes (p<0,05). ABCA1 mRNA basal expression was lower in HC when compared to NL independently of high (GM1) or low (GM2) basal expression rate. This effect was associated with C-14T and G70943A SNPs. After atorvastatin treatment, mRNA expression was reduced in HC individuals carrying -14T allele in comparison with the -14C allele carriers. These results are sugestive that ABCA1 SNPs are involved on variation of serum lipid profile and mRNA expression in response to atorvastatin.
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Hrusovar, Natalie. "Beeinflussung des LXR Alpha-abhängigen Cholesterintransporters ABCA1 durch Stigmasterol und seine Oxyderivate." Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-97539.
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Hrusovar, Natalie. "Beeinflussung des LXR Alpha-abhängigen Cholesterintransporters ABCA1 durch Stigmasterol und seine Oxyderivate." kostenfrei, 2009. http://edoc.ub.uni-muenchen.de/9753/.
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Schindlbeck, Ulrike [Verfasser], and Matthias [Akademischer Betreuer] Griese. "Charakterisierung neuer Missense Mutationen im Lipidtransporter ABCA3 / Ulrike Schindlbeck ; Betreuer: Matthias Griese." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/119981640X/34.
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Schicker, Maresa. "Die Charakterisierung der Funktion des Lipidtransporters ABCA3 in der Milchdrüse (am Mausmodell)." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-172584.
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ABCA3 ist als Phospholipidtransporter der ABC-Transporterfamilie wesentlich an der Synthese von Lungensurfactant beteiligt. Diese wichtige Rolle von ABCA3 in der Lunge ist mittlerweile bekannt und wird weiterhin näher erforscht. Des Weiteren wird ABCA3 auch in anderen Geweben exprimiert, darunter Leber, Niere, Gehirn [Stahlman et al. 2007]. ABCA3 wurde daneben auch in humanem Milchdrüsengewebe entdeckt und stellt in Mammakarzinomen einen Marker für eine gute Prognose dar [Schimanski 2010].
In der murinen Milchdrüse ist die Abca3-Expression molekularbiologisch auf Ebene der mRNA nachgewiesen worden [Hammel 2007]. Des Weiteren ist ABCA3 in immunhistochemischen Färbungen von humaner und muriner Milch darstellbar. Dort ist es auf der Außenseite der Milchfetttröpfchen-Membran lokalisiert [bislang nicht veröffentlichte Daten der eigenen Arbeitsgruppe]. Milchfetttröpfchen werden in Milchdrüsen-Epithelzellen gebildet, indem Lipidtransporter (unter anderem ABC-Transporter der ABCA-Subklasse wie ABCA1 oder ABCA7) Lipide importieren.
In der Milchdrüse ist über den Mechanismus, mit dem ABCA3 an der Milchsekretion beteiligt sein könnte, nicht viel bekannt. Es kann aber analog zu der Rolle in der Lunge davon ausgegangen werden, dass ABCA3 auch in der Milchdrüse Phospholipide transportiert. Phospholipide verfügen über wichtige Eigenschaften in der Milch als Emulgatoren und als protektive Faktoren für das Neugeborene. Es ist nachgewiesen, dass ein Einschnitt in der Phospholipid-Sekretion und eine veränderte Zusammensetzung der Phospholipide in der Milch zu nachteiligen Auswirkungen auf das Neugeborene führen [Isaacs 2005].
Es stellt sich die Frage, ob und inwieweit ABCA3 in der Brustdrüse an der Milchbildung und – sekretion beteiligt ist.
Dazu wurde ein Mausmodell mit spezifischer Deletion des ABCA3 Gens in der Milchdrüse generiert. Eine Mauslinie mit Cre-Expression unter dem während der Laktation spezifisch im Mammagewebe aktiven Lactoglobulin-Promotor wurde mit einer Mauslinie gekreuzt, welche im ABCA3-Gen LoxP Stellen enthielt. Es kommt zur Cre-getriggerten Deletion von ABCA3 im Mammagewebe. Das andere Allel wurde durch Einkreuzen einer klassischen Knockout-Linie gänzlich inaktiviert. Die Genotypisierung erfolgte mittels PCR. Zur quantitativen Bestimmung der Expression von Abca3 im Mammagewebe wurde die Methode der quantitativen RT-PCR angewendet.
Der Melkvorgang erfolgte mittels einer eigens konzipierten Melkvorrichtung. Diese beinhaltet eine Flüssigkeitsfalle, wodurch ein besseres Handling beim Melkvorgang erreicht wurde. So konnte unter anderem eine höhere Milchmenge pro Maus gewonnen werden mit weniger technisch bedingten Schwankungen. Die Milchproben an Tag 5, 10 und 15 der Laktation wurden massenspektrometrisch auf den Gehalt der einzelnen Phospholipide analysiert.
Es ergab sich eine Reduktion des Abca3-Gens im Milchdrüsengewebe der gefloxten Mäuse von 95% im Vergleich zum Wildtyp. Die Analyse der Phospholipide zeigte eine Verminderung von Phosphatidylethanolamin, Phosphatidylserin und Phosphatidylcholin, während innerhalb der Phosphatidylcholin-Spezies kurzkettige Moleküle (PC30:0, PC32:0) signifikant vermindert waren. Die Milchmenge der ABCA3 defizienten Linie an Tag 15 der Laktation war signifikant vermindert im Vergleich zur Wildtyp Gruppe (p = 0,005).
Der Nachweis von ABCA3 in Milchfetttröpfchen und die Verminderung der Milchmenge bei dessen Fehlen weist auf eine Rolle dieses Transporters für die Milchsekretion hin. Da Phospholipide nur einen geringen Anteil der Milchfette darstellen, aber vor allem in der Membran der Milchfetttröpfchen enthalten sind, könnte ABCA3 möglicherweise durch Bereitstellung von Phospholipiden für die Bildung der Membran von Milchfetttröpfchen an der Milchbildung beteiligt sein. Am Höhepunkt der Laktation kann das Phospholipid-Defizit in den Milchfetttröpfchen nicht meht kompensiert werden und die Milchmenge nimmt durch die verminderte Bildung von Milchfetttröpfchen signifikant ab. Dabei ändert sich die Gesamtzusammensetzung der Milch nur unbedeutend, da jeweils das gesamte Organell „Milchfetttröpfchen“ mitsamt Inhalt fehlt. Dies muss im Rahmen dieser Studie allerdings hypothetisch bleiben.
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Zarubica, Ana. "Influence du transporteur ABCA1 sur le microenvironnement lipidique de la membrane plasmique." Aix-Marseille 2, 2009. http://theses.univ-amu.fr.lama.univ-amu.fr/2009AIX22025.pdf.
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Le transporteur ABCA1 est impliqué dans le transfert des phospholipides et du cholestérol vers Apo A-I sur la membrane plasmique cellulaire. Comme ABCA1 est un transporteur des lipides, nous avons examiné son effet sur le microenvironnement lipidique de la membrane. Nous avons démontré que l'activité ATP-ase d'ABCA1 modifie sa répartition dans les radeaux lipidiques, ainsi que la répartition d’autres protéines de la membrane comme le récepteur de transferrine (TfR), la dynamique cinétique de TfR et réduit l’endocytose de TfR. Nous avons montré par des méthodes biophysiques, cationic sensors et FLIM des modifications significatives dans le feuillet membranaire, interne et externe, par l'expression d'ABCA1. Nous avons démontré aussi par FRAP un changement général de la dynamique de la membrane en présence d'ABCA1. Nous avons corrélé la modification des propriétés de la membrane via ABCA1, avec son influence sur l'activation des macrophages en interférant avec la signalisation de l’IFNγRThe ABCA1 transporter is involved in the Apo A-I/mediated removal of cellular phospholipids and cholesterol at the cell membrane. Considering that ABCA1 acts as lipid translocator we investigated the effect of the transporter on membrane lipid microenvironment. By biochemical assays, we demonstrated that the ATP-ase activity of ABCA1 modifies the partitioning in lipid rafts of the transporter itself and other membrane proteins such as the transferrin receptor (TfR), TfR dynamic kinetics and down regulates TfR-mediated endocytosis. We then assessed by biophysical methods, cationic sensors and FLIM, significant modifications of membrane attributes at the inner and outer leaflet in the presence of ABCA1. Furthermore, we evidenced overall changes in membrane dynamics in the presence of ABCA1 by FRAP. Finally, we correlate the mechanistic basis of ABCA1-dependent modulation of macrophage phenotype with the influence of ABCA1 on lipid raft dependent signaling downstream of IFNγR
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Azuma, Yuya. "Studies on intracellular trafficking and degradation of ABCA1 involved in HDL formation." Kyoto University, 2009. http://hdl.handle.net/2433/126527.
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Kyoto University (京都大学)0048
新制・課程博士
博士(農学)
甲第14841号
農博第1781号
新制||農||974(附属図書館)
学位論文||H21||N4481(農学部図書室)
27247
UT51-2009-F483
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 阪井 康能, 教授 三芳 秀人
学位規則第4条第1項該当
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Yu, Zhao. "Effect of sphingomyelin on the lipid-export activities of ABCA1 and ABCB4." Kyoto University, 2015. http://hdl.handle.net/2433/200507.
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Kyoto University (京都大学)0048
新制・課程博士
博士(農学)
甲第19241号
農博第2138号
新制||農||1036(附属図書館)
学位論文||H27||N4945(農学部図書室)
32240
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 矢﨑 一史, 教授 栗原 達夫
学位規則第4条第1項該当
44
Hozoji, Masako. "Post-translational modification and regulation of ABCA1 involved in cellular cholesterol homeostasis." Kyoto University, 2009. http://hdl.handle.net/2433/126528.
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Kyoto University (京都大学)0048
新制・課程博士
博士(農学)
甲第14842号
農博第1782号
新制||農||974(附属図書館)
学位論文||H21||N4482(農学部図書室)
27248
UT51-2009-F484
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 阪井 康能, 教授 三芳 秀人
学位規則第4条第1項該当
45
Brunham, Liam Robert. "The impact of genetic variation in ABCA1 on cholesterol metabolism, atherosclerosis and diabetes." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/400.
Full textAbstract:
The ATP-binding cassette transporter, sub-family A, member 1 (ABCA1) mediates the major pathway for cholesterol exit from non-hepatic cells and thereby controls the rate-limiting step in the biogenesis of high density lipoprotein (HDL) particles. In humans,ABCA1 deficiency results in Tangier disease, characterized by low levels of HDL cholesterol, cellular cholesterol accumulation and increased risk for atherosclerosis. More than 100 coding variants have been described in the ABCA1 gene. We attempted to understand how both naturally occurring and engineered mutations in ABCA1 impact its role in cholesterol transport in a variety of in vitro and in vivo systems. We attempted to correlate specific genetic variants in ABCA 1 with phenotypes in patients carrying the sevariants, and used an evolutionary approach to predict which specific variants in ABCA1would impact its function. We then turned to the study of tissue-specific genetic deletion of ABCA1 in mice to study its role in HDL biogenesis, atherosclerosis and glucose metabolism. We found that intestinal ABCA1 is an important site of HDL biogenesis and that activation of intestinal ABCA1 raises HDL levels in vivo. Hepatic ABCA1, which is a major site of HDL biogenesis, was shown to significantly contribute to susceptibility to atherosclerosis. Finally, we show that ABCA1 plays an unsuspected role in B-cell function and insulin secretion. These studies have contributed to our understanding of the impact of genetic variation in ABCA1 on diverse biological and pathological processes, and have identified novel aspects of ABCA 1 function in specific cell types.
46
Chigusa, Yoshitsugu. "Reduced ABCA1 expression and low Nrf2 activation due to decreased lectin-like oxidized LDL receptor 1 (LOX-1)in the placenta are involved in preeclampsia." Kyoto University, 2014. http://hdl.handle.net/2433/188637.
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47
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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Weichert, Nina. "Some ABCA3 mutations elevate ER stress and initiate apoptosis of lung epithelial cells." Diss., lmu, 2011. http://nbn-resolving.de/urn:nbn:de:bvb:19-137380.
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Huppmann, Marceline [Verfasser], and Andreas W. [Akademischer Betreuer] Flemmer. "Lungenmechanische Charakterisierung von heterozygoten ABCA3-Knockout-Mäusen / Marceline Huppmann. Betreuer: Andreas W. Flemmer." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2011. http://d-nb.info/1015169775/34.
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Landry, Yves D. "ABCA1 expression disrupts lipid raft plasma membrane microdomains through its ATPase-related functions." Thesis, University of Ottawa (Canada), 2007. http://hdl.handle.net/10393/27871.
Full textAbstract:
The ATP-binding cassette transporter A1 (ABCA1) is known to mediate cholesterol efflux to lipid-poor apolipoprotein A-I. In addition, ABCA1 has been shown to influence functions of the plasma membrane, such as endocytosis and phagocytosis. Here, we report that ABCA1 expression results in a significant redistribution of plasma membrane cholesterol and sphingomyelin from lipid rafts to non-raft regions. Caveolin, a lipid raft/caveolae protein marker, also redistributes from punctate, caveolae-like structures to the general area of the plasma membrane upon expression of ABCA1. Furthermore, we observed a significant reduction of Akt activation in ABCA1-expressing cells, consistent with lipid raft disruption. Cholesterol content in the plasma membrane was, however, not altered. Moreover, we provide evidence that the non-functional A937V-ABCA1 mutant, with a point mutation in the nucleotide binding domain, fails to redistribute cholesterol, sphingomyelin, or caveolin. A937V also fails to influence Akt activation. Finally, we show that apolipoprotein A-1 preferentially associates with non-raft membranes in ABCA1-expressing cells. Our results thus demonstrate that ABCA1 causes a change in overall lipid packing of the plasma membrane, likely through its ATPase-related functions. Such reorganization by ABCA1 effectively expands the non-raft membrane fractions and, consequently, pre-conditions cells for cholesterol efflux.