L’autisme est un syndrome neuro-développemental hétérogène à l’étiologie génétique complexe. Afin d’identifier les dérèglements initiaux responsables de ce mal-développement cérébral, des travaux antérieurs au sein de notre équipe se sont basés sur des cellules représentatives des stades précoces de l’ontogenèse : les cellules souches olfactives. Le gène MOCOS, codant pour la sulfurase du cofacteur à molybdène, a été trouvée sous-exprimé chez la majorité des patients autistes comparés à des sujets contrôles de même âge et du même sexe.Nous avons ensuite postulé que la dissection minutieuse des mécanismes moléculaires pouvant rendre compte de cette dérégulation aiderait à trouver des mécanismes sous-jacents contribuant aux troubles du spectre autistique (TSA). Ceci a conduit à l'identification de COSMOC, un long ARN non codant généré à partir d'une transcription divergente dans la région promotrice de MOCOS, dont l'expression est diminuée chez 10 des 11 patients autistes de notre cohorte. A l’aide de diverses techniques de biologie moléculaire, nous avons montré que la déplétion de COSMOC induit : (1) une sous-expression de MOCOS, (2) une déstabilisation de l'organisation de la chromatine, ce qui suggère une fonction de régulateur transcriptionnel, et (3) une altération du métabolisme des lipides et de l’homéostasie redox de la cellule, deux voies dérégulés dans les TSA. Par ailleurs, COSMOC régule de l’expression de la PTBP2 (polypirimidine track biding protein 2), un facteur d’épissage contrôlant l’expression de nombreuses protéines synaptiques. En conclusion, la dérégulation de COSMOC pourrait expliquer certains des dysfonctionnements observés dans les TSA. / Autism is a heterogeneous neuro-developmental syndrome with a complex genetic etiology. In order to unveil the initial disturbances responsible for this brain maldevelopment, previous works in our team relied on cells representative of the early stages of ontogenesis: olfactory stem cells. The MOCOS gene, coding for molybdenum cofactor sulfurase, was found under-expressed in most of autistic patients of our cohort when compared with age- and gender-matched control adults without any neuropsychiatric disorders. We postulated that the meticulous dissection of the molecular mechanisms involved this deregulation would help to unveil pathogenic mechanisms underlying autism spectrum disorders (ASD). This led to the identification of COSMOC, a long non-coding RNA, generated from a divergent transcription in the promoter region of MOCOS, whose expression is decreased in 10 out of 11 autistic patients in our cohort. Using various molecular biological techniques (interference RNA, DNA microarray, qPCR...), we showed that COSMOC depletion induces: (1) an under-expression of MOCOS, (2) a destabilization of chromatin organization, suggesting a transcriptional regulatory function, and (3) an alteration of cellular lipid metabolism and redox homeostasis, two deregulated pathways in ASD. In addition, COSMOC regulates the expression of PTBP2 (polypirimidine track biding protein 2), a splicing factor that controls the expression of many synaptic proteins, including PSD95. In conclusion, the deregulation of COSMOC may explain some of the dysfunctions observed in ASDs.

Made available in DSpace on 2016-04-25T16:44:51Z (GMT). No. of bitstreams: 1 Newton Jadon.pdf: 847893 bytes, checksum: e8d094fcdb7d61f1102dd161057e595c (MD5) Previous issue date: 2007-04-03 / This Dissertation was elaborated from a management perspective, in order to enlarge knowledge about management models adopted by Third Sector organizations, having as basis a comparative study between two social entities that actuate at the east zone of São Paulo City: Centro de Assistência e Promoção Social Nosso Lar (Our Home Assistance Center and Social Promotion) and Associação Cristã de Moços de São Paulo Divisão de Desenvolvimento Social (Christian Boys Association of São Paulo Social Development Division). The analysis done throughout this work are oriented by theoretical references that seek the concept and classification of the Third Sector, mainly the studies of Falconer (1999), Peter Drucker (1994), Ioschpe (2005), Dowbor (2001/2002/2003/2004), Landim (1994/1999/2000/2001), Rodrigues (2004), Salamon (1994/1998/), Coleman (1994/1998), Costa (2004), Costa Júnior (1997), Junqueira (2000), Montaño (2005), and Putnam (2000). By the end of this study suggestions and proposals are presented as a contribution so that the social management of these entities is not a simple transposition of management tools used by the business sector with profitable purposes, but developed based on reflections that consider the existing peculiarities on social entities of the Third Sector / Esta Dissertação foi elaborada a partir de uma perspectiva gerencial, com vistas na ampliação do conhecimento sobre os modelos de gestão adotados pelas organizações do Terceiro Setor, tendo como base um estudo comparativo entre duas entidades sociais que atuam na zona leste da Cidade de São Paulo, a saber, o Centro de Assistência e Promoção Social Nosso Lar e a Associação Cristã de Moços de São Paulo Divisão de Desenvolvimento Social. As analises realizadas ao longo deste trabalho são orientadas por referenciais teóricos que buscam a conceituação e a classificação do Terceiro Setor, principalmente, os estudos de Falconer (1999), Peter Drucker (1994), Ioschpe (2005), Dowbor (2001/2002/2003/2004), Landim (1994/1999/2000/2001), Rodrigues (2004), Salamon (1994/1998/), Coleman (1994/1998), Costa (2004), Costa Júnior (1997), Junqueira (2000), Montaño (2005), Putnam (2000). Ao final deste estudo são apresentadas sugestões e propostas como contribuição para que a gestão social dessas entidades não seja uma simples transposição das ferramentas de gestão utilizadas pelo setor empresarial com fins lucrativos, mas que seja desenvolvida com base em reflexões que consideram o universo das relações sociais, isto é, o capital social, bem como as peculiaridades existentes nas entidades sociais do Terceiro Setor