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41	A Model-Based Analysis of Culture-Dependent Phenotypes of mESCs Herberg, Maria, Kalkan, Tüzer, Glauche, Ingmar, Smith, Austin, Roeder, Ingo 11 July 2014 (has links) Mouse embryonic stem cells (mESCs) can be maintained in a proliferative and undifferentiated state over many passages (self-renewal) while retaining the potential to give rise to every cell type of the organism (pluripotency). Autocrine FGF4/Erk signalling has been identified as a major stimulus for fate decisions and lineage commitment in these cells. Recent findings on serum-free culture conditions with specific inhibitors (known as 2i) demonstrate that the inhibition of this pathway reduces transcription factor heterogeneity and is vital to maintain ground state pluripotency of mESCs. We suggest a novel mathematical model to explicitly integrate FGF4/Erk signalling into an interaction network of key pluripotency factors (namely Oct4, Sox2, Nanog and Rex1). The envisaged model allows to explore whether and how proposed mechanisms and feedback regulations can account for different expression patterns in mESC cultures. We demonstrate that an FGF4/Erk-mediated negative feedback is sufficient to induce molecular heterogeneity with respect to Nanog and Rex1 expression and thus critically regulates the propensity for differentiation and the loss of pluripotency. Furthermore, we compare simulation results on the transcription factor dynamics in different self-renewing states and during differentiation with experimental data on a Rex1GFPd2 reporter cell line using flow cytometry and qRT-PCR measurements. Concluding from our results we argue that interaction between FGF4/Erk signalling and Nanog expression qualifies as a key mechanism to manipulate mESC pluripotency. In particular, we infer that ground state pluripotency under 2i is achieved by shifting stable expression pattern of Nanog from a bistable into a monostable regulation impeding stochastic state transitions. Furthermore, we derive testable predictions on altering the degree of Nanog heterogeneity and on the frequency of state transitions in LIF/serum conditions to challenge our model assumptions. info:eu-repo/classification/ddc/500 ddc:500 info:eu-repo/classification/ddc/610 ddc:610
42	Evaluierung des Antibody Directed Enzyme Prodrug Therapy-Konzepts im Mammakarzinom- und Lymphom-Mausmodell / Evaluation of Antibody Directed Enzyme Prodrug Therapy-concept in mammary carcinoma- and lymphoma-mouse model Zientkowska, Marta 04 July 2007 (has links) No description available. 570 Biowissenschaften, Biologie Mathematics and Computer Science Antibody Directed Enzyme Prodrug Therapy ADEPT MDA-MB-231 Mammakarzinom Lymphom A20 anti-uPAR anti-CD19 fpVCT eXplore Optix anti-uPARβ-D-Galaktosidase SCID-Mäuse B-Zell Non-Hodgkin-Lymphom Antibody Directed Enzyme Prodrug Therapy ADEPT MDA-MB-231 mammary carcinoma lymphoma A20 anti-uPAR anti-CD19 fpVCT eXplore Optix anti-uPARβ-D-Galactosidase SCID-mice B-cell Non-Hodgkin-Lymphoma 42.13
43	Generierung und Analyse EMA/E2F-6-defizienter Mäuse Pohlers, Michael 12 December 2005 (has links) The present study focuses on the biological functions of the transcription factor EMA/E2F-6, a member of the E2F-family of transcription factors that play an import role in cell cycle progression, differentiation and apoptosis. EMA/E2F-6 functions as a transcriptional repressor by recruiting a large protein complex, that includes polycomb group proteins, to specific target genes in order to silence their expression. To identify the biological functions of EMA/E2F-6 mice lacking this factor were developed and subsequently analysed. EMA/E2F6-/- mice are born with the expected frequency, are fertile and develop normally up to 18 months of age. Then about 25 % of these mice develop a paralysis of the hind limbs and present with a severe primary myelination defect of the spinal cord (and in part of peripheral nerves, too) that is accompanied by a massive infiltration of macrophages. Importantly, the histological findings were also detected in EMA/E2F-6-/- mice lacking clinical symptoms albeit to a lesser extend. With respect to EMA/E2F-6 association with polycomb group (Pc-G) proteins there were no significant findings such as skeletal transformations. In addition, only a mild proliferation defect of T-lymphocytes was observed that, in a more severe form, is typical for Pc-G mutations in the mice. Surprisingly, embryonic fibroblasts from EMA/E2F-6-/- mice have no obvious cell cycle defects. Accordingly, gene expression profiles showed that classical E2F target genes were normally regulated in these cells. However, EMA/E2F-6-/- fibroblasts ubiquitously express genes like alpha-tubulin-3 and -7 that are normally expressed in a strictly testis-specific manner. All EMA/E2F-6-dependent target genes identified contain a conserved E2F-binding site in their promoters that is required both for EMA/E2F-6 binding and regulation. Zellzyklus Demyelinisierungen Gehirnveränderungen Geninaktivierung Gewebsspezifische Genexpression Lähmungen Makrophageninfiltration Mäuse/Nullmutanten Neuronenuntergang Oligodendrozytenreduktion Polycomb-Gruppe-Proteine Proliferation von T-Lymphozyten Regulation der Genexpression Rückenmarksveränderungen Skeletttransformationen Transkriptionsfaktoren Brain/Abnormalities Cell Cycle Demyelinisations Gene Targeting Infiltration of Makrophages Mice/Knockout Neuron Death Paralyses Polycomb-Group Proteins Proliferation of T-Lymphocytes Reduktion of Oligodendrocytes Regulation of Gene Expression Skeletal Transformations Spinal Cord/Abnormalities Tissue-specific Gene Expression Transkription Factors 570 Biowissenschaften, Biologie 32 Biologie WG 3580 WG 3700 ddc:570

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