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Marceau, Geoffroy. "Facteurs de transcription nucléaires (RARs, RXRs, LXRs) et membranes amniotiques : métabolisme des rétinoïdes et stratégies d'identification de nouveaux gènes cibles des rétinoïdes." Clermont-Ferrand 1, 2007. http://www.theses.fr/2007CLF1MM01.
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Les membranes amniotiques humaines constituent une entité tissulaire et fonctionnelle singulière dont l'intégrité est indispensable au bon déroulement de la grossesse. Elles se composent essentiellement de deux feuillets, l'amnios et le chorion, dont toute altération peut conduire à leurs ruptures. Structure transitoire en apparence simple, les membranes amniotiques présentent un grand nombre d'évènements tissulaires et cellulaires, suggérant probablement une fine régulation moléculaire. Cependant les connaissances sur des processus comme l'angiogenèse, la prolifération, la différenciation, ou l'apoptose restent fragmentaires et leurs mécanismes moléculaires de régulation sont à ce jour peu connus. La vitamine A exerce une grande variété d'effets sur la différentiation, l'homéostasie tissulaire, la prolifération cellulaire et l'apoptose. Nous avons donc initié ce travail dans le but d'explorer le rôle de la vitamine A dans la physiologie des membranes et l'implication moléculaire des rétinoïdes via des facteurs de transcription nucléaires, les Retinoic Acid Receptors ou RARs et les Retinoid X Receptors ou RXRs. En 1er lieu, nous avons caractérisé le profil d'expression des différents acteurs moléculaires du métabolisme de la vitamine A au niveau des tissus et cellules des membranes. Deuxièmement, nous avons étudié, dans les tissus humains et murins, un partenaire hétérodimérisant avec RXR, impliqué dans la physiologie membranaire : LXR. Troisièmement, nous avons développé des techniques de bioinformatique, de culture d'explants et moléculaires permettant d'identifier des gènes cibles des rétinoïdes potentiellement impliqués dans la physiopathologie membranaire. Parmi ces gènes, nous avons choisi d'étudier plus particulièrement le +PA. Nous avons pu démontrer l'induction directe du +PA en transcrits et en protéines en culture d'explants d'amnios ainsi que le rôle du DR5 dans son activation transcriptionelle. En conclusion, l'étude du métabolisme du rétinol et l'étude de ses gènes cibles dans les membranes amniotiques, nous a permis d'aborder la régulation moléculaire de processus physiopathologiques dans cette structure. A terme, ces données pourront être utilisées pour une meilleure compréhension de la physiopathologie des membranes amniotiques afin de développer une meilleure prise en charge diagnostique (test biologique de rupture prématurée des membranes amniotiques) et thérapeutique ("amniopatch" à la vitamine A) en obstétrique.
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Quintas, Ameixa Maria Clara. "Regulation of RXRa gene expression in embryonic cells." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.391704.
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Guzmán, Alerie. "RXR signalling in oligodendrocyte lineage cells." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708611.
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Di, Canio Ludovica. "Regulation of oligodendrocyte lineage cell function by the RXRγ nuclear receptor." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/289129.
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Remyelination is a spontaneous regenerative process whereby myelin sheaths are restored to demyelinated axons. Key players in this process are oligodendrocyte progenitor cells (OPCs), a widespread population of CNS progenitor cells which persist into adulthood. Remyelination is impaired in patients with chronic demyelinating conditions such as Multiple Sclerosis, and as with other regenerative processes, its efficiency declines with increasing age. Hence, there is a need for the development of therapeutic interventions that will aid in promoting endogenous remyelination when the endogenous regenerative potential is compromised. The nuclear receptor RXR$\gamma$ is an important positive regulator of OPC differentiation and an accelerator of endogenous remyelination in aged rats. RXR$\gamma$ functions as a ligand-induced transcription factor and is able to regulate gene transcription. It does so by heterodimerising with other nuclear receptors and recruiting co-regulators involved in chromatin remodelling. However, we lack understanding on the specific mechanism by which RXR$\gamma$ promotes OPC differentiation. With the work presented in this thesis I demonstrate that RXR$\gamma$ function is regulated at multiple signalling levels. Proximity ligation assays revealed that RXR$\gamma$ remains consistently bound to its partners throughout the oligodendrocyte lineage, and the biological relevance of each heterodimer is determined by the dynamic association of co-regulators. This is in turn influenced by ligand presence and subcellular receptor localisation. To identify the genes controlled by RXR$\gamma$ in OPCs I carried out ChIP sequencing, which revealed genes involved in proliferation and cell cycle control. Further functional assessments aided me in the development of a hypothesis whereby RXR$\gamma$ activation does not directly influence oligodendrocyte formation, but rather promotes cell cycle exit thereby accelerating and facilitating OPC differentiation. Altered nuclear receptor expression and ligand presence in ageing OPCs may consequently impair this process. My thesis provides an alternative hypothesis to how RXR$\gamma$ regulates lineage cell progression, highlighting a new avenue in the development of therapeutic interventions targeting generic stem cell functions for which drugs are already FDA approved, rather than oligodendrocyte-specific pathways.
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Krezel, Wojciech. "Fonction du recepteur nucleaire rxr chez la souris." Université Louis Pasteur (Strasbourg) (1971-2008), 1997. http://www.theses.fr/1997STR13090.
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L'acide retinoique (metabolite actif de la vitamine a) joue un role important au cours du developpement embryonnaire et dans la croissance et la differenciation cellulaires. Deux familles de recepteurs nucleaires des retinoides ont ete caracterisees : les recepteurs de l'acide retinoique, comprenant trois genes (rar, , ), et les recepteurs x de retinoides, comprenant egalement trois genes (rxr, , ). Nous avons etudie la fonction de rxr, en generant et analysant des souris portant une mutation nulle dans le gene correspondant. Il en ressort que rxr ne joue pas un role essentiel au cours de l'organogenese de la souris. D'autre part les souris rxr#+#/#-/rxr#-#/#-/rxr#-#/#- et rxr#-#/#-/rar (, ou ) sont viables et ne presentent pas de lesions majeures. Ceci suggere que rxr pourrait etre le mediateur principal de la fonction des rxrs au cours du developpement. Des etudes comportementales realisees chez les mutants rar/rxr et rxr/rxr ont revele que rxr joue un role dans le controle de l'activite locomotrice de la souris. Chez ces souris, nous avons observe une modification de l'expression des recepteurs dopaminergiques, ce qui pourrait etre a la base des problemes locomoteurs. Ce travail demontre pour la premiere fois un role des recepteurs des retinoides dans le fonctionnement du systeme nerveux central.
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Halftermeyer, Juliane. "Rôle de RXR sur la transformation par PML-RARα." Paris 7, 2011. http://www.theses.fr/2011PA077194.
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La leucémie aigüe promyélocytaire (LAP) est une maladie rare présentant une prolifération anormale de cellules bloquées au stade promyélocyte, majoritairement caractérisée par la translocation t(15,17) et la formation de la protéine de fusion PML-RARa. PML-RARa induirait notamment l'extinction de gènes essentiels à la différenciation des cellules myéloïdes. In vivo, les protéines RXR (Retinoid X Receptor) sont importantes dans ces mécanismes de transformation par PML-RARa. J'ai développé un modèle ex vivo de cellules primaires de moelle osseuse de souris transformées par PML-RARa dans lesquelles les RXRs peuvent être excisés de façon inductible. La perte des RXRs induit une baisse de la clonogénicité des cellules transformées et une diminution significative de leur survie en culture liquide. J'ai créé une lignée de souris RXRaf/f, RXRbf/f, RXRg-/- PML-RARa, et obtenu, suite à l'introduction de FLT3-ITD, une leucémie dans laquelle les RXRs peuvent être excisés de façon inductible. L'excision des RXRs in vivo provoque une différenciation des cellules leucémiques, comme observé en réponse à un traitement à l'acide rétinoïque (AR), mais sans dégradation de PML-RARa. La perte des RXRs permet aussi un allongement de la survie des souris leucémiques. La différenciation observée en réponse aux différents traitements de la LAP était considérée comme le résultat de la transcription active par PML-RARa. Cependant, mes résultats soutiennent un modèle de différenciation induite par la simple dérépression des gènes cibles de l'AR. La validation de ce nouveau modèle nécessite néanmoins l'étude de la liaison de PML-RARa à l'ADN en présence ou en absence de RXRaAcute promyelocytic leukemia (APL) is induced in 99% of cases by a translocation t(15-17) leading to the PML-RARa fusion oncoprotein. PML-RARa acts as a transcriptional repressor, thus inducing a characteristic differentiation block of myeloid cells. In vivo, PML-RARa is always found in association with the nuclear receptor RXR (Retinoid X Receptor). Actually, RXR is an essential protein for PML-RARa driven transformation. During my thesis, I developed in vivo and ex vivo models to study the functional role of RXR in APL, both models using conditional excision of RXR in RXRaf/f, RXRbf/f, RXRg-/- mice and the Cre-ERT2/Lox System inducible by 4-OHT. In primary bone marrow cells transformed with PML-RARa, excision of RXRs induces a dramatic loss of clonogenicity and growth arrest ex vivo. I also constructed a transgenic model of PML-RARa mice, with RXRaf/f, RXRbf/f, RXRg-/-. After introduction of a constitutively active FLT3 and Cre-ERT2,1 obtained a murine APL in which I was able to excise RXRs. In vivo, loss of RXRs results in a prolongation of mice survival and elicits full differentiation of leukemic cells, similar to that induced by treatment with retinoic acid (RA), but does not degrade PML-RARa. RA treatment was previously thought to activate transcription of target genes and thus promote differentiation by converting PML-RARa from a repressor to an activator protein. However, my results support an other model in which treatment-induced differentiation is promoted by the mere derepression of PML-RARa target genes. Further studies are needed to evaluate the DNA binding of PML-RARa in presence or absence of RXR in order to verify this hypothesis
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Ma, Xingjie. "Identification d'un nouveau régulateur et d'une nouvelle fonction de la sénescence cellulaire." Thesis, Lyon, 2018. http://www.theses.fr/2018LYSE1138.
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La sénescence cellulaire, arrêt stable de la prolifération cellulaire, est accompagnée de la sécrétion de nombreux facteurs pro-inflammatoires (programme sécrétoire associé à la sénescence appelé SASP). La sénescence est induite par divers stimuli, et joue un rôle clé dans de multiples contextes physiopathologiques. Cependant, la régulation de la sénescence est encore mal comprise. Notre laboratoire a récemment identifié le récepteur inositol 1,4,5-trisphosphate de type 2 (ITPR2, canal calcique du ER) comme nouveau régulateur de la sénescence. L'expression du gène ITPR2 est réprimée dans la plupart des cancers, mais sa régulation transcriptionnelle est peu connue. Dans ce contexte, le premier objectif de ma thèse était de caractériser de nouveaux régulateurs de l’expression d’ITPR2. Par un criblage (siRNA) et une analyse Nanostring, nous avons identifié le récepteur nucléaire RXRA comme répresseur transcriptionnel d’ITPR2. Nous avons montré que dans les fibroblastes primaires humains, le knockdown de RXRA induit l’expression d’ITPR2 et de ce fait la signalisation calcique, la production d’espèces réactives de l’oxygène (ROS), le dommage de l’ADN et finalement la sénescence via l’activation de la voie p53-p21. Inversement, la surexpression constitutive de RXRA retarde la sénescence réplicative. Les molécules du SASP, induisant ou renforçant la sénescence, peuvent réguler la signalisation calcique. Le deuxième objectif de ma thèse était d’étudier le rôle du SASP et la participation de la signalisation calcique dans celui-ci. Nous avons observé que le SASP induit la sénescence cellulaire accompagnée d’une différenciation neuroendocrine (NED) dans des cellules de cancer du sein. Le SASP induit une accumulation de calcium dans le cytoplasme qui paraît être impliquée dans la régulation de la NED. Une analyse de données d’échantillons de tumeurs du sein humaines et observé que les échantillons positifs pour la NED présentent des marques de sénescenceCellular senescence is a stable proliferation arrest accompanied with senescence-associated secretory phenotype (SASP). Senescence is induced by diverse stimuli such as telomere shortening and oncogene activation and plays key roles in many physiopathological contexts like embryonic development, cancer and aging. However the molecular mechanisms regulating senescence remain partially understood. Our laboratory recently identified a new senescence regulator: the inositol 1,4,5-trisphosphate receptor type 2 (ITPR2), an ER calcium release channel. ITPR2 is repressed in many cancers, but its transcriptional regulation is barely known. Therefore, the first aim of my thesis was to characterize new ITPR2 regulators. Through siRNA screen and Nanostring analysis, we identified the nuclear receptor RXRA as a transcriptional repressor of ITPR2. We found that in primary human fibroblasts, RXRA knockdown induces ITPR2 expression and thereby calcium signaling, reactive oxygen species (ROS) production, DNA damage and ultimately senescence through p53-p21 axis. Conversely, RXRA overexpression delays replicative senescence. SASP has been described to induce/reinforce senescence, and most of the SASP factors are able to regulate calcium signaling through their receptors. The second aim of my thesis was to investigate the role of the SASP and the participation of calcium signaling in it. We observed that the SASP induces senescence accompanied with a neuroendocrine differentiation (NED) in some breast cancer cells. Interestingly, SASP triggers calcium accumulation in the cytoplasm which seems to be involved in the regulation of NED. We then analyzed human breast tumor datasets and observed that NED-positive samples display some senescence marks: functional p53, low proliferation level and Sprouty 2 expression. Altogether, my work identified RXRA as a new senescence regulator and showed calcium signaling is involved in SASP-induced NED in breast cancer cells
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Dias, Sandra Martha Gomes. "Estudos estruturais dos receptores nucleares humanos para os hormônios tireoidianos Isoforma ß1 (hTRß1) e para o ácido retinóico 9-cis Isoforma a (hRXRa)." Universidade de São Paulo, 2004. http://www.teses.usp.br/teses/disponiveis/76/76132/tde-21092007-141432/.
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Os receptores nucleares são de suma importância para os processos de sinalização intercelular nos eucariotos, uma vez que possuem a capacidade de convergir diferentes sinais internos e externos na regulação de programas genéticos. Estas proteínas funcionam, na sua maioria, como fatores de transcrição ativados por ligantes, sendo a via de comunicação direta entre as moléculas de sinalização e a resposta transcricional eliciada pelas mesmas. A programação genética, estabilizada ou modificada pelos receptores, afeta virtualmente todos os aspectos da vida dos organismos multicelulares, tais como a embriogênese, a homeostase, a reprodução, o crescimento e a morte celular. A regulação transcricional e a seletividade promovida por estas proteínas têm fomentado intensas pesquisas, as quais estão decifrando a complexa rede de eventos moleculares que relatam sua forma de ação. Será um desafio para o futuro o conhecimento completo das regras moleculares que definem sua maneira de promover o controle espacial e temporal da expressão gênica. Estas informações prometem trazer detalhes cruciais para o desenvolvimento de drogas mais eficientes e de grande valor terapêutico. Neste contexto, o principal objetivo dos estudos aqui apresentados foi o de aumentar o conhecimento sobre o comportamento e estrutura do receptor nuclear humano dos hormônios tireoidianos, isoforma β1 (hTRβ1), e do receptor nuclear humano do ácido retinóico 9-cis, isoforma ? (hRXRα). Para tal, aplicou-se a técnica de espalhamento de raios X a baixos ângulos para determinar-se, em solução, o envelope destes receptores contendo os domínios de ligação ao DNA e ao ligante. Paralelamente, investiu-se em diversas tentativas de cristalização dos mesmos. Os resultados obtidos permitiram a determinação da localização espacial dos diferentes domínios e as organizações quaternárias dos homodímeros e homotetrâmeros. Conseqüentemente, foram propostos os primeiros modelos estruturais de receptores nucleares contendo os domínios de ligação ao DNA e ao ligante. O comportamento oligomérico, em solução, do hTRβ1 também foi analisado qualitativamente. Verificou-se que a formação do homodímero e do homotetrâmero é influenciada pela presença do hormônio T3, pela concentração protéica, pelos domínios presentes e por mutações específicas. Estes estudos geraram a hipótese de que o receptor nuclear hTRβ1 é capaz de se autoreprimir. Até então, dentro da superfamília dos receptores nucleares, esta capacidade de autorepressão somente havia sido descrita para o receptor hRXRα. Por fim, cristalizou-se o domínio LBD do receptor hTRβ1 com os ligantes T3, Triac e GC-1. O objetivo foi o de determinar estruturas cristalográficas importantes para o futuro desenvolvimento de tiromiméticos de ação isoforma-seletiva.In eukaryotes, nuclear receptors are of major importance for intercellular signaling because they join different intra and extracellular signals during regulation of genetic programs. The great majority of these proteins function as ligand activated transcription factors providing a direct link between signaling molecules and the transcriptional responses elicited by them. The genetic programs that these receptors establish or modify affect virtually all aspects of the multicellular organisms? life, such as embryogenesis, homeostasis, reproduction, cell growth, and death. Their gene-regulatory power and selectivity has prompted intense research which is now starting to decipher the complex network of molecular events involved in transcription regulation. The future challenge will be to uncover the molecular rules that define spatial and temporal control of gene expression. Such knowledge would be essential to the development of more efficient drugs with better therapeutic values. Therefore, the main purpose in this study was to extend the understanding on the behavior and the structure of human thyroid receptor, isoform ?1 (hTRβ1), and human retinoic acid X receptor, isoform ? (hRXRα). It was applied the small angle X-ray scattering technique to determine, in solution, the envelop of both receptors containing DNA and ligand binding domains. Beside this, several crystallization conditions were tried for both receptors. The results made possible to define the spatial localization of the domains and the quaternary structure of the homodimers and homotetramers. Consequently, we were able to propose the first structural models for nuclear receptors containing the DNA and ligand binding domains. The oligomeric behavior of the hTRβ1, in solution, was also analyzed qualitatively. We verified that it was influenced by the presence of T3 hormone, the protein concentration, the presence of both DNA and ligand binding domains, and by specific mutations. Based on these results, we were able to hypothesize that the hTRβ1 has the capacity of autorepression. Up to now, only the hRXRα, in the whole nuclear receptor superfamily, had been described to behave similarly. Finally, we crystallized the ligand binding domain of the hTRβ1 in the presence of the ligands T3, Triac, and GC-1. The objective was to solve crystallographic structures essential for the future development of tiromimetics with isoform-selective action.
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Alsudais, Hamood. "Activation of the Retinoid X Receptor Augments the Expression of Akt2 to Enhance Myogenic Differentiation." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/33395.
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Cachexia or muscle atrophy is a condition that is associated with a variety of diseases such as chronic heart failure and cancer. In North America, Europe and Japan, more than 8 million patients suffer from cachexia, and it is estimated that cachexia is the cause of death in 30% of cancer patients. Unfortunately, there is no available treatment for cachexia. Bexarotene, a retinoid X receptor (RXR) agonist, is a FDA approved drug used to treat cancer and is able to induce myogenic differentiation in embryonic stem cells. In this study, we investigated the mechanism by which bexarotene enhances myogenic differentiation. The Akt signaling pathway is required for myogenesis and thus we examined its involvement in bexarotene-enhanced myogenic differentiation. We showed that bexarotene, through the activation of RXR signaling, regulates Akt2 expression to enhance myoblast differentiation and fusion. Additionally, we showed that Akt2, but neither Akt1 nor Akt3, is required for bexarotene-enhanced differentiation. Furthermore, we showed that the activation of RXR signaling by bexarotene correlates with a specific histone acetylation mark at the Akt2 locus. More importantly, we demonstrated that bexarotene is able to rescue myoblast differentiation in an in vitro cachexia system. Taken together, our data revealed the significance of Akt2 in bexarotene-enhanced myogenic differentiation and the potential of using bexarotene as a treatment for cachexia.
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Delman, Emily. "Effects of Synthetic Ligands onHeterodimer Pairs Regarding Full-Length Human PPARa, RXRa and LXRa." Wright State University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=wright1472204976.
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Castaneda, Saucedo Eduardo. "Role of the retinoid X receptor α (RXRα) and its heterodimetric partners during skin carcinogenesis." Université Louis Pasteur (Strasbourg) (1971-2008), 2004. https://publication-theses.unistra.fr/public/theses_doctorat/2004/CASTANEDA_SAUCEDO_Eduardo_2004.pdf.
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Finney, Emily Q. "Using Radio Relics to Constrain the Dynamics of 1 RXS J0603.3+4214." Scholarship @ Claremont, 2014. http://scholarship.claremont.edu/scripps_theses/321.
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Galaxy clusters, the most massive gravitationally bound objects in the universe, provide an important setting for exploring the structure and interactions of matter in the cosmos. When galaxy clusters merge, there is ample opportunity to examine interactions between densely-packed halos of luminous and dark matter; thus, understanding the dynamics of merging clusters provides insight into understanding properties of dark matter. This paper examines the galaxy cluster 1 RXS J0603.3+4214 (“Toothbrush Cluster”), incorporating information about the polarization of its associated radio relics into Monte Carlo simulations to constrain knowledge about its inclination angle, time since collision, and the velocity and separation distance between its subclusters. We find that the collision velocity, time since merger, and 3D separation between subclusters are well-constrained, which allows for more accurate analysis of the history of the merger. This type of constraint could be applied to a variety of merging systems. Additionally, this constraint may allow opportunity for exploring the validity of different models of dark matter.
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Kovalevich, Jane. "Cocaine-Mediated Disruption of RXR-gamma Signaling: The Role of TNF-alpha." Diss., Temple University Libraries, 2014. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/242911.
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Biomedical NeurosciencePh.D.
Cocaine abuse poses a substantial health and economic burden for which no effective treatment currently exists. Exposure to cocaine results in altered signaling in a number of central nervous system (CNS) pathways. Previous studies have primarily focused on neurotransmitter systems, such as the dopaminergic and glutamatergic systems, as well as on drug-induced neuroplasticity within the mesolimbic system, which is believed to contribute to reward, addiction, and relapse following withdrawal. Furthermore, cocaine exerts a number of effects on gene regulation that contribute to many pathological conditions commonly afflicting users such as mood disturbances, psychotic symptoms, and long-term cognitive dysfunction. While some mechanisms by which cocaine regulates gene expression have been well-characterized, a large gap in our understanding regarding its downstream actions still exists and must be elucidated in order to develop effective treatment strategies. One pathway we have discovered to be disrupted in an animal model of chronic cocaine abuse is the retinoid X receptor (RXR) signaling pathway. Retinoid X receptors serve as obligate heterodimer partners for a number of nuclear receptor transcription factors, including the thyroid hormone receptor (TR), retinoic acid receptor, vitamin D receptor, and peroxisome proliferator activated receptor. Heterodimeric complexes bind to specific recognition sequences in or around the promoter of target genes to activate, or in some cases, repress, transcriptional activity. Therefore, alterations in the levels and function of RXRs can potentially disrupt numerous signaling cascades. In this context, we observed a significant down-regulation in mRNA and protein levels of RXR-y, an isoform predominantly expressed in the CNS that is involved in dopaminergic signaling, in brains of cocaine-administered mice. Additionally, we observed significantly decreased levels of the neuroplasticity protein, neurogranin, which is regulated transcriptionally by TR/RXR heterodimers. Mechanisms underlying regulation of RXR levels in cells of the CNS are vastly unexplored. Studies in other organ systems, including liver and cardiac systems, demonstrate pro-inflammatory cytokines and cellular stress pathways exert repressive effects on RXR signaling, although these studies solely investigated regulation of the RXR-a isoform. Recently, studies have highlighted the role of the immune system during chronic drug abuse, and demonstrate that significant amounts of proinflammatory factors are produced in the brains of chronic cocaine abusers. Therefore, we hypothesized that cocaine-mediated induction of inflammatory cytokines, such as tumor necrosis factor (TNF)-a may contribute to decreased RXR-y expression within the CNS. Utilizing in vitro neuronal systems, we have demonstrated that cocaine exposure induces neuronal expression of TNF-a and that this contributes to decreased levels of RXR-y, as inhibition of TNF-a or its downstream effector c-Jun-NH2-terminal kinase (JNK) prevents cocaine-mediated reductions in RXR-y protein levels. Furthermore, treatment of neurons with TNF-a alone mimics the effects on RXR-y levels observed in cocaine-treated cells. Additionally, we show that proteasome-dependent protein degradation likely plays a role, as inhibition of the 26 S proteasome with Bortezomib during cocaine or TNF-a exposure blocks the down-regulation of RXR-y levels. Degradation of RXR-y in response to cocaine and TNF-a may involve nuclear export, as our results show an increased level of RXR-y in the cytoplasmic compartment shortly after treatment, and inhibiting nuclear export during treatment with Leptomycin B prevents decreases in whole cell protein levels of RXR-y. In addition to the effects of chronic cocaine abuse on neurons, other CNS cell types such as oligodendrocytes may be negatively impacted by exposure to cocaine. Imaging studies and post-mortem microarray data from human cocaine abuse patients reveal loss of myelin and down-regulated expression of myelin-related genes in the nucleus accumbens and frontal cortex. Altered myelin integrity likely contributes to cognitive deficits that present in many chronic cocaine abuse patients and may also exacerbate damage to neurons. However, limited investigation has been performed to evaluate the effects of cocaine on oligodendrocyte health and function. We have employed an in vivo murine model of chronic cocaine administration to evaluate the impact of cocaine on white matter protein levels. Our data reveal that cocaine induces a significant decrease in white matter protein levels, even following an extended period of withdrawal, in the nucleus accumbens. One potential mechanism for cocaine-mediated white matter damage involves perturbations of glutamate homeostasis, as glutamatergic signaling can induce excitotoxicity in CNS cells, including oligodendrocytes. In this context, we found that administration of the B-lactam antibiotic, ceftriaxone, during cocaine withdrawal ameliorates loss of white matter proteins. Ceftriaxone has previously been shown to upregulate expression and activity of the glial glutamate transporter GLT-1, lending support to the theory that cocaine-mediated myelin loss may be due, in part, to disruption of glutamatergic signaling. Ceftriaxone treatment also decreased expression of cleaved caspase-3, a pro-apoptotic signaling molecule activated during excitotoxic cell death, in cocaine-administered mice. Taken together, our studies characterize two novel consequences of cocaine exposure: (1) decreased neuronal RXR-y expression and down-regulation of RXR-target genes, such as neurogranin, and (2) loss of myelin proteins in the nucleus accumbens which can be attenuated by administration of ceftriaxone. These findings yield insight into mechanisms underlying cocaine-mediated CNS cell death, and highlight potential treatment avenues for restoring brain health. Additionally, as inflammatory processes were identified as key mediators in some of these observations, our findings likely extend to a number of neurodegenerative diseases which are characterized by a neuroinflammatory component.
Temple University--Theses
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Podlesny-Drabiniok, Anna. "Role of RXR signaling in control of neuroinflammation : relevance for research into depression." Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAJ042.
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La dépression est un trouble neurologique grave et la deuxième cause d’invalidité dans le monde. Récemment, la signalisation du récepteur X aux rétinoïdes et l’inflammation chronique ont été identifiées comme facteurs génétiques et environnementaux. Au cours de ma thèse, j'ai étudié la façon dont le récepteur X gamma aux rétinoïdes (RXRg) contrôle la neuroinflammation dans deux modèles précliniques de dépression. J'ai montré que RXRg contrôle un signal spécifique lié à l'âge, entrainant la sénescence et l'hypoactivité des cellules microgliales. Ce signal impacte également la phagocytose microgliale et contribue à l'hypertrophie neuronale dans le striatum, elle-même associée à des symptômes dépressifs. De plus, j'ai pu mettre en évidence une activité antidépressive des rexinoïdes et des fibrates dans le stress de défaite sociale chronique, ainsi que leur mécanisme cellulaire. Les données obtenues pourraient permettre le développement de nouveaux traitements antidépresseursDepression is severe mental disorder that is a second leading contributor to diseases burden. Recently, retinoid X receptor signaling and chronic inflammation have been identified as genetic and environmental factors. However, a cross-talk between these two factors was poorly understood. During my PhD I have studied how retinoid X receptor gamma (RXRg) controls neuroinflammation in two pre-clinical models of depression. I have shown that RXRg controls age-specific signal that drives microglial senescence and hypoactivity. The latter, impacts also microglial phagocytosis and contribute to neuronal hypertrophy in the striatum that previously was associated with depressive symptoms. Additionally, I showed antidepressant activity and cellular mechanism of rexinoids and fibrates in chronic social defeat stress. Obtained data have strong therapeutic potential that may allow for development of new antidepressant therapies
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Бондар, О. В. "Розробка клієнтського застосування веб-програми «дозвіл» з використанням підходів реверс-інженерінгу." Thesis, Чернігів, 2020. http://ir.stu.cn.ua/123456789/23436.
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Бондар, О. В. Розробка клієнтського застосування веб-програми «дозвіл» з використанням підходів реверс-інженерінгу : випускна кваліфікаційна робота : 123 "Комп’ютерна інженерія" / О. В. Бондар ; керівник роботи Т. П. Бивойно ; НУ "Чернігівська політехніка", кафедра інформаційних та комп’ютерних систем. – Чернігів, 2021. – 89 с.Об'єктом розробки дипломної роботи є веб-клієнт для клієнт-серверного застосунку «Дозвіл», мета якого – облік екологічних дозволів. Клієнт був розроблений за допомогою програмного каркасу Angular, який може бути запущений на будь якій ОС з підтримкою Node.js. Angular – це легкий і багатофункціональний інструмент для створення клієнтських і односторінкових застосунків з підтримкою двохстороннього зв’язування. Метою розробки було створення зручного веб-клієнта для запису, організації, збору, групування і опрацьовування екологічних дозволів на викиди шкідливих речовин для підприємств. Основним методом проектування було обране структурне моделювання із використанням UML-діaгрaм. В ході виконання кваліфікаційної роботи був реалізований веб-клієнт, який взаємодіє з REST-сервером по HTTP протоколу. Для реалізації веб-клієнту системи обліку «Дозвіл» були використані технології Angular 9, RxJS 6.5.4, CORS 2.8.5, Bootstrap 4.4.1, а також редактор Visual Studio Code 1.45. Для розгортання веб-клієнту даного застосунку необхідно Node.js версії 13.13 або вище, та Angular CLI 9.1.2. Подальша розробка веб-клієнту «Дозвіл» можлива в сторону покращення механізму авторизації, автентифікації та отримання даних з API-серверу, підвищення зручності користування і удосконалення автоматизації введення даних.
The object of development is the web client for client-server application “Dozvil”, the purpose of which is accounting for environmental permits for enterprises. The client was developed on Angular framework and can be run on any machine which supports Node.js. The Angular is easy and multifunctional tool for creating client and one-page applications with two-way data binding. The purpose of the development was to create a ready-made comfortable client of system for recording, keeping, collecting, organizing, grouping and processing environmental permissions for enterprises. The main design method was structural modeling with using the UML diagrams. During performance of the qualification work was realized web client which communicates with REST-server over HTTP protocol. To implement the web client "Dozvil" were used technologies Angular 9, RxJS 6.5.4, CORS 2.8.5, Bootstrap 4.4.1, together with streamlined code editor Visual Studio Code 1.45. To deploy the web-client of this application are required Node.js 13.13 or higher and Angular CLI 9.1.2. Further development of the web-client "Dozvil" is possible in the direction of improving of authorization and authentication process, increasing convenience of using and improvement automatization of a data entry.
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Hennuyer, Nathalie. "Recepteurs nucleaires et metabolisme lipidique : effets des ppar et de rxr (doctorat : sciences pharmaceutiques)." Lille 2, 1999. http://www.theses.fr/1999LIL2P006.
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MASCREZ, BENEDICTE. "Etude des fonctions activatrices af 1 et af 2 de rxr chez la souris." Université Louis Pasteur (Strasbourg) (1971-2008), 1998. http://www.theses.fr/1998STR13247.
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L'acide retinoique (metabolite actif de la vitamine a) joue un role important au cours du developpement et dans la croissance et la differenciation cellulaire. Deux familles de recepteurs des retinoides ont ete caracterisees : les recepteurs de l'acide retinoique, comprenant trois genes (rar, , ) et les recepteurs du retinoide x, comprenant egalement trois genes (rxr, , ). Les rars et les rxrs comprennent, en n-terminale, une fonction activatrice autonome (af-1) et, en c-terminale, une fonction activatrice induite par le ligand (af-2). Au cours du developpement, rxr est le mediateur principal de la fonction des rxrs. Afin de mieux comprendre les fonctions de rxr, nous avons entrepris, chez la souris, l'inactivation specifique de la fonction af-1, d'une part, et de la fonction af-2, d'autre part, de ce recepteur. Les souris chez lesquelles la fonction af-1 de rxr est mutee sont vivantes et fertiles. Ceci montre que l'af-1 de rxr n'a pas de role essentiel dans les multiples fonctions exercees par le recepteur au cours du developpement. En opposition, les homozygotes pour la mutation af-2 (xaf2#0) meurent a la naissance et presentent, avec une frequence faible, la majorite des malformations rencontrees chez les mutants nuls pour rxr. De plus, l'analyse des mutants composes xaf2#0/rxr#-#/#-/rxr#-#/#-a montre pour la premiere fois, que des mutations dans les rxrs seulement reproduisent la majorite des phenotypes observes dans le syndrome de carence foetale en vitamine a et chez les mutants doubles nuls rars. Finalement, les doubles mutants xaaf2#0/rar(, ou ) presentent avec la meme penetrance et/ou severite l'essentiel des phenotypes observes chez les doubles mutants nuls rxr/rar (, ou ) correspondants. L'ensemble de ces resultats nous a permis de montrer le role important in vivo de la fonction af-2 de rxr dans les differents evenements controles par les heterodimeres rar/rxr au cours du developpement. Ces donnees nous suggerent egalement un role crucial du ligand de rxr dans ces differentes fonctions.
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Chiang, Ming-Yi. "Reverse genetic analysis of nuclear receptors, RXR[gamma], RAR[beta] and Tlx in mice /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1997. http://wwwlib.umi.com/cr/ucsd/fullcit?p9814539.
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Girardi, Carolina Saibro. "Papéis das isoformas de RXR na diferenciação neuronal mediada pelo ácido retinoico em SH-SY5Y." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2018. http://hdl.handle.net/10183/187266.
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O desenvolvimento e a otimização de terapias visando a reposição da função neuronal dependem largamente da melhor compreensão dos mecanismos moleculares por trás da diferenciação de células neurogênicas em neurônios maduros. O ácido retinoico (AR) promove diferenciação neuronal de diversos tipos celulares por meio de reprogramação gênica e de vias de sinalização citoplasmáticas. Os receptores nucleares RXRs são mediadores moleculares fundamentais para os efeitos celulares do AR; no entanto, o papel isolado de cada uma de suas três isoformas na diferenciação neuronal permanece pouco claro. Tendo isso em mente, foi investigada a diferenciação induzida pelo AR na linhagem de neuroblastoma humano SH-SY5Y. A caracterização dos parâmetros induzidos pelo AR nessas células demonstrou parada no ciclo celular e adoção de características típicas de neurônios maduros. Os perfis de expressão das isoformas presentes nas células SH-SY5Y, RXRα e RXRβ, mostraram-se variavelmente regulados ao longo da diferenciação neuronal, tanto a nível de transcritos quanto de proteína. Por fim, o silenciamento transitório e isolado de RXRα e RXRβ durante as primeiras etapas da diferenciação com AR afetou de forma distinta os fenômenos celulares induzidos pelo composto: enquanto RXRα mostra-se fundamental para efeitos genômicos e não genômicos na diferenciação, RXRβ modula negativamente a extensão de neuritos nas células SH-SY5Y. Assim, o trabalho indica a presença de funções distintas para as isoformas de RXR durante as primeiras etapas da diferenciação neuronal induzida pelo AR em neuroblastoma, e traz novas perspectivas para o estudo de RXRs como alvos moleculares nas abordagens clínicas de reposição neuronal.Developing and optimizing therapies aiming at restoring neuronal function depend on better understanding the molecular mechanisms behind differentiation of neurogenic cells into mature neurons. Retinoic acid (RA) promotes neuronal differentiation in multiple cell types through gene reprogramming and cytosolic signaling pathways. The nuclear RXR receptors are main molecular mediators of RA cellular effects. However, little is known about specific roles of distinct RXR isoforms in neuronal differentiation. In view of this, the RA-mediated differentiation of SH-SY5Y neuroblastoma cell line was investigated. Analysis of RA-induced parameters in SH-SY5Y cells showed cell cycle arrest and adoption of neuronal hallmarks. The expression profiles of RXR isoforms detected in SH-SY5Y cells, RXRα e RXRβ, were found varyingly modulated along neuronal differentiation both at transcript and protein levels. Finally, transitory silencing of RXRα and RXRβ single isoforms during the first stages of RA-mediated differentiation distinctly affected cellular phenomena induced by RA: whereas RXRα is required for genomic and non-genomic effects during differentiation, RXRβ negatively regulate neurite extension in SH-SY5Y cells. Results thus indicate distinct functions for RXR isoforms during the first stages of RA-dependent neuronal differentiation of neuroblastoma, and reveal new perspectives for studying RXRs as molecular targets in neuronal replacement therapies.
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Lalloyer, Fanny. "Facteurs de risque de l'athérosclérose : modulation et régulation par les récepteurs nucléaires PPARα et RXR." Lille 2, 2006. http://www.theses.fr/2006LIL2S028.
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Le syndrome métabolique associe un ensemble de symptômes prédisposant au développement de l'athérosclérose tels qu'une dyslipoprotéinémie, une intolérance au glucose, une diminution de sensibilité à l'insuline, une hypertension artérielle et une surcharge pondérale. Certaines de ces anomalies métaboliques (insulinorésistance et dyslipidémies) sont tout particulièrement associées à des dysfonctionnements d'expression de certains gènes clés du métabolisme des lipoprotéines et des glucides. De nombreux travaux ont montré l'implication physiopathologique des récepteurs nucléaires dans la modulation et la régulation de ces anomalies. Dans ce contexte, notre travail s'est focalisé plus particulièrement sur le rôle de deux de ces récepteurs nucléaires, PPARα et RXR. Dans un premier temps, nous avons étudié le rôle de PPARα dans le métabolisme glucidique et l'insulinorésistance. Pour cela, nous avons étudié des osuris déficientes pour le gène de la leptine (ob/ob) (modèle d'insulinorésistance et d'obésité) et déficientes , ou non, en PPARα et nous avons montr un rôle essentiel et bénéfique de PPARα dans la réponse adaptative du pancréas à l'insulinorésistance. Dans un deuxième temps, nous nous sommes intéressés à l'implication de PPARα dans la dyslipidémie et l'athérosclérose en analysant l'effet de son absence dans un modèle murin de dyslipidémie mixte t d'athérosclérose spontanée, les souris transgéniques knock-in pour l'apolipoprotéine E2 humaine (KI apoE2). Nous avons montré que PPARα en lui-même n'influence pas la progression des lésions athéroscléreuses induites par un régime gras mais est nécessaire pour l'effet athéroprotecteur du fénofibrate, médicament hypolipémiant largement utilisé chez l'homme. Enfin, en utilisant le modèle de souris KI apoE2, nous avons confirmé et précisé l'efet potentiellement athéroprotecteur des réxinoïdes. Pour cela, ous avosn utilisé le LG1069 (Bexarotène*, Targretin*), agoniste RXR largement employé aujourd'hui chez l'homme en oncologie. Malgré l'induction d'une hypertriglycéridémie que nous avons démontrée être LXR-dépendante, le LG1069 protège du développement des lésions, en partie en diminuant l'absorption intestinale du cholésterol. En conclusion, grâce à l'utilisation de momdèles murins adaptés, nos travaux ont permis de montrer l'implication favorable des récepteurs nucléaires PPARα et RXR dans l'insulinorésistance et les dylipidémies, deux facteurs de risque importants prédisposant à l'athéroscléroseMetabolic syndrome associates a set of symptoms predisposing to the development of atherosclerosis such as dyslipoproteinemia, glucose intolerance, decreased insulin sensitivity, high blood pressure and overweight. Many studies have demonstrated the physiopathological implication of the nuclear receptors in the modulation of some of these metabolic abnormalities particularly associated with dysregulated expressions of target genes implicated in lipoprotein and glucose metabolism. Our work has focused more particularly on two nuclear recpetors, PPARα and RXR, and their implication in insulin resistance and dyslipoproteinemias. First, we investigated the role of PPARα in glucose metabolism and insulin resistance. Therefore, we used leptin-deficient mice (ob/ob) (model of insulin resistance and obesity) which were deficient or not in PPARα and showed an essential and beneficial role of PPARα in the adaptative response of pancreas to insulin resistance. Secondly, we aimed to analyse the implication of PPARα in dyslipidemia and atherosclerosis by studying the effect of a lack of PPARα in a murine model of dyslipidemia and atherosclerosis, the human apolipoprotein E2-knock-in (apoE2-KI) mouse. We demonstrated that PPARα itself does not influence atherosclerosis progression under high fat diet but is necessary to mediate the atheroprotective effect of fenofibrate, a hypolipidemic drug widely used in humans. Finally, by using the model of apoE2-KI mice, we confirmed and precised the atheroprotective effect of rexinoids. We used LG1069 (Bexarotene*, Targretin*), RXR agonist widely used in clinical practice as an antitumoral agent. Despite the induction of hypertriglyceridemia which we demonstrated to be LXR-dependent, LG1069 protects against lesion development, in part by decreasing intestinal cholesterol absorption. To conclude, thanks to the use of suitable murine models, our studies have shown a beneficial implication of the nuclear receptors PPARα and RXR in insulin resistance and dyslipidemias, two risks factors predisposing to atherosclerosis
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Salek, Pawel. "Wave packet theory of resonant X-ray scattering." Doctoral thesis, KTH, Bioteknologi, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-3188.
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Juntunen, K. (Kari). "Functional and structural characterization of nuclear vitamin D receptor and its ligand binding domain." Doctoral thesis, University of Oulu, 2002. http://urn.fi/urn:isbn:9514268784.
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Abstract
The hormonally active form of vitamin D, 1,25(OH)2D3, is involved in many biological functions throughout the body, such as regulation of calcium and phosphate homeostasis, bone remodeling and controlling cell proliferation and differentiation. Vitamin D receptor (VDR), a member of the nuclear hormone receptor (NHR) super family, mediates those genomic actions of 1,25 (OH)2D3 by actively repressing or activating its target genes. In the present study recombinant human nuclear VDR and its ligand binding domain (LBD) were expressed in Spodoptera frugiperda (Sf9)
insect cells and in E.coli. Recombinant proteins were purified and their biochemical and biophysical properties were characterized.
Recombinant VDR was shown to bind to the vitamin D response element (VDRE) of osteopontin and osteocalcin genes as a homodimer or as a heterodimer with the retinoid X receptor (RXR)-αΔAB.
Full-length VDR and its LBD were demonstrated to bind natural ligand 1,25 (OH)2D3 with high affinity. The binding affinities of several vitamin D analogs were also determined. Ligand binding induced conformational change within the receptor was studied using several methods such as partial proteolytic digestion, small angle neutron scattering (SANS), native gel electrophoresis and circular dichroism (CD) spectroscopy. Results indicate that ligand binding induces conformational change within VDR and different 1,25(OH)2D3 analogs might induce a somewhat different conformation within the receptor. This is seen as an unequal capacity of analogs to stabilize receptor against proteases or heat and as differences in the promotion of receptor homodimerization.
Compared to other nuclear hormone receptors, VDR presents a large insertion region at the N-terminal part of the LBD between helices H1 and H3, encoded by an additional exon. In the present study this additional exon was deleted and the properties of mutated LBD were compared to the wild type LBD.
Biochemical analyses indicated that the mutant protein exhibits the same ligand binding, dimerization with RXR and transactivation properties as the wild-type VDR, suggesting that the insertion region does not affect these main functions. Furthermore, solution studies by small angle X-ray scattering indicated that the insertion region in the VDR locates on the surface of molecule and it is not structurally well ordered.
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Kanda, Hiroshi. "A nuclear complex containing PPARα/RXRα is markedly downregulated in the hypertrophied rat left ventricular myocardium with normal systolic function." Kyoto University, 2001. http://hdl.handle.net/2433/150585.
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Stonehouse, Timothy James. "Analysis of the role of RXR in monocyte-macrophage differentiation and function using U937 monoblastoid cells." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321988.
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Flora, Gagan Deep. "Non-genomic effects of the Pregnane X Receptor (PXR) and Retinoid X Receptor (RXR) in platelets." Thesis, University of Reading, 2018. http://centaur.reading.ac.uk/80709/.
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Grave, Nathália. "Influência de polimorfismos em genes da rota da vitamina D em parâmetros antropométricos e bioquímicos." reponame:Repositório Institucional da UNIVATES, 2015. http://hdl.handle.net/10737/1079.
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Introdução: Muitos estudos tem relacionado a deficiência de vitamina D com o risco para as doenças crônicas, principalmente obesidade e dislipidemia. A vitamina D age através da ligação ao receptor de vitamina D (VDR), o qual forma heterodímeros com o receptor do retinoide X gama (RXRG). O gene GC codifica a proteína de ligação da vitamina D (DBP), a qual é responsável pelo transporte da vitamina D na corrente sanguínea. Considerando que a genética desempenha um papel importante na etiologia destas doenças, poucos estudos analisam a associação de variantes em genes da rota da vitamina D com parâmetros antropométricos e bioquímicos relacionados a estes desfechos. Objetivo: Investigar a associação entre polimorfismos de genes relacionados à rota da vitamina D, rs2228570 (gene VDR), rs2134095 (gene RXRG), rs7041 (gene GC), e parâmetros antropométricos e bioquímicos em uma amostra de adultos. Métodos: Medidas antropométricas e bioquímicas foram avaliadas em 542 indivíduos adultos de ambos os gêneros em uma amostra de base populacional. O DNA genômico foi extraído a partir de amostra de sangue e os polimorfismos foram genotipados pela reação em cadeia da polimerase (PCR) através de discriminação alélica TaqMan (Applied Biosystems, Foster City, CA). As comparações dos desfechos entre os genótipos foram feitas usando ANOVA, Kruskal-Wallis, qui-quadrado de Pearson ou teste exato de Fisher, e as interações gene-gene foram avaliadas usando modelo linear geral. Resultados: Não identificamos nenhum efeito principal dos polimorfismos nos parâmetros avaliados. No entanto, ao analisarmos as interações gene-gene, detectamos uma interação significativa entre os genes RXRG e GC sobre os níveis de colesterol LDL. Conclusões: Nossos achados evidenciaram uma interação significativa entre polimorfismos de dois genes da rota da vitamina D, rs2134095 (RXRG) e rs7041 (GC) sobre os níveis de colesterol LDL, corroborando os achados da literatura que tem consistentemente relacionado a vitamina D com o perfil lipídico.
Introduction: Many studies have related vitamin D deficiency with the risk for chronic diseases, especially obesity and dyslipidemia. Vitamin D acts by binding to the vitamin D receptor (VDR), which form heterodimers with the retinoid X receptor gamma (RXRG). The GC gene encoding the binding protein Vitamin D (BPD), which is responsible for the vitamin D transport in the bloodstream. Considering that genetics play a significant role in the etiology of these diseases, few studies have analyzed the association of variants in genes of vitamin D route anthropometric and biochemical parameters related to these outcomes. Objective: To investigate the association between gene polymorphisms related to vitamin D route, rs2228570 (VDR gene), rs2134095 (RXRG gene), rs7041 (GC gene), and anthropometric and biochemical parameters in a sample of adults. Methods: anthropometric and biochemical measures were assessed in 542 adults of both genders in a population-based sample. Genomic DNA was extracted from blood sample and polymorphisms were genotyped by polymerase chain reaction (PCR) using the TaqMan allelic discrimination (Applied Biosystems, Foster City, CA). Comparisons of outcomes between genotypes were performed using ANOVA, Kruskal-Wallis test, chi-square test or Fisher's exact test, and gene-gene interactions were assessed using general linear model. Results: We have not identified any major effect of polymorphisms in the evaluated parameters. However, when we analyze the gene-gene interactions, we detected a significant interaction between RXRG and GC genes on LDL cholesterol levels. Conclusions: Our findings showed a significant interaction between polymorphisms in two genes of vitamin D route, rs2134095 (RXRG) and rs7041 (GC) on the levels of LDL cholesterol, corroborating literature findings that have consistently related to vitamin D with the profile lipid.
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Бондар, О. В. "Розробка інформаційної системи клієнт-сервер для організації робочої комунікації." Thesis, Чернігів, 2021. http://ir.stu.cn.ua/123456789/24991.
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Бондар, О. В. Розробка інформаційної системи клієнт-сервер для організації робочої комунікації : випускна кваліфікаційна робота : 123 "Комп’ютерна інженерія" / О. В. Бондар ; керівник роботи Є. В. Риндич ; НУ "Чернігівська політехніка", кафедра інформаційних та комп’ютерних систем. – Чернігів, 2021. – 105 с.Об’єктом розробки кваліфікаційної роботи є клієнт-серверна система для організації робочої комунікації. Серверна частина системи була розроблена з використанням програмної платформи ExpressJS, а в основі веб- клієнта лежить фреймворк Angular, що дозволяє компонентам системи бути запущеними на будь якій операційній системі. Метою розробки було створення системи, яка дозволить працівникам розділяти кожну ітерацію унікалього запиту клієнта на окрему задачу для обговорення та подальшого вирішення. Для проектування був обраний методом структурного моделювання із використанням діаграм UML. В ході виконання кваліфікаційної роботи було розроблено серверну частину, використовуючи середовище виконання Node.js, фреймворк ExpressJS та базу даних MуSQL та клієнтську, на основі програмної платформи Angular та бібліотеки RxJS. Сервер надає АРІ, та взаємодіє з клієнтом за допомогою HTTP протоколу. Для реалізації системи були використані такі технології, як база даних MySQL 8.0, Angular 12, RxJS 7.4.0, NodeJS та ExpressJS 4.17. Для розгортки сервера необхідно Node.js 14.0 або вище та MySQL 8.0, для клієнта достатньо будь якого веб-сервера. Подальше покращення системи можливе в сторону розширення АРІ, додавання нотифікацій та чатів на основі вебсокетів, покращення користувацкього інтерфейсу та досвіду.
The object of development in this qualification work is a client-server system for the organization of work communication. The server part was developed based on ExpressJS framework, and the web client is based on the framework Angular, which allows the components of the system to be launched on any OS. The purpose of the development was to create a system that would allow employees to divide each iteration of a unique customer request into a separate task for discussion and further solution. Method of structural modeling using UML diagrams was chosen for the design. While performing the qualification work, the server part was developed using the Node.js runtime environment, the ExpressJS framework and the MySQL database, based on the Angular software platform and the RxJS library. The server provides APIs and communicates with the client using the HTTP protocol. Technologies such as MySQL 8.0, Angular 12, RxJS 7.4.0, NodeJS and ExpressJS 4.17 were used to implement the system. Node.js 14.0 or higher and MySQL 8.0 are required to deploy the server, any web server is enough for the client. Further improvement of the system is possible by expanding API, adding notifications and chats based on web sockets, improving user interface (UI) and experience (UX).
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Eberhardt, Jérôme. "Etude de la dynamique structurale du domaine de liaison au ligand de RXRα et implication de la phosphorylation dans la transcription." Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ118/document.
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De nombreuses études révèlent que le domaine de liaison au ligand de RXRα est très dynamique, même en présence d'un ligand agoniste. Nous avons utilisé les données expérimentales (HDX, RMN et X-ray) disponibles sur ce domaine pour mettre en place un protocole, basé sur la dynamique moléculaire accélérée, permettant d'explorer efficacement la dynamique conformationnelle du domaine de liaison au ligand de RXRα et de valider les ensembles conformationnels obtenus. Ce protocole a été appliqué pour analyser l'influence de la phosphorylation pSer260, située à proximité de la surface d'interaction avec les protéines coactivatrice et impliquée dans le développement de carcinomes hépatocellulaires, sur la structure de ce domaine et sa dynamique. Parallèlement, une méthode de réduction de la dimensionnalité a été développé afin d'analyser de longues trajectoires de dynamique moléculaire. Ainsi grâce à cette méthode, nous avons pu identifier plusieurs nouvelles conformations alternative stables du domaine de liaison au ligand de RXRαMany studies reveal that the ligand binding domain of RXRα is very dynamic, still even in a presence of an agonist ligand. Therefore, the availability of experimental data (HDX, NMR and X-ray) on the domain was used as a leverage in order to set up a protocol, based on accelerated molecular dynamics, to explore its conformational dynamic and to validate it. This protocol was applied to understand the influence of the pSer260 phosphorylation, closed to the binding surface of coactivator proteins and implied in the hepatocellular carcinoma growth, on its structure and its dynamic. At the same time, a dimensional reduction method was developed to analyse long molecular dynamic trajectories. Thus, with this approach, we identified a couple of new alternative and stable conformations of the ligand binding domain of RXRα
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ADAM, STITAH SYLVIE. "Phosphorylation des recepteurs des retinoides rar et rxr. Consequences sur la transcription, la differenciation et la proliferation." Université Louis Pasteur (Strasbourg) (1971-2008), 1999. http://www.theses.fr/1999STR13165.
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Les retinoides agissent via deux familles de recepteurs nucleaires, les recepteurs de l'acide retinoique ou rars (, et ) et les recepteurs du retinoide x ou rxrs (, et ). Rars et rxrs possedent a leur extremite n-terminale une fonction d'activation de la transcription autonome, af-1. Nous avons montre que la region af-1 est phosphorylee de facon constitutive, independante du ligand, au niveau de residus appartenant a des sites consensus pour des kinases dependantes de proline. Dans le cas de rar, le residu phosphoryle est la serine 77. La phosphorylation de cette serine est indispensable a la fonction af-1 et met en jeu la kinase cdk7 associee au facteur general de transcription tfiih. De plus, rar interagit de facon stable avec tfiih. En ce qui concerne rxr, sa region n-terminale renferme neuf sites de phosphorylation potentiels pour des kinases proline-dependantes. Rxr est phosphoryle de facon constitutive dans cette region au niveau de la serine 22, specifique de l'isoforme 1, et au niveau de residus non identifies. Les kinases impliquees dans cette phosphorylation constitutive ne sont pas encore caracterisees, mais des resultats preliminaires suggerent qu'il s'agirait de cdks regulant le cycle cellulaire. L'interet de notre travail reside dans l'observation que rxr peut etre hyperphosphoryle par les jnks activees par les radiations uv au niveau des serines 61, 75 et de la threonine 87 localisees dans la region n-terminale et de la serine 265 situee dans la boucle. Le role de la phosphorylation de rxr a ete etudie dans les cellules f9. A partir des cellules rxr / , nous avons etabli des lignees reexprimant rxr mute au niveau des differents sites de phosphorylation. Nous avons ainsi montre que la phosphorylation constitutive de rxr est impliquee dans la proliferation basale et dans l'action antiproliferative de l'acide retinoique, et que l'hyperphosphorylation induite par les jnks est necessaire au blocage en g2/m induit par les radiations uv.
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Ghbeish, Nora Jamaleddin. "Analyzing nuclear receptor activation and repression : the role of ultraspiracle, the Drosophila RXR, in Drosophila eye development /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2001. http://wwwlib.umi.com/cr/ucsd/fullcit?p9993987.
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Leung, Kin-yue. "Involvement of NF-kB subunit p65 and retinoic acid receptors RARæ and RXRæ in the transcriptional regulation of the human GnRH II gene." Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B36367035.
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Leung, Kin-yue, and 梁建裕. "Involvement of NF-kB subunit p65 and retinoic acid receptors RARæ and RXRæ in the transcriptional regulation of the human GnRH II gene." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B36367035.
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Giovanelli, Martina. "Reactive programming: un caso di studio." Bachelor's thesis, Alma Mater Studiorum - Università di Bologna, 2016. http://amslaurea.unibo.it/10451/.
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L'obiettivo di questa tesi è analizzare e testare la programmazione reattiva, paradigma di programmazione particolarmente adatto per lo sviluppo di applicazioni altamente interattive.
La progettazione di sistemi reattivi implica necessariamente l'utilizzo di codice asincrono e la programmazione reattiva (RP) offre al programmatore semplici meccanismi per gestirlo.
In questa tesi, la programmazione reattiva è stata utilizzata e valutata mediante la realizzazione di un progetto real-world chiamato AvvocaTimer.
Verrà affrontata la progettazione, implementazione e collaudo di una parte del sistema attraverso l'approccio reattivo e, successivamente, confrontata con la prima versione, realizzata con i metodi attualmente usati per gestire codice asincrono, per analizzare vantaggi e/o svantaggi derivanti dall'utilizzo del nuovo paradigma.
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Bocanegra, Atoche Alessandra. "Detección y expresión de los receptores X retinoicos (RXR) en la mucosa yeyunal de crías de alpacas (Vicugna pacos)." Bachelor's thesis, Universidad Nacional Mayor de San Marcos, 2019. https://hdl.handle.net/20.500.12672/10964.
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Determina la presencia de los genes de las isoformas de los receptores X retinoicos (RXR) en el genoma de alpacas adultas y su expresión en la mucosa yeyunal de las crías de alpaca. Para la determinación de los genes en el genoma de las alpacas se utilizaron muestras de leucocitos sanguíneos de 5 alpacas adultas para detectar los genes de las isoformas RXRalfa, RXRbeta y RXRgamma por PCR utilizando primers específicos, y para determinar la expresión de las isoformas de los genes RXR se utilizaron 35 muestras de yeyuno de crías de alpacas de diversas edades, a los cuales se les realizó la prueba de RT PCR tiempo real. Los productos del PCR y RT PCR tiempo real fueron secuenciados para determinar su especificidad. Se obtuvo el ADN total de los leucocitos sanguíneos utilizando un kit de extracción de ADN para luego realizar un PCR con primers específicos para cada gen de las isoformas de los receptores RXR alfa, RXRbeta y RXRgamma, para luego ser reveladas mediante electroforesis en geles de agarosa.al 1.5%. De las muestras de yeyuno se obtuvieron los ARN mensajeros (ARNm) totales con el kit de extracción de “SV total RNA isolation system” (promega) y tratados con DNAsa.que sirvieron de molde para realizar RT-PCR tiempo real con primers específicos de los genes RXRalfa, RXRbeta y RXRgamma. Los resultados permitieron determinar que las alpacas tienen codificados las isoformas de RXR beta y gamma en su genoma y que tienen distintos grados de expresión en la mucosa yeyunal de crías de alpaca. Se detectó una alta expresión de RXRgamma y RXRbeta. No se pudo determinar la expresión de RXRalfa. Estos resultados indican que los receptores RXRgamma y RXRbeta se están expresando en la mucosa del yeyuno de crías de alpacas.Tesis
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Orlov, Igor. "Structural study of nuclear receptor RXR/VDR complex with its target DNA by cryo-electron microscopy and 3D reconstruction." Strasbourg, 2010. http://www.theses.fr/2010STRA6047.
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Les récepteurs nucléaires sont une classe de protéines qui régulent l'expression de gènes spécifiques de manière à contrôler des processus moléculaires impliqués dans le développement, l'homéostasie et le métabolisme. Ces protéines ont la capacité de se lier directement à l'ADN qui est unique en comparaison avec d'autres classes de molécules réceptrices, et en présence du ligand ils régulent l'expression des gènes adjacents à la région promotrice. Nous avons utilisé la cryo-microscopie électronique de particules isolées (cryo-ME) afin d’étudier l'architecture d'un ensemble représentatif des récepteurs nucléaires avec l'ADN. Nous avons déterminé la structure du complexe VDR-RXR des récepteurs nucléaires sur un fragment d'ADN court (20 paires de base) dans des conditions cryo à une résolution de 10-12Å. La structure du complexe révèle que hétéro dimère LBD est une unité assez rigide et stable au sein du complexe même en présence de DBDs et l'ADN. Notamment, la structure du complexe RXR / VDR avec l’ADN montre que hélice H12 de transactivation et le site de liaison du co-activateur VDR pointe vers la direction 3 'et side-on à l'ADN (en face de la DBDs), suggérant que les co-activateur agit en aval de l'élément de réponse NR. Ceci est cohérent avec l'idée que les récepteurs nucléaires auxquels l’ADN est lié maintiennent l’helice H12 de trans-activation accessible pour le recrutement de la chromatine, la modification de co-régulateur de protéines qui agissent sur la région nucléosome assortis de l'ADN en avalNuclear receptors are ligand-dependant transcription regulators that bind directly to the DNA in the promoter region of a target gene. Their regulation occurs through steroid hormones and vitamin A and D derivatives. Structural studies of different kinds of complexes of nuclear receptors with a DNA can provide a basis for the investigation of molecular mechanisms of the ligand-dependant transcription regulation by steroid hormones and vitamins. Until now, structural studies of nuclear receptors have focused mainly on their two individual core domains, the ligand-binding domain (LBD) and the DNA-binding domain (DBD). Here we present the architecture of the full nuclear receptor heterodimeric complex of the ligand-bound vitamin D receptor (VDR) and retinoid X receptor (RXR) bound to a consensus DNA response element forming a direct repeat (DR3). The structure of the RXR/VDR/DNA complex has been determined by single particle cryo-electron microscopy whilst overcoming technical challenges related to the 100kDa molecular weight of the object. The structure reveals an open conformation with the DBD and LBD parts connected through well-resolved hinges. The DBDs are bound side-on to the DNA partially facing the LBDs while keeping the area of transactivation helix H12 accessible for recruiting chromatin-modifying co-regulator proteins on the side oriented downstream of the DNA
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Etter, Guillaume. "Role of retinoid X receptor gamma and dopamine receptor D2 in hippocampal and memory functions." Thesis, Strasbourg, 2013. http://www.theses.fr/2013STRAJ055.
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Dans ce travail de thèse, j'ai cherché à comprendre les mécanismes de contrôle des fonctions mnésiques par Rxrγ ainsi que l’implication potentielle de la signalisation dopaminergique dans ces mécanismes. Dans ce cadre, j'ai focalisé mon étude sur les fonctions hippocampiques à différent niveaux. J'ai cherché (1) à identifier les populations cellulaires de l'hippocampe exprimant Rxrγ en utilisant des techniques histologiques(immunohistochimie, hybridation in situ) afin de pouvoir (2) étudier les fonctions électrophysiologiques de ces cellules en utilisant la technique du patch-clamp. Pour comprendre le rôle de Rxrγ dans le contrôle des fonctions autonomes de ces cellules et les conséquences sur le réseau neuronal environnant, j’ai étudié les effets de la perte de fonction chez les souris Rxrγ/.Étant donné que différentes sous régions de l'hippocampe sont impliquées dans différents processus mnésiques, et que notamment le gyrus denté a été associé au processus de pattern separation (Leutgeb et al., 2007), j'ai également (3) cherché à préciser les fonctions mnésiques qui dépendent de l'activité de Rxrγ en réalisant des analyses comportementales chez les souris Rxrγ/. Etant donné que Rxrγ possède une activité transcriptionnelle, entre autre sur le gène du récepteur D2 à la dopamine (Drd2) (Samad et al., 1997), j'ai également (4) étudié la signalisation dopaminergique dans l’hippocampe chez les souris sauvages et les mutants nuls Rxrγ/. Enfin, afin de démontrer la spécificité neuroanatomique et homéostatique du contrôle exercé par Rxrγ sur la mémoire,j’ai procédé à (5) l’inactivation spécifique de Rxrγ dans les hippocampes de souris floxées pour ce gène, au moyen d’un virus AAV exprimant la recombinase CreThe present thesis work is an attempt to understand the mechanisms of Rxrγ control of memory functions, as well as the potential involvement of dopaminergic signaling in these mecanisms. In this context, I focused my research on hippocampal functions at several distinct levels. The first part of my work (1) aimed at defining the hippocampal cell populations expressing Rxrγ using various histological techniques (immunohistochemistry, in situhybridization) in order to (2) study the electrophysiological functions of these cells using invitro patch-clamp.To identify the role of Rxrγ in the control of cell autonomous functions, as well as the consequences on the surrounding network, I have studied the effects of its loss of function in Rxrγ/mice.As the different subregions of the hippocampus are implicated indistinct aspects of learning and memory, and in particular the dentate gyrus being associated with pattern separation (Leutgeb et al., 2007), I have also tried to dissect the mnemonic processes that rely on Rxrγ activity by performing behavioral analyses of Rxrγ/mice. Considering the transcriptional activities of Rxrγ on Drd2, I have also (4) studied dopaminergic signaling in the hippocampus of wild type and Rxrγ null mutant mice. Finally, to demonstrate the neuroanatomical and homeostatic specificity of Rxrγ control on memory, I performed (5) specific inactivations of Rxrγ in hippocampi of conditional mutant mice that possessed floxed Rxrγ, using AAV vectors expressing recombinase Cre
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Daury, Laetitia. "Etude de l'implication de c-jun dans la régulation de la différenciation des myoblastes aviaires par la T3." Montpellier, ENSA, 2001. http://www.theses.fr/2001ENSA0023.
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Nous avons étudié l'implication de c-Jun dans la régulation de la différenciation des myoblastes aviaires par la T3. Nous montrons l'existence c-June interaction fonctionnelle entre c-Jun, c-ErbAal (T3Ral) et CMD 1 (MyoD aviaire) dans les myoblastes prolifératifs de caille, qui assure la transcription des gènes cibles de la T3. Nos résultats indiquent que l'expression de RXRg abroge cette interaction fonctionnelle positive. Ceci suggère que l'activité du T3Ral dans les myoblastes est assurée par des interactions différentes au cours de la prolifération (absence de RXR), et de la différenciation (expression de RXR). De plus, nous montrons que, indépendamment de la présence de T3, c-ErbAal inhibe l'activité transcriptionnelle des facteurs myogéniques CMDl et Myogénine ; deux séquences basiques du domaine charnière du T3Ral sont impliquées dans cette inhibition. Nous observons que l'expression conjointe de RXR et c-Jun abolit partiellement la capacité du T3Ral à réprimer l'activité des facteurs myogéniques. Ces données suggèrent que la séquestration de CMDl dans un complexe T3R/cJun/CMDl contribuerait à préserver la durée de prolifération des myoblastes. L'expression de RXR qui survient à confluence cellulaire, associée à l'augmentation de l'abondance de la protéine c-Jun mise en évidence dans cette étude, restaurerait l'activité du facteur myogénique dès l'induction de la différenciation. Enfin, nos travaux indiquent que la coopération c-Jun/ ATF2 est favorisée aux détriments de la coopération c-Jun/c-Fos ou Fra2 dès l'induction de la différenciation. Alors que nous montrons que c-Jun/c-Fos et c-Jun/Fra2 répriment efficacement l'induction et le déroulement de la différenciation, la coopération c-Jun/ATF2 stimule efficacement cette dernière, l'activité du promoteur myogénine et son expression. Nos résultats suggèrent également que la modification des interactions de c-Jun avec ses divers partenaires peut être induite par la T3 dès l'induction de l'expression de RXRIn this study, we have studied the implication of c-Jun in the T3 myogenic pathway. We describe the occurence of a functional interaction involving c-Jun, c-ErbAal (T3Ral) and CMDl (avian MyoD) in proliferative quail myoblasts, preserving transcription of T3 target genes. We found also that RXRg expression abrogates this positive interaction. These data suggest that T3 target genes expression involves different interactions with the T3 nuclear receptor during proliferation (no RXR expression) and differentiation (induction of RXR expression). Ln addition, we observed that, independently of the hormone presence, c-ErbAal inhibits CMDl and Myogenin. Furthermore, this influence involves two basic sequences of the hinge domain of the T3 receptor, probably inducing a physical interaction with similar sequences occurring in the myogenic factor. We found also that coexpression of RXR and c-Jun abrogates this influence. All these data suggest that sequestration of CMDl in a c-Erb/c-Jun/CMDl complex suggested by our previous data could preserve the duration of myoblast proliferation. RXR expression, in association to the increase in c-Jun protein levels observed in this study, could restore CMDl activity at the induction of differentiation. This study brings also evidence that c-Jun/ATF2 cooperation is increased at cell confluence versus c-Jun/c-Fos or c-Jun/Fra2 cooperation. In addition, we found that whereas c-Jun/c-Fos and c-
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Wallén, Åsa. "Some aspects of nuclear receptor function in the CNS : novel roles of Nurr1 and RXR in developing and mature neurons /." Stockholm, 2002.
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EGEA, PASCAL. "Etudes structurales des recepteurs nucleaires des retinoides : rxr et rar par diffusion aux petits angles et cristallographie des rayons x." Université Louis Pasteur (Strasbourg) (1971-2008), 1999. http://www.theses.fr/1999STR13131.
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Les recepteurs des retinoides rar et rxr sont des facteurs de transcription transduisant les effets pleiotropes des stereoisomeres 9-cis et tout-trans de l'acide retinoique. Les rar lient les deux isomeres alors que le rxr lie exclusivement le 9-cis. Nous avons resolu la structure cristallographique a 2. 5a de resolution du domaine de liaison du ligand du rxr1 humain complexe a son agoniste naturel ; cette structure revele les bases moleculaires de la selectivite entre recepteur et ligand. Dans le cristal le recepteur est sous forme monomerique adoptant une conformation canonique agoniste sans aucun contact direct etabli entre le ligand et l'helice h12 de transactivation. La comparaison avec la structure apo du rxr permet de decrire les changements conformationnels induits par le ligand et generant l'interface proteique fonctionnelle d'interaction recepteur/coactivateur. Cette structure permet de postuler l'existence d'une conformation agoniste commune a tout recepteur nucleaire. Les conformations en solution du rxr du rar et des heterodimeres rxr/rar ont ete etudiees par diffusion centrale des rayons x et des neutrons. Les conformations cristallographiques apo et holo des rxr et rar sont en accord avec celles observees en solution. La fixation du ligand provoque un compactage du domaine d'amplitude similaire a celle observee dans les structures cristallographiques. En solution le holo-rxr est un homodimere. Les heterodimeres rxr/rar sous trois etats distincts de saturation par les deux ligands naturels ont ete caracterises en solution ; la fixation selective des ligands sur les sous-unites induit un compactage progressif de l'heterodimere. La conformation en solution est en accord avec le mode d'association heterodimerique observe dans une structure cristallographique. Nous avons purifie deux complexes adn-proteine correspondants aux deux fragments multidomaines ab et de du rxr. Ces complexes adn-recepteur sont utilises dans des essais de cristallisation.
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Brocard, Jacques. "Mutagenese somatique conditionnelle chez la souris et controle spatio-temporel de l'inactivation du gene codant le recepteur des retinoides rxr alpha." Université Louis Pasteur (Strasbourg) (1971-2008), 1998. http://www.theses.fr/1998STR13235.
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Au cours de mon travail de these, j'ai participe au developpement d'un systeme de mutagenese somatique conditionnelle chez la souris utilisant la recombinase cre de bacteriophage p1. Cette enzyme excise tout fragment d'adn floxe c'est a dire encadre de sites specifiques appeles loxp. L'introduction de tels sites dans un gene d'interet par recombinaison homologue permet d'obtenir des animaux dont le genotype depend de la presence et de l'activite de la recombinase cre. Nous avons montre que ces deux parametres peuvent etre controles in vivo, en produisant des proteines de fusion entre la recombinase et le domaine de liaison au ligand de recepteurs steroidiens modifies. Les recombinases chimeriques obtenues sont inactives en absence de ligand ou en presence d'hormones naturelles mais excisent efficacement des sequences floxees placees dans le genome, en presence de ligand synthetique. L'utilisation de ces recombinases sous le controle de promoteurs specifiques chez la souris permet la regulation spatio-temporelle de l'inactivation de tout gene d'interet floxe, in vivo. Parmi les recepteurs nucleaires, le recepteur rxr alpha des retinoides (metabolites actifs de la vitamine a) joue un role majeur dans un grand nombre de voies de signalisation. La mort des mutants nuls pour ce recepteur au cours de leur developpement interdit l'attribution d'une fonction specifique a rxr alpha chez l'adulte. En revanche, l'introduction de sites loxp dans le gene codant ce recepteur permet de controler son expression in vivo via l'utilisation du systeme de mutagenese somatique decrit ci-dessus. L'inactivation conditionnelle du recepteur rxr alpha dans l'epiderme de souris adulte permet de preciser sa fonction de mediateur du signal retinoide dans ce tissu, en particulier dans les phenomenes d'hyper-proliferation induits par des applications de retinoides.
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Khilji, Saadia. "Dissecting the Epigenetic Signaling Underlying Early Myogenic Differentiation." Thesis, Université d'Ottawa / University of Ottawa, 2021. http://hdl.handle.net/10393/42092.
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Savage, Julie C. "Nuclear Receptors License Phagocytosis in Mouse Models of Alzheimer's Disease." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1430907654.
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Hamed, Munerah. "Characterization of the Epigenetic Signature Underlying Early Myogenic Differentiation." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39559.
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Although skeletal myogenesis is largely controlled by myogenic regulatory factors, epigenetic modifications have recently emerged as an essential regulatory mechanism of gene expression. Molecular regulation of stem cell differentiation is exerted through both genetic and epigenetic factors over distal enhancer regions. Understanding the mechanistic action of active or poised enhancers is therefore, imperative for the control of stem cell differentiation. Based on the genome-wide co-occurrence of different epigenetic marks in proliferating myoblasts, we have generated a chromatin state model to profile differentiation- and rexinoid-responsive histone acetylation in early myoblast differentiation. Here, we delineate the functional mode of transcription regulators during early myogenic differentiation using genome-wide chromatin state association. We define a role of transcriptional coactivator p300, when recruited by muscle master regulator MyoD, in the establishment and regulation of myogenic loci at the onset of myoblast differentiation. In addition, we reveal an enrichment of loci-specific histone acetylation at p300 associated active or poised enhancers, mainly when enlisted by MyoD. We have previously established that bexarotene, a clinically approved agonist of retinoid X receptor (RXR), promotes the specification and differentiation of skeletal muscle lineage. Hence, we investigated the genome-wide impact of rexinoids on myogenic differentiation and uncovered a new mechanism of rexinoid action, which is mediated by the nuclear receptor and largely reconciled through direct regulation of MyoD gene expression. In addition, we determined rexinoid-responsive residue-specific histone acetylation at a distinct chromatin state associated with MyoD and myogenin. Finally, through ChIP-seq and RNA-seq analyses, we have identified dystroglycan (Dag1) as a differentiation-dependent and a rexinoid-responsive model target, and we revealed a possible co-regulation of Dag1 by p300 and MyoD accompanied by enrichment of loci-specific histone acetylation. Taken together, we provide novel molecular insights into the regulation of myogenic enhancers by p300 in concert with MyoD. Furthermore, we provide novel mechanistic perceptions into the interplay between RXR signaling and chromatin states pertinent to myogenic programs in early myoblast differentiation. Our studies present a valuable insight for driving condition-specific chromatin state or enhancers pharmacologically to treat muscle-related diseases and for the identification of additional myogenic targets and molecular interactions for therapeutic development.
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Dubuquoy, Laurent. "Rôle de l'hétérodimère récepteur activé par les proliférateurs de peroxysomes gamma (PPARγ) / récepteur X des rétinoi͏̈des (RXR) au cours de l'inflammation intestinale." Lille 2, 2002. http://www.theses.fr/2002LIL2MT14.
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Le récepteur activé par le proliférateur des péroxysomes g (PPARg) est un récepteur nucléaire fortement exprimé dans le tissu adipeux et jouant un rôle crucial dans la différenciation adipocytaire. Des taux élevés de PPARg ont récemment été détectés dans le côlon. Pour être fonctionnel, PPARg doit former un hétérodimère avec le récepteur X des rétinoïdes (RXR). En réponse à la fixation de ligands, l'hétérodimère RXR/PPARg reconnaît son élément de réponse et active la transcription de nombreux gènes. PPARg a récemment été impliqué dans l'inflammation. Le but de notre travail était d'étudier le rôle et la régulation de PPARg au niveau du côlon au cours de processus inflammatoires. Notre étude a montré que le traitement de souris par des agonistes de PPARg et de RXR (rexinoïdes) diminuait significativement les lésions de colite induites chez la souris par un agent chimique (TNBS). La susceptibilité accrue des souris PPARg +/- et RXRa +/- confirmait le rôle anti-inflammatoire de l'hétérodimère RXR/PPARg. L'existence d'un effet synergique anti-inflammatoire des agonistes de PPARg et RXR ouvre de nouvelles perspectives encourageantes pour la prise en charge thérapeutique des pathologies inflammatoires coliques. La rectocolite hémorragique (RCH) et la maladie de Crohn (MC) sont deux maladies inflammatoires intestinales (MICI) dont l'étiologie est inconnue. Nous avons observé un déficit d'expression de PPARg par les cellules épithéliales coliques de patients atteints de RCH par rapport à des patients atteints de MC et des témoins. Nous avons montré que les bactéries intestinales ainsi qu'un de leur récepteur (TLR-4), augmentaient l'expression de PPARg dans le côlon. Ces résultats mettent en évidence que PPARg pourrait être un nouveau facteur de régulation de l'inflammation induite par les bactéries au niveau colique à l'origine de nouvelles pistes physiopathologiques dans la RCHThe peroxisome proliferator-activated receptor g (PPARg) is a nuclear receptor which is highly expressed in adipose tissue where it has a crucial role in adipogenesis. Recently, new sites of PPARg expression have been described especially in colon mucosa and new functions have been attributed in the regulation of inflammation. To activate transcription, PPARg requires heterodimerization with the retinoid X receptor (RXR). Proof of a role for the RXR/PPARg heterodimer in intestinal inflammation was limited to pharmacological studies demonstrating the efficacy of PPARg agonists. In a first study, we evaluated the involvement of both RXR and PPARg in intestinal inflammation. To this aim, colitis was induced by intra-rectal administration of trinitrobenzene sulfonic acid (TNBS) in mice. The intensity of colitis was evaluated in PPARg +/- and RXRa +/- mice and also after administration of selective RXR (rexinoid) and PPARg agonists. The intensity of colitis was evaluated by macroscopic and histologic scores and quantification of inflammatory mediators and the signaling pathway activation. Those experiments revealed that PPARg +/- and RXRa +/- mice both displayed an increased susceptibility to TNBS-induced colitis compared to WT mice. Colitis was significantly reduced by the administration of both PPARg and RXR agonists, reflected by increased survival rates and an improvement of the different biological parameters. When co-administered, a synergistic effect of PPARg and RXR ligands was observed. This first demonstration that RXR plays a role in intestinal homeostasis, as well as PPARg, opens a new field of investigation in a therapeutic point of view. Since PPARg is mainly expressed in the colon where bacteria are numerous, we hypothesized that intestinal flora and more particularly the major LPS receptor TLR-4 may modulate PPARg expression by colon epithelial cells. PPARg expression and gene were studied in patients with Crohn's disease (CD) and ulcerative colitis (UC), two inflammatory bowel diseases (IBD) resulting from an abnormal immune response against bacteria. Intestinal flora and TLR-4 induced PPARg expression in colon epithelial cells. While PPARg levels appeared normal in CD and controls, UC patients displayed an impaired expression of PPARg confined to colon epithelial cells without mutation in the PPARg gene. These data suggest that PPARg could be a new marker to diagnose UC and fueled speculations about the roles of this nuclear receptor in the physiopathology of UC
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Blumentrath, Jörg. "Wirkung von RAR- und RXR-Agonisten (Retinoiden) und einem PPAR[gamma]-Agonisten (Rosiglitazon) auf die Insulinsekretion, Proliferation und GLUT2 von INS-1-Zellen /." [S.l.] : [s.n.], 1999. http://www.gbv.de/dms/bs/toc/305260308.pdf.
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Lobato, Maria Inês Rodrigues. "Estudo de marcadores moleculares relacionados a cadeia dos retinóides (TTR e RXR[beta] e suas relações com endofenótipos clínicos e dismórficos em esquizofrenia)." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2004. http://hdl.handle.net/10183/5554.
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Solomin, Ludmila. "Nuclear hormone receptor signaling in the developing CNS : studies on the retinoid receptors RAR and RXR, and the orphan receptors NURR1, NOR1 and NGFI-B /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3663-3/.
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Ouadah-Boussouf, Nafia. "Analyse in vivo de la dynamique du tissu adipeux blanc après exposition à des polluants chimiques ou à des molécules pharmacologiques chez le poisson zèbre." Thesis, Bordeaux 1, 2012. http://www.theses.fr/2012BOR14755/document.
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Un régime alimentaire déséquilibré et/ou la présence de composés contaminantsexogènes peuvent modifier la signalisation endocrine et l’homéostasie des lipides et induirel’obésité. Les travaux réalisés dans le cadre de cette thèse ont permis, dans un premier temps,de développer une méthode simple et rapide, dénommée "zebrafish obesogenic (ZO) test",pour identifier in vivo, par utilisation de la larve de poisson zèbre, des facteurs qui peuventaugmenter ou diminuer la taille de l’adipocyte blanc et ainsi moduler le niveau de l’adiposité(Tingaud-Sequeira, Ouadah, Babin, J. Lipid Res. 52, 1765-1772, 2011). Ce test permetd’identifier des composés et des mélanges de molécules obésogènes et anti-obésogènes etfournit des informations pertinentes pour l'évaluation des risques liés leur présence maiségalement pour élucider les mécanismes impliqués. Les travaux ont, dans un second temps,permis d’apporter des réponses quant aux modalités d’action d’un obésogène puissant, lechlorure de tributylétain, contaminant retrouvé très largement dans notre environnement.Cette molécule agit sur l’adipocyte blanc à une concentration de l’ordre du nano molaire viales récepteurs nucléaires RXR et LXR, et non pas via les isoformes PPARgamma/delta(Ouadah et Babin, manuscrit en préparation)An unbalanced diet and / or the presence of exogenous compounds contaminants mayalter endocrine signaling and lipid homeostasis and induce obesity. The work done in thisthesis have, at first, developed a simple and rapid method, called "zebrafish obesogenic (ZO)test" to identify in vivo by using the zebrafish larva, the factors that may increase or decreasethe size of the white adipocyte and therefore modulate the level of adiposity (Tingaud-Sequeira, Ouadah, Babin, J. Lipid Res. 52, 1765-1772, 2011). This test helps to identifycompounds and mixtures of obesogenic and anti-obesogenic molecules and providesinformation relevant to the risk assessment of their presence but also to elucidate themechanisms involved. Work in a second time allowed to answer as to how the action oftributyltin chloride, a powerful obesogenic contaminant found widely in the environment.This molecule acts in vivo on white adipocytes in a concentration of the order of nano molarvia nuclear receptors LXR and RXR, and not via the PPARgamma isoforms / delta (Ouadahand Babin, manuscript in preparation)
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Beyer, Christine. "Der Einfluss von all-trans-Retinol, 13-cis-Retinsäure, Methanol und TSH unter verschiedenen Kulturbedingungen auf den 125I-Stoffwechsel von kultivierten Thyreozyten und deren RAR alpha- und RXR alpha- Rezeptoren." [S.l. : s.n.], 2004. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB11312764.
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Taylor, Jennifer. "Engineering and improving a molecular switch system for gene therapy applications." Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/39501.
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Molecular switch systems that activate gene expression by a small molecule are effective technologies that are widely used in applied biological research. Previously, two orthogonal ligand receptor pairs (OLRP) were developed as potential molecular switch systems by modifying nuclear receptors, ligand-activated transcription factors, to bind and activate gene expression with the synthetic ligand LG335 and not with the natural ligand 9-cis retinoic acid (9cRA). The two OLRP previously discovered were RXR variant 130 (I268A, I310A, F313A, and L436F) (also known as GR130) and the RXR variant QCIMFI (Q275C, I310M, and F313I) and (also known as GRQCIMFI).
The OLRP were further developed into molecular switches to provide controlled gene expression and potentially benefit gene therapy applications by replacing the DNA binding domain (DBD) with a Gal4 DBD, a yeast transcription factor. Both molecular switches are able to bind Gal4 RE in response to LG335 and activate expression of a luciferase or GFP reporter gene in either a two- or one-component system. When characterizing the GR130 variant in the two-component system, no activation was observed with the natural ligand 9cRA, and the variant displayed a 19±5-fold activation and a 50 nM EC50 value in the presence of LG335. When the GRQCIMFI variant was evaluated in the two-component system, activation was observed in the presence of LG335 with a 10 nM EC50 value and a 6±2-fold induction, and 9cRA induced activation only at the highest concentration. The GRQCIMFI variant was also characterized with the one-component system containing the reporter gene GFP in a transient transfection as well as through retroviral transduction, displaying green fluorescence in 30% of the cells in the presence of 10 µM LG335.
Several attempts were made to improve the molecular switch system. The VP16 activation domain was fused to GRQCIMFI in an effort to increase the fold induction; however, the addition of the VP16 created a constitutively active protein. Another approach to improve the molecular switch incorporated error-prone PCR to discover a new variant, Q275C, I310M, F313I, L455M (QCIMFILM), which displayed a 10-fold increase in sensitivity towards LG335 with a 5 nM EC50 value. Examination of the L455 position in the crystal structure of RXR revealed this residue is located outside of the ligand binding pocket on helix 12 (H12), but is able to significantly enhance receptor function. In fact, the single variant, L455M, was able to enhance receptor activation, compensate for a nonfunctional variant, as well as influence coactivator association.
The long-term goal of this research is to develop a gene regulation system that would be used in human gene therapy trials. In the process of creating this system a deeper assessment of the nuclear receptor structure and function is made, which can be used for the enhancement and development of transcriptional regulation mechanisms.