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Variability of genomic imprinting in human diseaseMcCann, Jennifer January 2004 (has links)
Genomic imprinting is the differential expression of genetic material depending on the parent from which it is transmitted. It is involved in the pathogenesis of many diseases, especially those involved in development, growth abnormalities and cancer. We examined the extent of and the variability of genomic imprinting amongst individuals in three human diseases, Wilms' tumour, Type 1 diabetes and Silver-Russell syndrome. / Wilms' tumour (WT) is a renal embryonal cancer associated with overexpression of the insulin-like growth factor 2 (IGF2). IGF2 is directed to the lysosomes for degradation by the mannose-6-phosphate/insulin-like growth factor two receptor (M6P/IGF2R) encoded by the IGF2R gene, a known tumour suppressor gene on 6826. IGF2R is imprinted in the mouse, with exclusive maternal expression. In humans, however, IGF2R imprinting is a polymorphic phenomenon only being found in a small subset of people. We present results suggesting that IGF2R imprinting provides the first "hit" in IGF2R inactivation in WT, and show the presence of a second "hit" in the form of deletions detectable as loss of heterozygosity. / Another disease investigated in this report is Type 1 diabetes (TID), an autoimmune, polygenic disease. Of the several T1D loci, IDDM8 on 6q, has been found to be subject to parent-of-origin effects and encompasses IGF2R. M6P/IGF2R is involved in immune system regulation. In this study we show an association between TID and IGF2R that is confined to maternally inherited alleles. Our results strongly suggest that IGF2R is a TID susceptibility gene and may be universally imprinted at some tissue or developmental stage not yet studied. / A third disease displaying both tissue-specific and isoform-specific imprinting is Silver-Russell syndrome (SRS), a growth disorder associated with double dose of a maternally expressed gene within 7p11.2--p13, a region in which the imprinted GRB10 gene was a prime candidate. We studied the complex tissue and isoform-dependence of GRB10 imprinting and demonstrated absence of imprinting in growth plate cartilage, the tissue most directly involved in linear growth thus eliminating GRB10 as the gene responsible for SRS. / It is evident that genomic imprinting plays a prominent role in various diseases. Imprinted genes can be expressed in a tissue-specific, isoform-specific or a temporally regulated manner. In addition, there is a wide variability of imprinting between individuals.
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Genetic and environmental influences on asthma susceptibility in developing lungCarpe, Nicole January 2011 (has links)
Asthma is a worldwide health problem and leading cause of childhood morbidity. The increasing prevalence of asthma places importance on understanding the biological mechanisms behind this complex disease. Considerable evidence suggests that asthma originates early in life. Environmental allergen exposures acting on a genetic background susceptible to asthma, may modify innate patterns of respiratory development and gene expression, facilitating the initiation of disease. The origins of asthma susceptibility and the influence of in utero allergen exposure on respiratory development were studied in rat models of atopy (Brown Norway [BN]) and airway hyperresponsiveness (Fisher). BN animals demonstrated increased epithelial proliferation, goblet cell hyperplasia, elevated eosinophils and IgE levels. Fisher rats displayed increased lung resistance and elevated neutrophils. The distinct respiratory phenotypes and gene expression patterns demonstrated were impacted by in utero allergen exposure, influencing asthma susceptibility. Studying causes of asthma susceptibility during this critical period has implications for asthma treatment and prevention. / L'asthme est un problème de santé mondial et une des causes premières de morbidité chez les enfants. L'augmentation des cas d'asthme souligne l'importance de la compréhension des mécanismes biologiques de cette maladie complexe. Plusieurs évidences suggèrent que l'asthme tient son origine très tôt dans la vie. De plus, l'exposition à des allergènes présents dans l'environnement peut agir sur un fond génétique susceptible et ainsi modifier les patrons innés du développement respiratoire et l'expression des gènes. L'influence sur le développement du système respiratoire de la susceptibilité à l'asthme et de l'exposition in utero à des allergènes ont été étudié dans des lignées de rat modelant l'atopie (Brown Norway [BN]) et l'hypersensibilité des voies respiratoires (Fisher). Les rats BN démontrent une augmentation de la prolifération des cellules épithéliales, une hyperplasie des cellules caliciformes et des niveaux élevés d'éosinophiles et d'IgE. Les rats Fisher montrent une augmentation de la résistance pulmonaire et un niveau élevé de neutrophiles. L'exposition in utero à des allergènes a eu des impacts sur le phénotype respiratoire et l'expression génétique des rats, influençant ainsi la susceptibilité à l'asthme. L'étude des causes de l'asthme pendant cette période critique a des implications importantes pour le traitement et la prévention de cette maladie.
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Identifying the novel GTPase function of FLCN and characterizing its role in agingGhazi, Abbas January 2011 (has links)
Birt-Hogg-Dube syndrome (BHD) is an inherited neoplasia syndrome that predisposes affected individuals to skin hamartomas, lung cysts, pneumothorax and renal carcinoma. Mutations within the BHD locus (also known as FLCN) have been found associated with the disease. Almost all mutations in BHD patients cause a truncated FLCN protein product suggesting a loss-of-function mechanism leading to tumor formation. FLCN is highly conserved across species from yeast to humans suggesting an important biological function. Earlier this year, the exact molecular function of FLCN was still unclear. However, with the aid of the first crystal structure of folliculin carboxy-terminal domain we provide the first insight into the function of folliculin as a novel GTPase. Interestingly this GTPase activity is lost in a naturally occurring disease-causing mutant (C1844G). We then characterize the role of FLCN-1 in the nematode Caenorhabditis elegans in an attempt to determine the signalling pathway(s) to which FLCN-1 belongs. We report a novel role of FLCN-1 in C. elegans aging as a component of the insulin/IGF-1 signalling pathway. FLCN-1 regulates lifespan via a mechanism that is AAK-2/AMPK, DAF-16/FOXO and autophagy dependent. We demonstrate that FLCN-1 negatively regulates AAK-2 phosphorylation independent of the constitutively active PAR-4 kinase. Moreover, flcn-1 null mutants have elevated levels of β oxidation of fatty acids, mitochondrial respiration and ROS generation all of which are dependent on AAK-2. We hypothesis that ROS generation stimulates autophagy activation as a downstream mechanism required for lifespan extension of flcn-1 null mutants. Taken together, these studies are aimed to identify the functional role of FLCN and to clarify its metabolic role in relation to AMPK in order to better understand its tumor suppressor function. / Le syndrome de Birt-Hogg-Dubé (BHD) est un syndrome néoplasique héréditaire, qui rend les personnes atteintes plus susceptibles de développer les maladies telles que les harmatomes de la peau, kystes pulmonaires, pneumothorax et carcinomes rénaux. Des mutations dans le locus BHD au niveau du gène de la folliculine (FLCN) sont souvent associées à cette maladie. La majorité des patients présentent des mutations entrainant la troncation de la protéine FLCN, suggèrant un mécanisme de perte de fonction qui entraine la formation de tumeurs. Très conservée à travers les espèces de la levure à l'homme, la FLCN semble avoir une fonction biologique importante, cependant son mécanisme d'action est encore obscure. Néanmoins l'obtention récente de la structure cristallographique du domaine carboxyle terminal de la folliculine suggère qu'elle pourrait fonctionner telle une GTPase. Chose intéressante, cette activité GTPase est perdue naturellement chez les malades portant la mutation C1844G. Afin de déterminer dans quelle voie de signalisation la folliculine appartient, nous avons analysé son rôle chez le nématode Caenorhabditis elegans. Nous rapportons ici le nouveau rôle de la FLCN-1 dans le vieillissement de C. elegans, comme étant un acteur de la voie de signalisation insuline/IGF-1. La FLCN-1 régule la durée de vie à travers un mécanisme dépendant de l'AMPK/aak-2, FOXO/DAF-16 et de l'autophagie. Nous démontrons qu'elle régule négativement la phosphorylation de AAK-2 indépendamment de la kinase constitutivement active PAR-4. Chez les mutants nul flcn-1, les acides gras B oxydes, la respiration mitochondriale ainsi que la production de ROS présentent des niveaux élevés, qui dépendent de AAK-2. Nous proposons que la production de ROS stimule l'activation de l'autophagie, nécessaire pour l'extension de la durée de vie des mutants flcn-1 nul. Ainsi, nos études ont permis d'identifier le rôle fonctionnel de la FLCN et de clarifier son rôle métabolique en lien avec l'AMPK, permettant de mieux comprendre sa fonction de suppresseur de tumeur.
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Genetic control of susceptibility to carcinogen-induced colorectal cancer in miceMeunier, Charles January 2011 (has links)
Colorectal cancer (CRC) is a complex multi-step disease that involves both an intrinsic genetic component, and extrinsic environmental factors. Using a set of AcB/BcA recombinant congenic strains (RCS) derived from CRC-susceptible A/J and CRC-resistant C57BL/6J progenitors, we have identified and characterized a major locus on a 14Mb segment of chromosome 3, as controlling azoxymethane-induced susceptibility to tumorigenesis in AcB/BcA strains, the Colon cancer susceptibility locus 3 (Ccs3). In following studies, we further ascertained the close phenotype/genotype correlation in additional AcB/BcA strains, as well as in groups of backcross populations bearing unique recombinant chromosomes for the interval. We reduced the Ccs3 interval to a 2.2Mb segment, containing 13 annotated transcripts, one of these genes coding for the NFkB p105 protein. As it is involved in pathological inflammation in the gut, Nfkb1 is also expressed at high levels in A/J intestinal mucosa but at low levels in CRC tumors. Sequencing of the 13 positional candidates identified a copy number variant (CNV) consisting of a strain-specific deletion of a 54bp duplication sequence near the Nfkb1 exon/intron junction of exon 15. Loss of one of the duplicated 54 bp-repeat is associated with CRC susceptibility in A/J. Finally, we observed the presence of additional genetic effects influencing the Ccs3-mediated CRC phenotype in AcB/BcA strains. Hence, we performed a linkage analysis by whole genome-scanning on 208 (B6 X A/J)F2 mice. These studies validated the effect of Ccs3 [LOD = 4.89] and identified an additional locus on distal chromosome 9 [LOD = 3.76], denoted Colon cancer susceptibility 5 locus (Ccs5). Ccs5 modulates tumor multiplicity in F2 animals bearing at least one A/J-derived susceptibility allele at Ccs3, with A/J-derived Ccs5 susceptibility alleles being inherited in a recessive manner. In F2 mice, a strong additive effect is observed between susceptibility alleles at both loci. Therefore, the work in this thesis also identifies a two-locus system (Ccs3, Ccs5) that regulates predisposition to CRC in mice. / Le cancer colorectal (CRC) est une maladie complexe résultant de l'interaction de composantes génétiques et environnementales. Nous avons identifié, puis caractérisé, un important locus nommé Colon cancer susceptibility locus 3 (Ccs3) contrôlant la susceptibilité à l'induction de CRC des lignées AcB/BcA, Les lignées de souris AcB/BcA recombinantes (recombinant congenic strains (RCS)) sont dérivées de la lignée A/J (susceptible à l'induction de CRC) croisée sur la lignée C57Bl/6J (résistante à l'induction de CRC), Nous avons ensuite confirmé la corrélation entre le génotype/phénotype du locus Ccs3 de lignées AcB/BcA additionnelles, de même que la corrélation des groupes générés par rétrocroisement incluant certains animaux portant un chromosome recombinant pour la portion du locus Ccs3. Cette approche a réduit l'intervalle physique correspondant à Ccs3 à un segment minimum de 2.2Mb. Cette région contient 13 transcrits annotés, notamment celui encodant la protéine NFκB p105. Nous avons examiné l'expression du gène Nfkb1 : celui-ci est fortement exprimé dans la muqueuse intestinale des souris A/J mais très peu dans leurs tumeurs de côlon. Le séquençage des 13 gènes candidat a identifié une variation du nombre de copies (CNV) d'une duplication de 54pb spécifique à une lignée A/J près du site d'épissage 3' de l'exon 15 de Nfkb1. La perte d'une de ces copies est associée avec l'apparition de tumeurs intestinales chez la souris A/J. Enfin, nous avons utilisé une approche génétique d'association par balayage du génome entier sur un total de 208 souris (B6 x A/J)F2 qui a confirmé l'effet majeur de Ccs3 [LOD = 4.89], et a détecté un locus additionnel dans la portion distale du chromosome 9 [LOD = 3.76], identifié Colon cancer susceptibility locus 5 (Ccs5). Ccs5 module la multiplicité de tumeurs chez les animaux F2 porteurs d'au moins un allèle de susceptibilité A/J au locus Ccs3, héritée de manière récessive. Nous avons donc identifié un système de deux loci (Ccs3, Ccs5) contrôlant la prédisposition au cancer colorectal chez la souris.
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Implications of CD9 and its partners in prostate cancer progressionZvieriev, Valerii. January 2005 (has links)
Prostate cancer is still the most diagnosed cancer in man in the Western world and in this group, one of the leading causes of cancer death. CD9 protein is a member of the tetraspanin family, whose members are often down-regulated in advanced prostate cancers. The objective of our study is to decipher the role of the CD9 protein in prostate cancer progression. / We have demonstrated that over-expression of exogenous CD9 in highly tumorigenic and metastatic PC-3M-LN4 cell line did not suppress its tumorigenic and metastatic properties in vivo while it even increased its invasive properties in vitro. These data contrast with our previous study, which demonstrated that over-expression of wild type CD9 has a deleterious effect on growth properties of human PC-3 prostate cancer cells in vitro. Since CD9 is still expressed in some human prostate cancers, we linked putative inactivation of CD9 in PC-3M-LN4 cells with presence or absence of certain CD9 partners. Using co-immunopreciptation, mass-spectrometry, Bacterial two-hybrid system and Ciphergen ProteinChip technology we identified six novel CD9 protein partners, namely MORTALIN, OVCA2, HES4, GALECTIN3, RAB5A, TM4SF9. These partners could affect CD9 function in prostate cancer cells. We also detected ASPP2 protein expression only in PC-3 cells. / Pursuing the characterization of some of these partners, we showed that simultaneous over-expression of CD9 and OVCA2 in PC-3M-LN4 cells lead to mitotic catastrophe and eventually cause cell death. / Furthermore, immunocolocalization studies demonstrated that CD9 and MORTALIN interaction depend on CD9 over-expression in an appropriate cell context, putatively explaining the differential effect of CD9 in PC-3 and PC-3M-LN4 prostate cancer cells. / Overall, the data presented in this thesis demonstrated that the biological properties of CD9 protein are dependent on protein-protein interactions and cell type environment. The demonstrated interactions of CD9 with OVCA2 and MORTALIN highlighted the importance of CD9 as a potential tumor and/or metastasis suppressor gene.
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Nonfatal suicidal behaviors: contributions of personality traits, genes, and gene-environment interactionsBrezo, Jelena January 2008 (has links)
Despite decades of dedicated research, individuals and groups at risk for suicidality are not easily identified and prevention and management of suicidal tendencies present considerable clinical challenges. The well-documented heterogeneity and multifactorial character of suicidal behaviors has also faced us with unique research challenges. In order to understand the many components involved in suicidal diathesis and its complex dynamics, we used a multidimensional approach investigating independent, additive contributions of factors across risk domains simultaneously, in addition to moderating and mediating influences. Using a powerful study design and a population-based cohort of young individuals, we assessed independent contributions of personality traits; identified personality and environmental factors whose influence on suicidal behaviors may be conditional on specific genotypes and gender; and, refined suicidal phenotypes and tested personality traits as candidate endophenotypes. The last two aims, investigation of gene-environment interactions and improved phenotypic characterization, address two important, rarely tackled limitations in the molecular studies of suicidal phenotypes. Results and implications of seven studies are presented and discussed in sections II through V. In Section II, we used a longitudinal approach to investigate epidemiology and interrelationships of several types of suicidal behaviors in our cohort. In the five chapters of Section III, we examined different aspects of the relationship of personality traits and non-fatal suicidal behaviors, addressing some of the methodological drawbacks in the field: the predominantly cross-sectional rather than developmental approaches; strong emphasis on bro / Malgré des années de recherche dédiées, les individus et groupes a risque de comportement suicidaire ne sont pas identifiés facilement. De plus, la prévention et le traitement des tendances suicidaires nous présentent aves des difficultés cliniques complexes. En outre, la recherche sur ce problème est compliquée par la hétérogénéité et un caractère multifactoriel du comportement suicidaire. Pour mieux comprendre des facteurs de diathèse suicidaire et leurs interactions complexes, on a employé une approche multidimensionnelle. Cette approche nous permit d'examiner les contributions indépendantes des facteurs de risques provenant de plusieurs domaines. Elle nous également permit d'étudier les effets modérateurs et médiateurs. En utilisant un plan d'échantillonnage stratifié et une cohorte de jeunes individus issus de la population générale, on a évalué des contributions indépendantes de traits de personnalité; on a identifié les traits de personnalité et des facteurs environnementaux dont l'influence sur le comportement suicidaire dépend du génotype spécifique et du sexe. On a également essayé de raffiner les phénotypes suicidaires et tester agressivité-turbulence, un trait de personnalité, comme endophénotype. Ces deux derniers objectifs - une exploration des interactions entre les gènes et les environnements et une caractérisation améliorée de phénotype – nous ont permis de contrôler des limitations importantes des études moléculaire du comportement suicidaire et d'autres phénotypes psychiatrique complexes. Les résultats de nos sept études sont présentées aux sections II-V. Dans la section II, on utilise une approche longitudinale pour étudier l'épidémiologie et la rel
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From cells to organs: the developmental challenge of multicellular organismsHebeisen, Michaël January 2009 (has links)
During the development of a multicellular organism, the cell cycle must be tightly regulated in order to ensure that cell division and growth are coordinated with the ongoing cell fate specification and morphogenetic programs. Although the molecular mechanisms that drive cell division are well understood, many of the signaling pathways regulating their functions during development remain to be discovered. The nematode Caenorhabditis elegans represents a unique model system to investigate developmental regulation of the cell cycle since the division pattern of its multiple lineages are invariant, allowing for easy detection of lineage defects following modification of gene activity by means such as mutagenesis or RNAi. We isolated mutations that affect the different cell cycles occurring in the intestinal lineage in order to identify the developmental pathways that control their stage-specific execution or transition. Our initial work focused on the characterization of a stabilizing gain-of-function mutation in the cdc-25.1 phosphatase that triggers intestinal hyperplasia during embryogenesis. We found that CDC-25.1 is targeted for degradation during a short developmental period by an SCF E3 ubiquitin ligase containing the F-box protein LIN-23/β-TrCP. To find regulators of CDC-25.1 levels and/or function during embryogenesis, we performed a genetic modifier screen of the cdc-25.1(gf)-dependent hyperplasia. Analysis of an intragenic suppressor that destabilizes CDC-25.1 revealed that multiple cues control its stability and turnover, so as to ensure timely coordination of intestinal cell division with organogenesis. In addition, we found that one of the extragenic / Durant le développement d'un organisme multicellulaire, il est primordial que le cycle cellulaire soit régulé de façon à ce que la division et la croissance des cellules soient coordonnées avec les programmes de spécifications cellulaires et de morphogenèse en cours. Bien que les mécanismes moléculaires sous-jacents à la division cellulaire soient bien compris, il reste encore à découvrir l'identité des voies de signalisation qui les régulent durant le développement. Le nématode Caenorhabditis elegans représente un organisme modèle idéal pour l'analyse de la régulation du cycle cellulaire durant le développement, dû en majeure partie au mode de division invariable de ces multiples lignées cellulaires. Cette caractéristique permet de détecter facilement des défauts de divisions suite à la modification de l'activité génique par mutagenèse ou par interférence d'ARN (RNAi). Nous avons isolé des mutations affectant les différents types de cycles cellulaires présents dans la lignée intestinale de C. elegans, afin d'identifier les voies de signalisation agissant durant les différentes périodes du développement pour en contrôler l'exécution ou la transition. Notre recherche initiale portait sur la caractérisation d'une mutation dominante stabilisant la phosphatase CDC25.1 et donnant lieu à une hyperplasie intestinale durant l'embryogenèse. Nous avons découvert que CDC-25.1 est dégradée durant une courte période du développement par une ligase d'ubiquitine E3 de type SCF contenant la protéine F-box LIN-23/β-TrCP. Afin de trouver des gènes régulant les niveaux et/ou la fonction de CDC-25.1 durant l'embryogenèse, nous avons ef
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The expression and role of «Tmed2»/TMED2 during the development of the murine embryo and placentaAchkar, Tala January 2009 (has links)
Normal development of the placenta is crucial for embryonic survival and growth. Tmed2 is a gene, which has been found to be necessary for the formation of the labyrinth layer of the placenta, as well as for embryonic development. The objectives of this thesis are to: describe the transcripts of Tmed2 using Northern Blot analysis; elucidate the expression pattern of Tmed2 in the developing embryo and placenta using whole mount and section in situ hybridization; determine whether homozygous mutant embryos (Tmed299J/99J) are undergoing ER stress using RT-PCR. Tmed2 has three transcripts; however, only one of these transcripts contains exon 1 of the gene. Tmed2 is expressed during the development of the embryo and placenta in those tissues that are affected in the Tmed299J/99J mutants. Finally, Tmed2 homozygous mutant embryos are not experiencing ER stress. Tmed2 is probably required for the trafficking of an important protein(s) during development. / Le développement normal du placenta est essentiel à la survie et la croissance embryonnaire. Tmed2 est un gène qui s'est révélé nécessaire et important pour la formation de la couche labyrinthe du placenta, ainsi que pour le développement embryonnaire. Les objectifs de cette thèse sont : de décrire la transcription de Tmed2 en utilisant Northern Blot analysis; d'élucider le modèle selon lequel s'exprime Tmed2 dans le développement de l'embryon et du placenta en utilisant l'hybridation in situ complète ou en section; de déterminer si les embryons mutants homozygotes (Tmed299J/99J) subissent un stress ER en utilisant le RT-PCR. Tmed2 possède trois transcriptions; par contre, une seule de ses transcriptions contient l'exon 1 du gène. Tmed2 s'exprime lors du développement de l'embryon et du placenta dans les tissus qui sont affectés dans les Tmed299J/99J mutants. Finalement, les embryons mutants homozygotes Tmed2 ne subissent pas de stress ER. Tmed2 est probablement utilisé pour le trafic et le déplacement d'une ou de plusieurs protéines importantes lors du développement.
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Effects of the Saccharomyces cerevisiae endo-exonuclease NUDI gene expression and poly(ADP-ribose) polymerase inhibition on homologous recombination in mammalian cells : potential application to gene targetingSemionov, Alexandre. January 1999 (has links)
In eukaryotes homologous recombination is the basis of such important biological events as meiotic recombination, generation of the antigen recognition molecule repertoire of the immune system and repair of DNA double strand breaks (DSBs). / Homologous recombination between an exogenous DNA sequence and a chromosomal sequence is termed "gene targeting". In the future, gene therapy will predictably become the treatment of choice for a number of inherited and acquired genetic diseases. The main obstacle to the application of gene targeting to gene therapy is the low frequency of homologous recombination in mammalian somatic cells. The ability to specifically increase the frequency of homologous recombination in mammalian cells could make gene targeting applicable to gene therapy of hereditary genetic disorders and cancer. / Here, we present the results of our studies in which we explored two approaches for transient increase of the frequency of homologous recombination in mammalian somatic cells: expression of the S. cerevisiae endo-exonuclease (EE) NUD1 gene, and inhibition of poly(ADP-ribose) polymerase (PARP) with 1,5-isoquinolinediol (ISQ). / We have demonstrated that transient expression of NUD1 in HeLa cells increased the resistance of the latter to ionizing radiation and cis-platin, two agents known to cause DNA DSBs, whereas it had no effect on cells' resistance to DNA-methylating agents. We have also shown that transient expression of NUD1 enhanced the frequency of extrachromosomal homologous recombination in mouse Ltk-cells. These results provide additional evidence for the involvement of EEs in homologous recombination in mammalian cells. They also demonstrate that overexpression of EEs, such as Nud1p, can potentially be used as a means of selectively increasing the frequency of homologous recombination in mammalian cells without a concomitant increase in the frequency of illegitimate recombination. / Our studies of PARP inhibition showed that treatment of cells with 0.622 mM ISQ results in an average 4.6-fold increase in the frequency of extrachromosomal homologous recombination in mouse Ltk-fibroblasts. We have also demonstrated that treatment of mouse Ltk-cells with ISQ leads to an increase of up to 8-fold in the absolute frequency of gene targeting of the stably integrated HSV tk gene. We believe that our results concerning the effect of ISQ on gene targeting may have potential application for the improvement of such technologies as the generation of genetic knock-outs and the ex vivo gene therapy. Our findings also appear to solve the conflict in the previously reported results that PARP inhibition stimulates chromosomal recombination but not extrachromosomal homologous recombination or gene targeting.
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A role for astroycte-related genes in suicideErnst, Carl Philip January 2009 (has links)
Astrocytes are the most abundant cell-type in the nervous system, yet are perhaps the least acknowledged players in brain function. Long considered support cells or ‘glue’, astrocytes are gradually being recognized as integral not only to the cytoarchitecture and the inflammatory process, but also to cell signaling and synaptic plasticity. This thesis will describe how a network of astrocyte-related genes may play a role in suicide. Through global gene expression analysis, a network of astrocyte-related genes was identified in brain of suicide completers as down-regulated compared to people who did not die by suicide. In particular, we identified an astrocyte-expressed TrkB gene, whose reduction of expression in suicide brain seems partially accounted for by epigenetic mechanisms. Finally, we investigated an astrocyte-expressed transcription factor, Sox9, that may partially regulate this astrocyte-related gene network. This work identifies a novel contributor to suicide, namely astrocyte dysfunction, which may impact behavior and mood. / Les cellules en plus grand nombre dans le système nerveux sont les astrocytes, mais leur rôle dans le fonctionnement du cerveau demeure nébuleux. Longtemps considérées comme des cellules de support permettant à plusieurs types cellulaires d'interagir entre eux, les astrocytes sont désormais mieux reconnues comme faisant partie intégrale de la cytoarchitecture du cerveau et de la plasticité neuronale. Cette thèse décrira le rôle que jouent les gènes astrocytaires sur le suicide. Par une analyse de l'expression génétique globale, des gènes astrocytaires ont été identifiés dans le cerveau de personnes décédées par suicide qui présentaient un niveau d’expression beaucoup plus faible chez les suicidaires que chez les sujets contrôles décédés de causes naturelles. Plus particulièrement, la variante astrocytaire du gène du récepteur trkB, dont l’expression est significativement réduite dans les cerveaux des suicidaires, semble être partiellement sous contrôle de mécanismes de régulation épigénétiques. Finalement, nous avons examiné l’implication du facteur de transcription astrocytaire sox9 dans la régulation partielle de l’expression de la variante astrocytaire du récepteur trkB et dans la formation des réseaux neuronaux. Pour conclure, cet ouvrage identifie un nouveau marqueur du suicide, notamment ladysfonction astrocytaire, comme ayant un rôle prédominant dans la régulation de l'humeur et la susceptibilité au suicide.
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