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  • 1
    UID:
    (DE-627)166108367
    Format: 88 S , graph. Darst , 21 cm
    Edition: Als Ms. gedr
    ISBN: 3826502531
    Series Statement: Berichte aus dem Bauwesen
    Note: Zugl.: Berlin, Techn. Univ., Diss. : 1994
    Language: German
    Keywords: Scheibe ; Finite-Elemente-Methode ; Platte ; Finite-Elemente-Methode ; Hochschulschrift
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  • 2
    UID:
    (DE-602)b3kat_BV024395881
    Format: 88 S. , graph. Darst.
    Edition: Als Ms. gedr.
    ISBN: 3826502531
    Series Statement: Berichte aus dem Bauwesen
    Note: Zugl.: Berlin, Techn. Univ., Diss., 1994
    Language: Undetermined
    Keywords: Hochschulschrift
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  • 3
    Online Resource
    Online Resource
    [Erscheinungsort nicht ermittelbar] : Inst för biovetenskaper och näringslära / Dept of Biosciences and Nutrition
    UID:
    (DE-627)1803285281
    Content: Liver lipid metabolism is coordinated via transcriptional networks composed of transcription factors and coregulators. Disturbance of such networks leads to metabolic dysregulation and is linked to the progression of obesity-related metabolic disorders, such as non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease. Lipid-sensing nuclear receptors, particularly liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs), play a crucial role in cholesterol and triglyceride regulation and have emerged as significant targets for drug development. The major obstacles of targeting nuclear receptors are the undesired and often unpredictable side effects due to their genome-wide activities in multiple cell-types. Therefore, investigating the associated coregulators and the posttranslational modifications might help to better understand the gene-, cell-type- and signalspecific regulation of nuclear receptors, especially upon pathophysiological conditions. Of particular interest is G-protein pathway suppressor 2 (GPS2), subunit of a fundamental corepressor complex, which seems involved in cholesterol homeostasis and antiinflammatory crosstalk in a variety of tissues. Although lipid dysregulation and inflammation are two major mechanisms to promote metabolic disorders, the role of GPS2 in the development of those diseases remained enigmatic. The objective of this thesis was therefore to characterize the roles and relationship of GPS2, along with the corepressor complex, to individual transcription factors/nuclear receptors at the physiological and genomic level with an emphasis on obesity-associated metabolic disorders. In Paper I, we discovered a hitherto unknown function of GPS2 in the progression of NAFLD to non-alcoholic steatohepatitis (NASH). We demonstrated that GPS2 selectively repressed PPARα activity in liver lipid catabolism via the corepressor complex. Hepatocytespecific Gps2 knockout mice were protected from diet-induced liver steatosis and fibrosis, by enhancing fatty acid oxidation and ketogenesis as result of PPARα de-repression and epigenome alterations. Further, by studying human NAFLD/NASH biopsies we found that GPS2 expression positively correlated with fibrogenic and inflammatory gene expression. Thus, the selective modulation of GPS2-PPARα interactions could be of therapeutic interest for NAFLD/NASH. In Paper II, we identified GPS2 as a pivotal regulator of lipopolysaccharides (LPS)-induced ABCA1 expression and cholesterol efflux, independent of LXR and the corepressor complex, in inflammatory macrophages. This study advanced our understanding of GPS2 in linking obesity-associated inflammation to cardiovascular diseases. As GPS2 is downregulated whilst the circulating endotoxin is elevated in obesity, the LPS-GPS2-ABCA1 axis may provide a potential link to explain the increased cardiovascular risk in obesity and T2D. In Paper III, we demonstrated that LXRα phosphorylation played a crucial role in NAFLD progression in mice. In phosphorylation-deficient LXRα knockin mice, diet-induced NAFLD was attenuated by repressing the expression of multiple inflammatory and fibrotic mediators. We uncovered a unique group of diet-specific phosphorylation-sensitive LXRα target genes in liver, different from those affected by loss of LXRα. Moreover, evidence is provided that phosphorylation may modulate the interaction of LXRα with the corepressor complex. This study highlights the role of post-translational modifications in defining the gene-selective transcriptional activity of nuclear receptors. In conclusion, this thesis revealed novel insights into the multifaceted regulatory roles of nuclear receptors and GPS2 in altering transcriptional and epigenomic networks linked to metabolic and inflammatory processes. These insights may contribute to the better understanding of the development of obesity-associated metabolic disorders and to novel intervention strategies.
    Note: Dissertation Inst för biovetenskaper och näringslära / Dept of Biosciences and Nutrition 2019
    Language: English
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  • 4
    UID:
    (DE-627)180328529X
    Content: The Tuberous Sclerosis Complex (TSC) is a genetic disease characterized by growth of hamartomas in different organs including brain, kidney, lung, skin, and heart. These lesions are sources of morbidity and mortality in patients with TSC, as they may cause intractable epilepsy, autism, developmental delay, renal and pulmonary failure. Known causes of TSC are loss of function mutations in TSC1 and TSC2 genes. The majority of TSC lesions contain multiple cell types of the mesenchymal lineage, as in the case of angiomyolipomas, lymphangioleiomyomatosis and angiofibromas. A unique cell type named perivascular epithelioid cell (PEC) is constantly present in mesenchymal TSC lesions, such as angiomyolipomas and lymphangioleiomyomatosis, basing on morphological features and the common expression of melanocytic and myogenic markers. Therefore, these lesions are officially classified, along with other tumors, as PEComas. Their cell of origin and the molecular mechanisms underlying their pathogenesis remain poorly defined. Here we generated a novel mosaic Tsc1 knockout mouse model which develop renal mesenchymal lesions recapitulating human Perivascular Epithelioid Cell tumor (PEComa) observed in TSC patients. We identified YAP, the transcriptional coactivator of Hippo pathway, was upregulated in both renal lesions of TSC mouse model and human angiomyolipoma samples in a mTOR-dependent manner. Inhibition of YAP with genetic or pharmacological tools greatly attenuates the proliferation and survival of Tsc1 null cells in vivo and in vitro. Futhermore, we found YAP accumulation in TSC1/TSC2 deficient cells is due to impaired degradation of the protein through the autophagosome/lysosome system. Thus the regulation of YAP by mTOR and autophagy is a novel mechanism of growth control, matching YAP activity with nutrient availability under growth permissive conditions. It may serve as a potential therapeutical target for TSC and other diseases with dysregulated mTOR activity. ; La sclérose tubéreuse complexe (TSC) est une maladie génétique caractérisée par une croissance des hamartomes dans différents organes y compris le cerveau, les reins, les poumons, la peau et le cœur. Ces lésions sont des sources de morbidité et de mortalité chez les patients TSC, car ils peuvent provoquerl' épilepsie, l'autisme, le retard de développement et l'insuffisance rénale et pulmonaire. Les causes connues de TSC sont la perte de la fonction et les mutations des gènes TSC1 et TSC2. La majorité des lésions TSC contient plusieurs types cellulaires de la lignée mésenchymateuse, comme dans le cas des angiomyolipomes, l'lymphangioleiomyomatose et les angiofibromes. Un type unique de cellules épithélioïdes périvasculaires nommé (PEC) est constamment présent dans les lésions de TSC mésenchymateuses, comme angiomyolipomes et lymphangioleiomyomatose, basant sur les caractérisations morphologiques et l'expression des marqueurs communs mélanocytaires et myogéniques. Par conséquent, ces lésions sont officiellement classées, ainsi que d'autres tumeurs, comme PEComes. Leur origine cellulaire et les mécanismes moléculaires impliqués dans la pathologie restent à élucider. Ici, nous avons généré un modèle souris mosaïque TSC1 knockout qui développe des lésions rénales mésenchymateuses récapitulant périvasculaire épithélioïde cellules tumorales humaines (Pecoma) observés chez les patients TSC. Nous avons identifié YAP, le co-activateur transcriptionnel de la voie Hippo, a été régulée d'une manière mTOR-dépendante dans les lésions rénales de notre TSC1 knockout souris et les échantillons de l'angiomyolipome humaines. L'inhibition de YAP avec des outils génétiques ou pharmacologiques atténue considérablement la prolifération et la survie des cellules nulles TSC1 in vivo et in vitro. En outre, l'accumulation de YAP dans les cellules déficientes TSC1 / TSC2 pourra être dû à la dégradation de la protéine altéré par le système de l'autophagosome / lysosome. Ainsi, la régulation de YAP par mTOR et l'autophagie est un nouveau mécanisme de contrôle de la croissance, l'activité de YAP correspondant à la disponibilité des éléments nutritifs dans les conditions de croissance permissives. Il pourra servir comme une cible thérapeutique potentielle pour TSC et d'autres maladies avec une activité de mTOR dérégulée.
    Note: Dissertation HAL CCSD 2014
    Language: English
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  • 5
    UID:
    (DE-101)942248597
    Format: 88 S. , graph. Darst. , 21 cm
    Edition: Als Ms. gedr.
    ISBN: 9783826502538 , 3826502531
    Series Statement: Berichte aus dem Bauwesen
    Note: Zugl.: Berlin, Techn. Univ., Diss., 1994
    Language: German
    Keywords: Scheibe ; Finite-Elemente-Methode ; Platte ; Finite-Elemente-Methode ; Hochschulschrift
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  • 6
    UID:
    (DE-605)HT006452094
    Format: 88 S. : graph. Darst.
    Edition: Als Ms. gedr.
    ISBN: 3826502531
    Series Statement: Berichte aus dem Bauwesen
    Note: Berlin, Techn. Univ., Diss., 1994
    Language: Undetermined
    Keywords: Scheibe ; Finite-Elemente-Methode ; Platte ; Finite-Elemente-Methode
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  • 7
    UID:
    (DE-627)223044113
    Format: 88 S , graph. Darst
    ISBN: 3826502531
    Series Statement: Berichte aus dem Bauwesen
    Note: Literaturverz. S. 87 - 88 , Zugl.: Berlin, Techn. Univ., Diss., 1994
    Language: German
    Keywords: Strukturmechanik ; Finite-Elemente-Methode ; Hochschulschrift
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  • 8
    UID:
    (DE-627)1477127615
    Format: Lit.Hinw.
    In: Taiwan development perspectives, Taipei, 2003, (2011), Seite 137-147
    In: year:2011
    In: pages:137-147
    Language: English
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  • 9
    UID:
    (DE-602)gbv_1477127615
    Format: Lit.Hinw.
    In: Taiwan development perspectives, Taipei, 2003, (2011), Seite 137-147
    In: year:2011
    In: pages:137-147
    Language: English
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  • 10
    UID:
    (DE-602)kobvindex_DGP1477127615
    Format: Lit.Hinw.
    In: Taiwan development perspectives, Taipei, 2003, (2011), Seite 137-147
    Language: English
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