La progéria est une maladie génétique rare caractérisée par un vieillissement global, prématuré et accéléré entrainant le décès des enfants atteints aux alentours de l’âge de 13 ans. La compréhension des mécanismes moléculaires à l’origine de ce syndrome ont récemment permis de démarrer deux protocoles d’essai clinique, avec un objectif commun : ralentir la progression de la maladie en bloquant la maturation de la protéine mutée. Cependant, l’identification de nouvelles voies thérapeutiques reste encore, pour cette pathologie, un défi à relever. L’objectif de ce travail de thèse a consisté à utiliser le potentiel unique des cellules souches induites à la pluripotence (iPSCs) pour explorer les mécanismes cellulaires et moléculaires de ce syndrome, identifier de nouvelles cibles thérapeutiques et proposer des pistes innovantes de traitement.La première étape de cette thèse s’est consacrée à la dérivation et la caractérisation des lignées d’iPSCs à partir de cellules de patients atteints par ce syndrome. De manière surprenante,cette étude a mis en évidence une préservation des neurones générés à partir d’iPSCs de patients progeria. L’étude des mécanismes moléculaires à l’origine de cette protection neuronale a par la suite permis d’identifier l’implication d’un microARN, miR-9, capable de réguler l’expression de la progérine et de protéger les neurones de ce vieillissement accéléré. La seconde partie de ces travaux de thèse s’est attachée à explorer le potentiel de ces cellules pour étudier l’efficacité des composés proposés aux patients dans le cadre des différents essais cliniques réalisés ces dernières années. Bien que l’ensemble des molécules testées améliore de façon significative les défauts de structuration de l’enveloppe nucléaire, nos travaux soulignent un certain nombre de différences fonctionnelles tant au niveau de leurs effets sur la prolifération cellulaire que sur la différentiation ostéogénique ou encore le métabolisme énergétique. Enfin, sur la base de ce travail de modélisation pathologique, la dernière partie de ce projet de thèse a eu pour objectif de développer et réaliser un criblage à haut contenu de plus de vingt mille petites molécules pouvant réguler le processus de maturation de la prélamine A. Au cours de cette étude, onze composés à fort potentiel thérapeutique ont été identifiés, dont trois appartenant à la même famille chimique, les mono-aminopyrimidines, ouvrant de nouvelles perspectives thérapeutiques dans la progéria. / Progeria is a rare genetic disease characterized by a global, premature and accelerated aging, leading to patient death at average 13 years old. The understanding of the molecular mechanism of this syndrome has recently opened the possibility to start two clinical trials, with one common objective: slow down the disease progression blocking the maturation of the mutated protein. However, the identification of new therapeutic pathway is still a challenge to rise for this pathology. The objective of this PhD thesis has consisted to use the unique potential of induced pluripotent stem cells (iPSCs) to explore cellular and molecular mechanisms of this syndrome, identify new therapautical target and propose innovative trails of treatment. The first step of this thesis was focused on the derivation and the characterization of the iPSCs lines from patient's cells affected by this syndrome. In a surprising manner, this study has highlighted a preservation of neurons generated from progeria patients. The study of the molecular mechanisms led to the identification of the microRNA miR-9 involvement. This latter regulates progerin expression, protecting neurons from accelerated aging. The second part of this work has endeavored to explore the potential of progeria iPSCs to study the efficiency of chemical compounds proposed to patients in the different clinical trials realized these last years. Although the set of tested molecules significantly improved nuclear architecture, differences in proliferation or in osteogenic differentiation or in metabolic energetic have been detected. Finally, on the basis of this pathological modeling work, the last part of this thesis praject was to develop and realize a high content screening of more than twenty thousand small molecules to select drugs which block the maturation process of prelamin A. Eleven molecules with a high therapeutical potential have been identified, with three belonging to the same chemical family, the mono-aminopyrimidins, opening new therapeutical perspectives in progeria.

Heidelberg, University, Diss., 2001.

Made available in DSpace on 2014-06-11T19:25:35Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-08-03Bitstream added on 2014-06-13T20:14:13Z : No. of bitstreams: 1 000739847.pdf: 1497375 bytes, checksum: 323121923378634f36af730ba11e938a (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Proposição: As células epiteliais das vias respiratórias desempenham uma importante função na patogênese da asma. Elas são responsáveis pela liberação de mediadores químicos ativadores do sistema imunológico na resposta inflamatória das vias aéreas. Citocinas e quimiocinas produzidas por leucócitos ativam as células estruturais dos brônquios e incitam a síntese de outros mediadores químicos que potencializam a inflamação no local. A interleucina-9 (IL-9) é uma importante citocina ativadora das células epiteliais, regula a produção de muco e induz a expressão de quimiocinas e citocinas. Os objetivos deste estudo foram investigar se células epiteliais de pulmão murino (LA-4) estimuladas com a citocina IL-9 produzem a quimiocina do timo regulada por ativação (CCL17/TARC) e o mediador lipídico leucotrieno-C4 (LTC4), e quais vias de sinalização intracelular estariam envolvidas nesse processo. Julga-se que as proteínas quinases desempenhem uma função primordial na expressão e ativação de citocinas e quimiocinas nas vias aéreas, portanto, foi investigada a função da p38 proteína quinase ativada por mitógeno (MAPK), MAPK p42/44, e fosfatidilinositol 3-quinase (PI3K) sobre o efeito da IL-9 na expressão da quimiocina CCL17/TARC em células LA-4. Abordagem experimental: a expressão de CCL17/TARC por LA-4 foi avaliada utilizando Reação em Cadeia da Polimerase Transcriptase Reversa (RT-PCR). A produção de leucotrieno C4 (LTC4) e CCL17/TARC foi avaliada por ELISA. As células LA-4 foram pré-tratados com o antagonista do receptor de cisteinil leucotrieno (CysLT) (MK 571) (10 μM), com o inibidor da p42/44 MAPK (PD98059) (30 μM), inibidor... / Background and propose: The airway epithelial cells play an important role in the pathogenesis of asthma, are responsible for the release of chemical mediators of the immune system triggers inflammation in the airways. Cytokines and chemokines produced by leukocytes activate structural bronchial cells and induce the synthesis of other chemical mediators which enhance the site inflammation. Interleukin-9 (IL-9) is an important cytokine activating epithelial cells, regulating mucus production and induces the expression of chemokines and cytokines. The objectives of this study were to investigate whether murine lung epithelial cells (LA-4) IL-9-stimulated produce the thymus and activation-regulated chemokines (CCL17/TARC) and lipid mediator leukotriene-C4 (LTC4) and what intracellular signaling pathways would be involved in this process. Kinases are believed to play a crucial role in the expression and activation of cytokines and chemokines in the airways. Therefore the role of p38 mitogen-activated protein kinase (MAPK), p42/44 MAPK, and phosphatidylinositol 3-kinase (PI3K) upon the effect of IL-9 on the CCL17/TARC expression in murine lung alveolar epithelial cells (LA-4) was investigated. Experimental approach: CCL17/TARC expression in LA-4 was evaluated using Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). Leukotriene C4 (LTC4) and CCL17/TARC production were assessed by ELISA. LA-4 had been pre-treated with cysteinyl leukotriene receptor antagonist (CysLT) (MK 571) (10 μM), p42/44 MAPK inhibitor (PD98059) (30 M), p38 MAPK inhibitor (SB203580) (30 M), and PI3K inhibitor (Wortmannin) (0.1 M) 30 min prior to IL-9 (40 ng.mL-1) stimulation. Key results: IL-9-stimulated LA-4 induced CCL17/TARC mRNA expression after 24 hours. PD98059 and...

Orientador: Sandra Helena Penha de Oliveira / Banca: Lucia Helena Faccioli / Banca: Ana Paula Campanelli / Resumo: Proposição: As células epiteliais das vias respiratórias desempenham uma importante função na patogênese da asma. Elas são responsáveis pela liberação de mediadores químicos ativadores do sistema imunológico na resposta inflamatória das vias aéreas. Citocinas e quimiocinas produzidas por leucócitos ativam as células estruturais dos brônquios e incitam a síntese de outros mediadores químicos que potencializam a inflamação no local. A interleucina-9 (IL-9) é uma importante citocina ativadora das células epiteliais, regula a produção de muco e induz a expressão de quimiocinas e citocinas. Os objetivos deste estudo foram investigar se células epiteliais de pulmão murino (LA-4) estimuladas com a citocina IL-9 produzem a quimiocina do timo regulada por ativação (CCL17/TARC) e o mediador lipídico leucotrieno-C4 (LTC4), e quais vias de sinalização intracelular estariam envolvidas nesse processo. Julga-se que as proteínas quinases desempenhem uma função primordial na expressão e ativação de citocinas e quimiocinas nas vias aéreas, portanto, foi investigada a função da p38 proteína quinase ativada por mitógeno (MAPK), MAPK p42/44, e fosfatidilinositol 3-quinase (PI3K) sobre o efeito da IL-9 na expressão da quimiocina CCL17/TARC em células LA-4. Abordagem experimental: a expressão de CCL17/TARC por LA-4 foi avaliada utilizando Reação em Cadeia da Polimerase Transcriptase Reversa (RT-PCR). A produção de leucotrieno C4 (LTC4) e CCL17/TARC foi avaliada por ELISA. As células LA-4 foram pré-tratados com o antagonista do receptor de cisteinil leucotrieno (CysLT) (MK 571) (10 μM), com o inibidor da p42/44 MAPK (PD98059) (30 μM), inibidor... / Abstract: Background and propose: The airway epithelial cells play an important role in the pathogenesis of asthma, are responsible for the release of chemical mediators of the immune system triggers inflammation in the airways. Cytokines and chemokines produced by leukocytes activate structural bronchial cells and induce the synthesis of other chemical mediators which enhance the site inflammation. Interleukin-9 (IL-9) is an important cytokine activating epithelial cells, regulating mucus production and induces the expression of chemokines and cytokines. The objectives of this study were to investigate whether murine lung epithelial cells (LA-4) IL-9-stimulated produce the thymus and activation-regulated chemokines (CCL17/TARC) and lipid mediator leukotriene-C4 (LTC4) and what intracellular signaling pathways would be involved in this process. Kinases are believed to play a crucial role in the expression and activation of cytokines and chemokines in the airways. Therefore the role of p38 mitogen-activated protein kinase (MAPK), p42/44 MAPK, and phosphatidylinositol 3-kinase (PI3K) upon the effect of IL-9 on the CCL17/TARC expression in murine lung alveolar epithelial cells (LA-4) was investigated. Experimental approach: CCL17/TARC expression in LA-4 was evaluated using Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). Leukotriene C4 (LTC4) and CCL17/TARC production were assessed by ELISA. LA-4 had been pre-treated with cysteinyl leukotriene receptor antagonist (CysLT) (MK 571) (10 μM), p42/44 MAPK inhibitor (PD98059) (30 M), p38 MAPK inhibitor (SB203580) (30 M), and PI3K inhibitor (Wortmannin) (0.1 M) 30 min prior to IL-9 (40 ng.mL-1) stimulation. Key results: IL-9-stimulated LA-4 induced CCL17/TARC mRNA expression after 24 hours. PD98059 and... / Mestre

No description available.

La pop culture japonaise (principalement le manga et l’animation), connaît en France un succès durable depuis plus de trente ans, et attire un public croissant, composé en partie de passionnés très investis. Par ailleurs, cette diffusion n’est pas uniquement circonscrite à la France, il s’agit aujourd’hui d’un succès mondial, avéré et reconnu depuis le début du 21ème siècle.C’est dans ce contexte que s’inscrit cette thèse, qui s’efforce de montrer comment se fait la relation entre goût pour la pop culture nippone, imaginaire du Japon et désir de voyage. Nous nous intéresserons donc aux fans devenus touristes, qui mobilisent pour ce séjour les images qu’ils ont élaborés du Japon via la familiarité entretenue avec sa pop culture. Prenant pour modèle le cadre de l’anthropologie du tourisme, cette présentation se fera en trois parties, qui correspondent aux trois temps du voyage. Tout d’abord, nous nous intéresserons à l’avant-voyage, moment où s’élabore l’imaginaire d’une destination. Nous nous pencherons ensuite sur le temps du séjour, pendant lequel les visiteurs jouent le jeu de l’immersion en superposant images préalables et expérience en situation. Enfin, nous aborderons l’après-voyage, en essayant de comprendre comment ce phénomène fait écho sur le territoire japonais, et engendre reconnaissance et légitimation des productions de pop culture, qui est alors comprise comme un témoignage de la spécificité de l’identité japonaise.Le fil conducteur de cette recherche est donc la légitimation de la pop culture, qui passe par son plébiscite en dehors de l’Archipel, dans un mouvement de reconnaissance qui entremêle regards étrangers et autochtones. / Japanese pop culture (manga and animation) has been successful in France for more than thirty years now, and it attracts more and more audience, with very deep lovers as a part of it. Anyway, this diffusion is not only a French phenomenon, as it has been a recognized and acknowledged success since the beginning of the 21st century.This is the frame of this research, which aims to show how the taste for Japanese pop culture, the imaginary of the country and the desire to visit it are linked. We will look at fans of Japanese pop culture and how they become tourists, since they use for the travel the pictures they have built about Japan through their strong intimacy with its pop culture.Taking the anthropology of tourism as a model, this presentation is divided in three parts, which are the three moments of a travel. Firstly, we are going to look at the moment before the trip, when the imaginary of the place is built. Then, we will move during the stay, when travelers are trying to immerge themselves in the country, using their previous picture of place and superimposing it to their concrete experience. So, we will conclude with the third stage, after the stay, trying to understand how this phenomenon is echoing into Japanese territory. We will see that it creates a sort of legitimization of the pop culture and its objects, which becomes a testimony of the Japanese cultural identity.The conducting thread of this research is then that legitimization of the Japanese pop culture, which is allowed by that praise outside of Japan, in a movement of recognition, when foreign and local looks are intertwining.

Pas de résumé / The aim of the study was to evaluate in controlled retinal risk LED lighting conditions compared to other common household lighting such as CCFL or CFL, in standard lighting conditions, on different animal species pigmented and non-pigmented. At first, we characterized the conditions of adaptation before enlightenment. We found that housing conditions before the light exposure is a source of artifact. Indeed, the location of the cages in a ventilated cabinet and the period before stalling before illumination generates a variable response to retinal light toxicity. Then, we tested the relative sensitivity of the albino strains and pigmented. After 3 weeks of stabulation, the animals were exposed for 24 hours to cold white LED at a luminance of 6000 lux, with dilation of pupils, and the retinas were examined in a week. In these extreme illumination conditions, retinas showed a significant loss of photoreceptors in superior retina, not only in albino animals, but also in pigmented animals. In another experiment, we tested different luminance in cages provided for this purpose. We have used as control a compact fluorescent lighting at 500 lux, with a homogeneous on the floor of the cage. An illumination of 24 hours dilation was performed after the time of dark adaptation. A luminance of 500 lux is a classic condition of a good visual quality domestic lighting. Unlike a compact fluorescent lighting at 500 lux, white LEDs result in a significant loss of photoreceptor nuclei of retinal pigmented rats (LE) 500 lux with an increasing toxicity in function of the luminance of the LED lighting. Finally, to assess the effects prolonged exposure we exposed the rats for one week or one month, but in alternating illumination only during the day, and without dilated pupils (day / night cycle 12h / 12h, no dilated pupils) with LED different spectra. We have compared these lighting conditions to a compact fluorescent lighting at 500 lux and non-illuminated rats. After one week, only albino rats showed a loss of photoreceptors and only after exposure to blue LEDs. These results show that the blue LEDs are more toxic than the white LEDs confirming the effects of short wavelengths. After 1 month of illumination, a significant loss of photoreceptors is observed in the retinas of non-pigmented rats, not only with the blue LEDs, but also with green LEDs and cool white LEDs. An increase of the exposure time under standard conditions leads to a loss of photoreceptors accumulated suggesting a potentially toxic effect of LED light, not observed with a compact fluorescent lighting even luminance.

My dissertation is the first empirically based study to closely examine the impacts of 9/11 on Canadian Muslim youth. It develops a critical analysis of how the general public supported by state practices, undermine the citizenship of Canadian Muslims, thereby impacting their identity formation. Conducting qualitative analysis, through the use of 50 in-depth interviews with Canadian Muslim men and women, aged 18 to 30, I have arrived at several important findings. These include findings related to citizenship, the racialization of gender identities and identity formation. First, despite having legal citizenship, Canadian Muslims often do not have access to substantive citizenship (the ability to exercise rights of legal citizenship), revealing the precarious nature of citizenship for minority groups in Canada. My research shows that the citizenship rights of Canadian Muslims may be undermined because they do not have access to allegiance and nationality, important facets of citizenship. Second, young Canadian Muslims are racialized and othered through increasingly stereotypical conceptions about their gender identities. Muslim men are perceived as barbaric and dangerous and Muslim women are imagined as passive and oppressed by their communities. As a result of these dominant conceptions, in their struggle against racism, young Canadian Muslims have to invest a great deal of time establishing themselves as thinking, rational, educated and peaceful persons. Third, to cope with their marginalization, many young Canadian Muslims have asserted their Muslim identities. In order to understand this social process, I extend the work done on ‘reactive ethnicity’ and theorize Muslim identity formation in a post 9/11 context, something not yet been done in academic literature. To do so, I coin the term ‘reactive identity formation,’ and illustrate that the formation of reactive identities is not limited to strengthening ethnic identity and that religious minority groups can experience a similar phenomenon. Furthermore, I find that while claiming their Muslim identity, most of my interviewees also retain their Canadian identity in order to resist the notion that they are not Canadian. By doing so, they attempt to redefine what it means to be Canadian.

My dissertation is the first empirically based study to closely examine the impacts of 9/11 on Canadian Muslim youth. It develops a critical analysis of how the general public supported by state practices, undermine the citizenship of Canadian Muslims, thereby impacting their identity formation. Conducting qualitative analysis, through the use of 50 in-depth interviews with Canadian Muslim men and women, aged 18 to 30, I have arrived at several important findings. These include findings related to citizenship, the racialization of gender identities and identity formation. First, despite having legal citizenship, Canadian Muslims often do not have access to substantive citizenship (the ability to exercise rights of legal citizenship), revealing the precarious nature of citizenship for minority groups in Canada. My research shows that the citizenship rights of Canadian Muslims may be undermined because they do not have access to allegiance and nationality, important facets of citizenship. Second, young Canadian Muslims are racialized and othered through increasingly stereotypical conceptions about their gender identities. Muslim men are perceived as barbaric and dangerous and Muslim women are imagined as passive and oppressed by their communities. As a result of these dominant conceptions, in their struggle against racism, young Canadian Muslims have to invest a great deal of time establishing themselves as thinking, rational, educated and peaceful persons. Third, to cope with their marginalization, many young Canadian Muslims have asserted their Muslim identities. In order to understand this social process, I extend the work done on ‘reactive ethnicity’ and theorize Muslim identity formation in a post 9/11 context, something not yet been done in academic literature. To do so, I coin the term ‘reactive identity formation,’ and illustrate that the formation of reactive identities is not limited to strengthening ethnic identity and that religious minority groups can experience a similar phenomenon. Furthermore, I find that while claiming their Muslim identity, most of my interviewees also retain their Canadian identity in order to resist the notion that they are not Canadian. By doing so, they attempt to redefine what it means to be Canadian.

No description available.