Made available in DSpace on 2014-07-29T16:25:14Z (GMT). No. of bitstreams: 1 Dissertacao_Mestrado_Aline_Faria.pdf: 2562180 bytes, checksum: 9fa5ff2aaca58f1e432aee4a2fb0428e (MD5) Previous issue date: 2009-03-27 / The present research aims at describing the integration process among the artistic languages taking place in some schools in Goiânia. They are: Centro de Ensino e Pesquisa Aplicado à Educação Cepae/UFG (regular school), Centro Livre de Artes CLA (public school for the teaching of Arts) and Mvsika! Centro de Estudos (private school for the teaching of Arts). Thus the main theme in this work is the integrated arts. The option for such an approach is not based on a devaluation of the musical education or any other specific area of the artistic education. The work seeks a contextualization of education through art that takes into account the current needs and changes influenced by globalization and the efficiency of the information which has made the individual more demanding and thirsty for something creative and different. This integration can happen in many ways, which have been described as pluridisciplinarity, interdisciplinarity, and transdisciplinarity. Some principles, defended by specialists, can help to understand each of these integration forms and, in this work, give support to the description and analysis of the integrative processes. This study seeks to describe and to analyze the practices that involve this integrative methodology in three schools of Goiânia, presenting three case studies. In each of them, the specific characteristics and the coherence level between the concepts and the practice of the educators stand out. From the theoretical reference of this research, it is possible to distinguish the presence of principles that classifies the practices as integrative and that help to define the integration form proposed. These practices are described considering, also, the situation of the integrative experiences in other places around Brazil. To do so, contact with educators (ANPPOM, ABEM, FAEB) that work with integrated artistic languages was attempted. Although only a few answers were received, the information obtained help for a better understanding of the data collected in the schools of Goiania. Considering the description of the reality of each school, relations between the information obtained through observation and the questionnaire are established, which brings a broader view of each process. Finally, the specificity of each practice is focused, as well as the common aspects of all of them, of what brings them together or draws them apart from the theoretical reference of this work and the practices described by educators of other parts of Brazil. / A presente pesquisa teve como objetivo descrever os processos de integração entre as linguagens artísticas que ocorrem em algumas escolas de Goiânia. São elas: Centro de Ensino e Pesquisa Aplicado à Educação Cepae/UFG (escola regular), Centro Livre de Artes CLA (escola pública de ensino específico de artes) e Mvsika! Centro de Estudos (escola particular de ensino específico de artes). Portanto, o tema central do trabalho são as artes integradas. A opção por tal abordagem não se baseia numa desvalorização da educação musical ou de qualquer outra área específica da educação artística. Busca-se uma contextualização da educação pela arte que leve em consideração as necessidades e mudanças na atualidade, influenciada pela globalização e pela agilidade das informações, que tornam o indivíduo mais exigente e sedento de algo criativo e diferenciado. Essa integração pode ocorrer de várias formas, que vêm sendo descritas como pluridisciplinaridade, interdisciplinaridade e transdisciplinaridade. Há princípios, defendidos por estudiosos do assunto, que auxiliam na compreensão de cada uma dessas formas de integração e que, nesse trabalho, dão suporte à descrição e análise dos processos integrativos. Este estudo busca, portanto, descrever e analisar as práticas que envolvem essa metodologia integrativa em três escolas de Goiânia, apresentando três estudos de caso. Em cada um deles, ressaltam-se as características específicas e o nível de coerência entre os conceitos e a prática dos educadores. A partir do referencial teórico do trabalho, destaca-se, em cada prática, a presença de princípios ou subsídios que as caracterizem como integrativas e que ajudam a definir a forma de integração proposta. Tais práticas são descritas considerando, também, a situação em que se encontram as experiências integrativas em outros lugares do Brasil. Para tanto, tentou-se estabelecer contatos com educadores (ANPPOM, ABEM, FAEB) que trabalhassem com as linguagens artísticas de forma integrada no Brasil. Apesar do pequeno número de respostas recebidas, as informações obtidas auxiliam numa melhor compreensão dos dados coletados nas escolas goianas. Tendo em vista a descrição da realidade de cada escola, estabelecem-se relações entre as informações obtidas através das observações das aulas e dos questionários, o que possibilita uma visão mais abrangente de cada processo. Ao final, ressalta-se não apenas a especificidade de cada prática, mas, também, os aspectos comuns a todas ou, ainda, aquilo que as aproxima ou distancia do referencial teórico do trabalho e das práticas relatadas por educadores de outras partes do país

Com a Política Nacional de Educação Especial na perspectiva da Educação Inclusiva (2008), as escolas regulares vêm recebendo um número maior de estudantes surdos ou com deficiência auditiva (S/DA), que antes frequentavam escolas especializadas. No entanto, dados apontam a diminuição do número de estudantes S/DA matriculados no ensino fundamental para o ensino médio, e do ensino médio para o ensino superior; ou seja, existem razões para se acreditar que barreiras educacionais se impõem no caminho desses estudantes para que conquistem uma formação educacional completa. Neste contexto, o objetivo deste trabalho é propor um modelo de aceitação de tecnologias levando em consideração fatores que envolvam aspectos do contexto da educação inclusiva, bem como efetuar experimento da interação de usuários S/DA com uma tecnologia para avaliar o modelo. Dentre os fatores mencionados um deles se refere às potenciais barreiras educacionais vivenciadas pelos estudantes S/DA em salas de aula inclusivas. Com relação à metodologia de pesquisa, o estudo desenvolveu-se em ciclos. Na medida em que as investigações avançavam, um novo estudo iniciava, se desenvolvia e se fechava. Isso permitiu que a proposta inicial tivesse sucessivos refinamentos ao longo do tempo até o ponto em que os questionamentos iniciais foram respondidos e o objetivo foi atingido. O modelo proposto mostrou resultados positivos, no sentido de conseguir capturar os fatores que podem influenciar a aceitação de tecnologias considerando o contexto de aplicação específico, uma vez que estes incorporam os aspectos da qualidade pragmática e os aspectos da qualidade hedônica, questões relacionadas à utilidade percebida da minimização de potenciais barreiras educacionais, expectativas futuras, e condições facilitadoras. Conclui-se que o modelo engloba tanto a investigação sobre questões motivacionais pessoais dos usuários quanto a investigação de aspectos do contexto de uso, e que o modelo pode ser utilizado para a finalidade a qual foi proposto, a avaliação de aceitação de tecnologias em ambientes de educação incluvisa. / With the foundation of the National Policy on Special Education on the Perspective of Inclusive Education (2008), mainstream schools are receiving a greater number of deaf or hard of hearing (D/HH) students, that once before were attending specialized schools. However, data point to the declining number of D/HH students enrolled from primary school to high school, and from high school students to higher education; ie, there are reasons to believe that educational barriers are imposed on the way of these students to conquer a complete education. In this context, the goal of this work is to propose a technology acceptance model that takes into account factors that ivolve aspects of the inclusive education context, as well as performing experiment on the interaction of D/HH users with a technology to evaluate the model. Among the factors, one of them refers to the potential educational barriers experienced by D/HH students in inclusive classrooms. With regard to research methodology, the study was developed in cycles. To the extent that the investigations progressed, a new study began, was unfolded and closed. This allowed successive refinements over time to the point where the initial questions were answered and the goal was reached. The proposed model has shown positive results in capturing factors that influence technology acceptance given the domain specific context, since they incorporate aspects of pragmatic quality and hedonic quality, also issues related to perceived usefulness in minimizing potential educational barriers, future expectations, and facilitating conditions. We conclude that the model encompasses both users personal motivation and context of use aspects, and the model can be used for the purpose for which it was proposed, technology acceptance evaluation considering inclusive education contexts.

In Fred Chappell’s Kirkman tetralogy, narrator Jess Kirkman synthesizes a multiplicity of perspectives for understanding the nature of truth. Blurring the distinction between art and life, Jess's narrative structure mirrors the imaginative reconstruction of experience; the novels are largely non-chronological emotive interactions with and reflections of his most salient memories and imaginings. Synthesizing an impressive cacophony of voices, Jess's stories both describe and apply the wisdom and tales Jess acquires from and with his family members. Each story informs the prior and the next, and the rhizomatic interaction between language, narrative, and reader explores Jess's numerous identities and understandings as narratives venture through space, time, and imagination.

<p>Syftet med denna uppsats är att utforska socialtjänstens arbete med brottsoffer i Sverige enligt 5 kapitlet 11 § i socialtjänstlagen. I studien undersöktes hur socialsekreterare definierar brottsoffer samt hur de bedömer och prioriterar offrens behov. Det har också varit centralt att studera hur socialsekreterare tolkar och förstår regleringen av socialtjänstens ansvar för brottsoffer. Kvalitativa intervjuer med 18 socialarbetare är grunden för studien. Analysen av socialtjänstens arbete med brottsoffer baseras på ovan nämnda intervjuer. Intervjuerna analyseras med hjälp av rättssociologiska teorier. För att illustrera hur socialsekreterare definierar brottsoffer har teorier om brottsoffer använts i analysen. Studien visar att ett brottsoffer måste vara oskyldig, svag och lida av brottet för att personen skall definieras som brottsoffer av socialsekreterarna. Socialsekreterarna har dock olika prioriteringar. Vissa socialsekreterare baserar sin bedömning efter varje enskilt fall, medan andra socialsekreterare anser att det är specifika målgrupper som ska få hjälp av socialtjänsten. Undersökningen visar också att de brottsoffergrupper som främst får hjälp inom socialtjänsten kvinnor och barn som fallit offer för våld i nära relationer. Stöd till brottsoffer som ges genom socialtjänstens arbete är ofta i syfte för att anpassa de kvinnor och barn som utsätts för våld, såsom kvinnojourer, rådgivning och ekonomiskt stöd.</p> / <p>The purpose of this essay is to explore the social services work with crime victims in Sweden, according to Chapter 5, § 11 of the Social Services Act. The study examined how social workers define the victim and assessing and prioritizing victims' needs. It has also been central to study how social workers interpret and understand the regulation of social services responsible for crime victims. Qualitative interviews with 18 social workers is the basis for the study. The analysis of the social services work with victims based in the above-mentioned interviews. The interviews analyzed using the sociology of law theory. To illustrate how social workers define victims of crime have theories of crime victims been used in the analysis.</p><p>The study shows that a crime victim must be innocent, weak and suffering from the crime to be defined as crime victims by social secretaries. Social workers do, however, different priorities. Some are based on an assessment of each individual victims need help, while others believe that the specific target groups will be using social services. The study also indicates that the groups which mainly receive help in the social services are victims of violence women and children. Assistance to victims in the social services designed to adapt the groups exposed to violence against women and children, such as women’s shelters, counseling and financial help.</p>

Tyrimo tikslas – įvertinti neformaliojo ugdymo pedagogų profesinių kompetencijų raišką procese. Darbe iškeltas tikslas konkretizuojamas su šiais uždaviniais: atskleistos ir apibūdintos neformaliojo ugdymo institucijų pedagogų kompetencijų raiškos teorinės prielaidos, įvardintos ir išanalizuotos devynios neformaliojo ugdymo pedagogų kompetencijos:pedagoginis išprusimas, veiklos prognozavimas ir planavimas, ugdymo proceso organizavimas, pedagoginis bendravimas ir bendradarbiavimas, kūrybinė, asmeninė, edukacinė, socialinė ir profesinė. Remiantis Vyriausybės nutarimais, aptartos visos svarbiausios su nagrinėjama tema susijusios sąvokos, vadovaujantis švietimo sistemos lygių galimybių, kontekstualumo, veiksmingumo, tęstinumo principais, švietimo tikslais ir uždaviniais. Pagal iš anksto susidarytą tyrimų programą buvo atliktas diagnostinis tyrimas, įgyvendinti iškelti tyrimo programoje tikslas ir uždaviniai, sudaryti klausimynas, aprašai. Apklausti šimtas dvylika Vilniaus vaikų ir jaunimo klubų ir moksleivių namų pedagogų ir dvylika vadovų. Diagnostinio tyrimo duomenys atskleidė, kad daugelis neformaliojo ugdymo įstaigų pedagogų didelį dėmesį skiria kompetencijų plėtotei ir tobulinimui. Tyrimo rezultatai rodo, kad siekiant švietimo kokybės geresnių rezultatų, tobulinant veiklos planavimo, ugdymo proceso organizavimo, pedagoginio bendravimo ir bendradarbiavimo kompetencijas, pedagogams derėtų dažniau derinti savo veiklą su tėvais, kolegomis, ugdymo institucija, mokėti ir gebėti... [toliau žr. visą tekstą] / In the Thesis, the set object is concretized through the following tasks: the theoretical preconditions for the expression of competences of pedagogues of informal education institutions are disclosed and defined, nine competences of informal education pedagogues, such as pedagogical sophistication, prognostication and planning of the activities, organizing of the educational process, pedagogical communication and cooperation, creative, educational, social and professional competence, were identified and analyzed. On the base of decisions of the Government, all key concepts related to the subject under discussion were discussed upon, following the principles of equal opportunities, contextualises, efficiency and succession of the system of education as well as the objects and tasks of education. According to the previously developed programme of the investigation, the diagnostic investigation was carried out, the object and the tasks set in the programme were implemented, a questionnaire and descriptions were developed. One hundred and twelve pedagogues and twelve heads of Vilnius children and youth clubs and schoolchildren centers were interviewed. The data of the diagnostic investigation disclosed that a majority of pedagogues of informal education institutions pays a great attention to extension and improvement of their competences. The results of the investigation show that pedagogues should more frequently coordinate their activities with parents of the children as well... [to full text]

Chapter One will outline the way I will be using the constructs of "national" and "personal" identity, and will then move on to provide a brief contextual setting for the creation and importance of certain literary conventions of Irish topography and character, in particular by examining the cultural nationalism in Yeats's poems. In doing so, I will outline the metaphor of evolution which is crucial in this dissertation, and will examine some of the ethical implications of employing this metaphor. Chapter Two will examine the 1996 memoir Angela's Ashes by Frank McCourt, outline McCourt's employment of various stock Irish tropes, and show how this leads to a conflation of "personal" and "national" identity, to the detriment of the memoir. Chapter Three will turn to critique Are You Somebody?, the memoir by Nuala O'Faolain which was also published in 1996. I will argue that, in contrast to Angela 's Ashes, Are You Somebody? offers a constructive fusion of both kinds of identity national and personal. In Chapter Four, I will compare and contrast key issues in the texts, in relation to their both being memoirs of (Irish) national significance, published at the same time in a changing Ireland, and I will conclude by arguing that the process of invention which is necessary for the writing of a memoir is equally necessary for the creation of a national identity. / Thesis (M.A.)-University of Natal, Pietermaritzburg, 2001.

Denna studie syftar till att se på hur barn tar sig an konstruktionsritningar i jämförelse med fritt byggande i en lekfull gruppmiljö. Tidigare forskning visar skillnad mellan mängden män och kvinnor i tekniska yrken och även män och kvinnors inställning till de tekniska ämnena. Vissa forskare visar också på åldersskillnader mellan hur barn lär sig tekniska ämnen. Tar fyra- och femåringar frivilligt sig an konstruktionsritningar, följer dem och färdigställer de konstruktionen? Studien har särskilt tittat på om det fanns skillnader mellan flickorna och pojkarna när de byggde? Hur påverkar barnens eget intresse hur de bygger? Om barn, fyra och fem år gamla kan följa bygginstruktioner? Resultatet av denna studie, i viss mån, stödjer tidigare forskning om att det finns en genus aspekt redan i förskoleåldern, pojkarna var mer försekomna och hade lättare för att följa lego instruktioner än flickorna, men frågan kvarstår; varför finns denna skillnad? Förutom genusaspekten fanns det också ett tydligt resultat som visade på skillnad i byggkunskap mellan fyraåringar och femåringar. Fyraåringarna utforskade främst byggmaterialet, medan många av femåringarna kunde följa en Legobygginstruktion näst intill perfekt. / This study aims to look at how children approach building instructions compared to free building in a playful group environment. Researchers have found age differences, between how young children learn technical subjects. Other studies show that there are differences between the number of men and women in technical professions and also between men and women’s approach to the technical subjects. This study seeks discover if and how four and five year olds voluntarily use, follow, and complete a building exercise using instructional drawings. The study paid close attention to if girls and boys had different approaches to building; how does the children’s own interests affect the process of building? If children aged four and five years are capable of following building instructions. The results of this study to some extent support earlier research that there is a gender difference already at four to five years of age, but the question still remains why this difference exists. As well as the gender difference, there was also a strong result showing a difference in building knowledge between the four year olds and the five year olds. The four year olds mainly explored the building material whereas many of the five year olds could successfully follow the building instructions.

This PhD aimed to elucidate the mechanisms by which polymorphisms may alter androgen-induced transactivation of androgen receptor (AR) target genes which may be important in prostate cancer aetiology. The second aspect of this PhD focused on identifying and characterising functional polymorphisms that may have utility as predictive risk indicators for prostate cancer and which may aid in earlier therapeutic intervention and better disease management. Analyses were carried out on the kallikrein-related peptidase 3 (KLK3), also known as the prostate specific antigen (PSA), gene and the kallikrein-related peptidase 4 (KLK4) gene. The PSA and KLK4 genes are part of the serine protease family that have trypsin or chymotrypsin like activity and are thought to play a role in the development of hormone-dependent cancers in tissues such as those in the prostate, breast, endometrium and ovaries. In the prostate, PSA is regulated by androgens and three androgen response elements (AREs) have been described in the promoter and upstream enhancer region. The PSA ARE I harbours a polymorphism at -158 bp from the transcription initiation site (TIS) that results in a G to A transition (G-158A). This PhD investigated the functional significance of the PSA G-158A polymorphism which has been reported to be associated with prostate cancer risk. Electromobility shift assays (EMSAs) investigating the interaction of ARE I variants with the AR DNA binding domain (AR-DBD) demonstrated that the A allele had a two-fold increased binding affinity for the AR-DBD when compared with the G allele. This was confirmed with endogenous AR in limited proteolysis-EMSA experiments. The limited proteolysis-EMSA experiments also demonstrated differential sensitivities of PSA ARE I alleles to trypsin digestion, which suggests that the G-158A polymorphism has an allosteric effect on the AR that alters AR/ARE I complex stability. Furthermore, Chromatin Immunoprecipitation (ChIP) assays suggest that the A allele more readily recruited the AR in vivo when compared with the G allele and is consistent with the in vitro binding data. Luciferase reporter assays carried out in both LNCaP and 22Rv1 prostate cancer cells, and using the natural (dihydrotestosterone; DHT) ligand demonstrated that the A allele was more responsive to androgens in LNCaP cells. Hence, this study has elucidated the potential mechanisms by which the G-158A polymorphism may differentially regulate PSA expression (of which up-regulation of PSA is thought to be important in prostate cancer development and progression). KLK4 has similar tissue-restricted expression as PSA and is up-regulated by steroid hormones in many endocrine cells including those in the prostate. A putative ARE (KLK4-pARE) located at -1,005 to -1019 relative to the more predominantly used transcription initiation site, TIS3, was initially found in supershift assays using AR antibodies to interact with endogenous AR. However, subsequent EMSA analysis using purified AR-DBD suggest that KLK4-pARE may be interacting with the AR indirectly. To investigate this hypothesis, a tandem construct of KLK4-pARE was cloned into the pGL3-Promoter vector for hormone-induced reporter assays. However, reporter assays did not demonstrate any responsiveness of KLK4-pARE to androgens, estradiol or progestins. Consequently, Real-Time PCR was carried out to reassess the hormonal regulation of KLK4 at the mRNA level. Consistent with the literature, data from this study suggests that KLK4 may be up-regulated by androgens, progestins and estradiol in a cyclical manner. Hormone-induced luciferase reporter assays were then carried out on seven promoter constructs that span 2.8 kb of the KLK4 promoter from TIS3. However, none of the seven promoter constructs demonstrated any significant responsiveness to androgens, estradiol or progestins. This study suggests that hormone response elements (HREs) that may drive the hormonal regulation of KLK4 in prostate cancer may be located further upstream from the promoter region investigated in this PhD, or alternatively, may lie 3' of TIS3. The characterisation of KLK4 promoter polymorphisms and their flanking sequences were also carried out in parallel to the functional work with the intent to assess the functional significance of any polymorphisms that may be located within HREs. In total 19 polymorphisms were identified from the public databases and from direct sequencing within 2.8 kb of the KLK4 promoter from TIS3. However, the functional and clinical significance of these 19 polymorphisms were not further pursued given the negative findings from the functional work. The PSA AR enhancer region was also assessed for potential polymorphisms that may be associated with prostate cancer risk. A total of 12 polymorphisms were identified in the PSA enhancer of which two (A-4643G and T-5412C) have been reported to alter functionality of the enhancer region and thus, prioritised for further analysis. Association analysis for prostate cancer risk was then carried out on these PSA enhancer polymorphisms as none of the KLK4 promoter polymorphisms were found in functional HREs. No significant association for either the A-4643G or T-5412C polymorphism with prostate cancer risk was found at the P = 0.05 level. However, under an age-adjusted dominant model a 1.22- (95% CI = 1.16-1.26) and 1.23-fold (95% CI = 1.17-1.29) increased risk for prostate cancer was found for the A-4643G or T-5412C polymorphisms, respectively. Both polymorphisms were also assessed for association with tumour grade and stage and PSA levels. Genotypes were significantly different for the A-4643G and T-5412C polymorphisms with tumour stage and PSA levels, respectively. However, these results are likely to be biased by the case population which consist primarily of men who presented with incidental (pT1) and organ-confined (pT2) tumours. To summarise, the A-4643G and T-5412C polymorphisms are unlikely to be associated with prostate cancer risk, PSA levels or stage/grade of disease. However, further analyses in a larger cohort is warranted given that these polymorphisms alter androgen responsiveness of the PSA enhancer and that elevated PSA levels are indicative of men with prostate cancer. To summarise, this PhD has elucidated the functional significance of the PSA G-158A polymorphism in prostate cancer and which may be important in prostate cancer patho-physiology. This PhD has also furthered the understanding of the hormonal regulation of KLK4 in prostate cancer cells. Finally, this PhD has carried out a pilot study on two functional PSA enhancer polymorphisms (A-4643G and T-5412C) with prostate cancer risk.

The aim of this study is to use an intermedial theory to analyse and contextualize embodiment and violence in the Chinese author Mo Yan’s Life and Death Are Wearing Me Out. I use Jørgen Bruhn’s mediality model, introduced in The Intermediality of Narrative Literature: Medialities Matter (2016), to analyse medial phenomena such as intra- and intermediality in the novel. Bruhn’s model mainly covers relations between several media and within a single medium. The focus of this study lies on the blending of different media within the novel. My hypothesis is that the depiction of embodied violence in the novel is a literary strategy, based on cognitive functions and Chinese oral traditions to communicate historical events, as well as through an intermedial depiction of those events, a way to avoid censorship. Of particular importance to this study are medial phenomena connected to visualization of memories, and intermediality as discipline a voice between media texts, to establish how a literary text through narrative techniques can create an illusion of cinematic blending. I see this as an illustration of the historical hierarchical struggle between art forms. This is a broader perspective on literary depiction in Mo Yan’s novel than generally can be found in interpretations originating in a Western discourse. The result of my study shows that medial phenomena such as inter- and intramediality are woven into a narrative theme of remembrance of historical political events. Such memories are communicated through depictions of embodied violence, as well as the impact of trauma on anonymous bodies reminiscent of cinematic techniques, heightened by the metafictive voice of Mo Yan within the novel. It is a perspective that is also accentuated through auditory and visual elements that recall the ability of audio-visual media techniques to create identification with exposed bodies through close-up depictions of body and violence. Hence, Mo Yan has constructed a grid of medial phenomena in the novel through which he is able to convey historical processes without risking censorship.

La formation de nouveaux vaisseaux sanguins ou angiogenèse soutient la croissance tumorale en fournissant l'oxygène et les nutriments qui lui sont nécessaires. Le rôle clé du facteur de croissance de l'endothélium vasculaire VEGF dans ce processus a suscité le développement de stratégies anti-angiogéniques pour le traitement du cancer. Cependant, des travaux précliniques et des données cliniques suggèrent l'émergence de résistances aux anti-angiogéniques, en raison notamment de la redondance des facteurs de croissance pro-angiogéniques. Il est donc nécessaire de développer des stratégies alternatives plus efficaces. En 2010, notre laboratoire a apporté la preuve de concept d'une thérapie anti-tumorale et anti-angiogénique innovante basée la dégradation des ARNm à demi-vie courte par la protéine à doigts de zinc TIS11b. Néanmoins, l'instabilité de la protéine thérapeutique a entravé la caractérisation plus détaillée de cette stratégie. Dans ce contexte, l'objectif majeur de ma thèse était l'optimisation de la stabilité et de l'activité de TIS11b et l'évaluation de son efficacité thérapeutique. Pour cela, nous avons généré une nouvelle protéine TIS11b génétiquement modifiée sur la base d'études biochimiques et moléculaires. Notamment, nous avons observé que la phosphorylation de la sérine 334 située dans le domaine C-terminal de TIS11b augmente de façon très significative la stabilité de la protéine et potentialise son activité déstabilisatrice de l'ARNm du VEGF. De plus, la délétion du domaine N-terminal augmente également la stabilité de TIS11b sans altérer son activité. Nous avons alors généré deux nouvelles protéines thérapeutiques, la protéine ZnC et la protéine ZnC334D pour laquelle la troncation du domaine N-terminal et la substitution de la sérine S334 par un aspartate mimant une phosphorylation ont été combinées. Les nouvelles protéines ont été fusionnées à une étiquette polyarginine R9 leur permettant de traverser les membranes cellulaires (R9-ZnC et R9-ZnCS334D). Nous avons montré que R9-ZnC et R9-ZnCS334D inhibent l'expression de VEGF in vitro dans la lignée de cancer du sein murin 4T1. De plus, R9-ZnCS334D exerce une activité anti-proliférative, anti-migratoire et anti-invasive dans ces cellules. In vivo, l'injection intra-tumorale de R9-ZnCS334D dans des tumeurs 4T1 préétablies inhibe significativement l'expression du VEGF, la croissance et la vascularisation tumorales. De façon remarquable, l'analyse des extraits tumoraux indique que le traitement diminue l'expression de chimiokines clés dans les processus d'angiogenèse, d'inflammation et d'invasion (Fractalkine, MCP-1, NOV, SDF-1, Pentraxin…). Enfin, R9-ZnC et R9-ZnCS334D inhibent l'expression de marqueurs de la transition épithélio-mésenchymateuse, un processus impliqué dans la dissémination métastatique. L'ensemble de ces travaux indique que R9-ZnC et R9-ZnCS334D sont des molécules anti-tumorales multi-cibles, qui inhibent plusieurs étapes clés de la progression tumorale. Cette étude confirme que le ciblage de la stabilité des ARNm est une stratégie prometteuse et novatrice pour le développement de nouvelles thérapies anti-cancéreuses. / One of the innovative aspects of anti-cancer therapies is the possibility of preventing tumor growth by blocking blood supply. Cancer cells induce the formation of their own blood vessels from pre-existing vasculature, a process called angiogenesis. One of the most important proangiogenic factors is vascular endothelial growth factor (VEGF). The success of bevacizumab (a humanized anti-VEGF monoclonal antibody) combined to chemotherapy for the treatment of human metastatic cancers has validated VEGF as an efficient target. However, despite the initial enthusiasm, resistance to these anti-angiogenic treatments resulting from compensatory mechanisms occurs upon time. For this reason, there is a real need for new anti-angiogenic drugs that will target the angiogenic process through distinct mechanisms. In 2010, our laboratory has successfully developed an anti-angiogenic and anti-tumoral therapy based on destabilization of short-lived mRNAs by the zinc finger protein TIS11b. However, the therapeutic protein was highly unstable, thus making it difficult to further characterize the experimental therapy. In this context, the main task of my thesis was the optimization of TIS11b stability and activity followed by the evaluation of the multi-target action of our novel protein on tumor development. In a first part of this work, biochemical and molecular approaches allowed us to demonstrate that phosphorylation of the C-terminal serine S334 in TIS11b protein markedly increases its stability. In addition, deletion of the N-terminal domain of TIS11b highly increases its protein stability without affecting its activity. Therefore, we integrated N-terminal truncation (ZnC) and C-terminal substitution of S334 by an aspartate to mimic a permanent phosphorylation at S334 (ZnCS334D) as a novel TIS11b engineering strategy. Both proteins were fused subsequently to a cell-penetrating peptide polyarginine (R9). In vitro studies revealed that R9-ZnC and R9-ZnCS334D inhibit VEGF expression in the murine breast cancer cells 4T1. In addition, R9-ZnCS334D impaired proliferation, migration, invasion and anchorage-independent growth of 4T1 cells. In vivo, intra-tumoral injection of either protein significantly reduced VEGF expression and tumor vascularization. Strikingly, antibody array analyses of tumor extracts demonstrated a reduced expression of several chemokines such as Fractalkine, MCP-1, NOV, SDF-1 and Pentraxin upon R9-ZnC or R9-ZnCS334D treatment. These factors, which are produced by several cell types within tumor tissue, are key drivers of tumor angiogenesis, tumor-promoting inflammation and invasion. Furthermore, the expression of markers of the epithelial-to-mesenchymal transition was also significantly reduced, suggesting an anti-metastatic effect of R9-ZnC and R9-ZnCS334D. Thus, we provide R9-ZnC and R9-ZnCS334D as potential novel multi-target agents which inhibit key hallmarks of cancer progression. This work supports the emerging link between mRNA stability and cancer and proposes novel concepts for the development of innovative anti-cancer therapies.