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匹配条件: “ Val�rie Gailus-Durner” ,找到相关结果约4201条。
MausDB: An open source application for phenotype data and mouse colony management in large-scale mouse phenotyping projects
Holger Maier, Christoph Lengger, Bruno Simic, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabé de Angelis
BMC Bioinformatics , 2008, DOI: 10.1186/1471-2105-9-169
Abstract: We present MausDB, the German Mouse Clinic web-based database application that integrates standard mouse colony management, phenotyping workflow scheduling features and mouse phenotyping result data management. It links mouse phenotype data with genotype data, metadata and external data such as public web databases, which is a prerequisite for comprehensive data analysis and mining. We describe how this can be achieved with a lean and user-friendly system built on open standards.MausDB is suited for large-scale, high-throughput phenotyping facilities but can also be used exclusively for mouse colony management within smaller units or projects. The system is successfully used as the primary mouse and data management tool of the German Mouse Clinic and other mouse facilities. We offer MausDB to the scientific community as open source software to provide a system for storage of data from functional genomics projects in a well-structured, easily accessible form.The concept of standardized, high-throughput and comprehensive screening of mice has proven to be successful for identifying new phenotypes in mutant mouse lines by the German Mouse Clinic (GMC) [1-7] and others [8,9].In the GMC, experts from various fields of mouse behavior, physiology, morphology, metabolism and pathology work side-by-side in one building in 14 individual modules (allergy, behavior, cardiovascular system, clinical chemistry, dysmorphology, energy metabolism, eye development and vision, immunology, lung function, molecular phenotyping, neurology, nociception, pathology and steroid metabolism) in close collaboration with clinicians and veterinarians [2].Mouse mutants and their littermate controls pass through the different modules of the GMC in multi-parallel phenotyping pipelines following a standardized workflow. In the course of the high-throughput primary screen, up to 320 parameters per mouse line are measured, and these findings may be supplemented by results from secondary and tertiary scr
Comparison of particle-exposure triggered pulmonary and systemic inflammation in mice fed with three different diets
Alexander A G?tz, Jan Rozman, Heiko G R?del, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabě de Angelis, Martin Klingenspor, Tobias Stoeger
Particle and Fibre Toxicology , 2011, DOI: 10.1186/1743-8977-8-30
Abstract: In this study we addressed the question, whether a diet challenge increases the inflammatory response in the alveolar and the blood compartment in response to carbon nanoparticles (CNP), as a surrogate for ambient/urban particulate air pollutants.Mice were fed a high caloric carbohydrate-rich (CA) or a fat-rich (HF) diet for six weeks and were compared to mice kept on a purified low fat (LF) diet, respectively. Bronchoalveolar lavage (BAL) and blood samples were taken 24 h after intratracheal CNP instillation and checked for cellular and molecular markers of inflammation.The high caloric diets resulted in distinct effects when compared with LF mice, respectively: CA resulted in increased body and fat mass without affecting blood cellular immunity. Conversely, HF activated the blood system, increasing lymphocyte and neutrophil counts, and resulted in slightly increased body fat content. In contrast to higher pro-inflammatory BAL Leptin in CA and HF mice, on a cellular level, both diets did not lead to an increased pro-inflammatory basal status in the alveolar compartment per se, nor did result in differences in the particle-triggered response. However both diets resulted in a disturbance of the alveolar capillary barrier as indicated by enhanced BAL protein and lactate-dehydrogenase concentrations. Systemically, reduced serum Adiponectin in HF mice might be related to the observed white blood cell increase.The increase in BAL pro-inflammatory factors in high caloric groups and reductions in serum concentrations of anti-inflammatory factors in HF mice, clearly show diet-specific effects, pointing towards augmented systemic inflammatory conditions. Our data suggest that extended feeding periods, leading to manifest obesity, are necessary to generate an increased susceptibility to particle-induced lung inflammation; although the diet-challenge already was efficient in driving pro-inflammatory systemic events.Obesity and its common sequelae (e.g. type II diabetes and car
In Vivo Functional Requirement of the Mouse Ifitm1 Gene for Germ Cell Development, Interferon Mediated Immune Response and Somitogenesis
Ingeborg Klymiuk, Lukas Kenner, Thure Adler, Dirk H. Busch, Auke Boersma, Martin Irmler, Valérie Gailus-Durner, Helmut Fuchs, Nicole Leitner, Mathias Müller, Ralf Kühn, Michaela Schlederer, Irina Treise, Martin Hrabě de Angelis, Johannes Beckers
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044609
Abstract: The mammalian Interferon induced transmembrane protein 1 (Ifitm1) gene was originally identified as a member of a gene family highly inducible by type I and type II interferons. Based on expression analyses, it was suggested to be required for normal primordial germ cell migration. The knockdown of Ifitm1 in mouse embryos provided evidence for a role in somitogenesis. We generated the first targeted knockin allele of the Ifitm1 gene to systematically reassess all inferred functions. Sperm motility and the fertility of male and female mutant mice are as in wild type littermates. Embryonic somites and the adult vertebral column appear normal in homozygous Ifitm1 knockout mice, demonstrating that Ifitm1 is not essential for normal segmentation of the paraxial mesoderm. Proportions of leucocyte subsets, including granulocytes, monocytes, B-cells, T-cells, NK-cells, and NKT-cells, are unchanged in mutant mice. Based on a normal immune response to Listeria monocytogenes infection, there is no evidence for a dysfunction in downstream IFNγ signaling in Ifitm1 mutant mice. Expression from the Ifitm1 locus from E8.5 to E14.5 is highly dynamic. In contrast, in adult mice, Ifitm1 expression is highly restricted and strong in the bronchial epithelium. Intriguingly, IFITM1 is highly overexpressed in tumor epithelia cells of human squamous cell carcinomas and in adenocarcinomas of NSCLC patients. These analyses underline the general importance of targeted in vivo studies for the functional annotation of the mammalian genome. The first comprehensive description of the Ifitm1 expression pattern provides a rational basis for the further examination of Ifitm1 gene functions. Based on our data, the fact that IFITM1 can function as a negative regulator of cell proliferation, and because the gene maps to chromosome band 11p15.5, previously associated with NSCLC, it is likely that IFITM1 in man has a key role in tumor formation.
Prdm5 Regulates Collagen Gene Transcription by Association with RNA Polymerase II in Developing Bone
Giorgio Giacomo Galli,Kristian Honnens de Lichtenberg,Matteo Carrara,Wolfgang Hans,Manuela Wuelling,Bettina Mentz,Hinke Arnolda Multhaupt,Cathrine Kolster Fog,Klaus Thorleif Jensen,Juri Rappsilber,Andrea Vortkamp,Les Coulton,Helmut Fuchs,Valérie Gailus-Durner,Martin Hrabě de Angelis,Raffaele Adolfo Calogero,John Robert Couchman,Anders Henrik Lund
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002711
Abstract: PRDM family members are transcriptional regulators involved in tissue specific differentiation. PRDM5 has been reported to predominantly repress transcription, but a characterization of its molecular functions in a relevant biological context is lacking. We demonstrate here that Prdm5 is highly expressed in developing bones; and, by genome-wide mapping of Prdm5 occupancy in pre-osteoblastic cells, we uncover a novel and unique role for Prdm5 in targeting all mouse collagen genes as well as several SLRP proteoglycan genes. In particular, we show that Prdm5 controls both Collagen I transcription and fibrillogenesis by binding inside the Col1a1 gene body and maintaining RNA polymerase II occupancy. In vivo, Prdm5 loss results in delayed ossification involving a pronounced impairment in the assembly of fibrillar collagens. Collectively, our results define a novel role for Prdm5 in sustaining the transcriptional program necessary to the proper assembly of osteoblastic extracellular matrix.
Loss of the Actin Remodeler Eps8 Causes Intestinal Defects and Improved Metabolic Status in Mice
Arianna Tocchetti,Charlotte Blanche Ekalle Soppo,Fabio Zani,Fabrizio Bianchi,Maria Cristina Gagliani,Benedetta Pozzi,Jan Rozman,Ralf Elvert,Nicole Ehrhardt,Birgit Rathkolb,Corinna Moerth,Marion Horsch,Helmut Fuchs,Valérie Gailus-Durner,Johannes Beckers,Martin Klingenspor,Eckhard Wolf,Martin Hrabé de Angelis,Eugenio Scanziani,Carlo Tacchetti,Giorgio Scita,Pier Paolo Di Fiore,Nina Offenh?user
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0009468
Abstract: In a variety of organisms, including mammals, caloric restriction improves metabolic status and lowers the incidence of chronic-degenerative diseases, ultimately leading to increased lifespan.
Dll1 Haploinsufficiency in Adult Mice Leads to a Complex Phenotype Affecting Metabolic and Immunological Processes
Isabel Rubio-Aliaga, Gerhard K. H. Przemeck, Helmut Fuchs, Valérie Gailus-Durner, Thure Adler, Wolfgang Hans, Marion Horsch, Birgit Rathkolb, Jan Rozman, Anja Schrewe, Sibylle Wagner, Sabine M. Hoelter, Lore Becker, Thomas Klopstock, Wolfgang Wurst, Eckhard Wolf, Martin Klingenspor, Boris T. Ivandic, Dirk H. Busch, Johannes Beckers, Martin Hrabé de Angelis
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006054
Abstract: Background The Notch signaling pathway is an evolutionary conserved signal transduction pathway involved in embryonic patterning and regulation of cell fates during development and self-renewal. Recent studies have demonstrated that this pathway is integral to a complex system of interactions, involving as well other signal transduction pathways, and implicated in distinct human diseases. Delta-like 1 (Dll1) is one of the known ligands of the Notch receptors. The role of the Notch ligands is less well understood. Loss-of-function of Dll1 leads to embryonic lethality, but reduction of Delta-like 1 protein levels has not been studied in adult stage. Methodology/Principal Findings Here we present the haploinsufficient phenotype of Dll1 and a missense mutant Dll1 allele (Dll1C413Y). Haploinsufficiency leads to a complex phenotype with several biological processes altered. These alterations reveal the importance of Dll1 mainly in metabolism, energy balance and in immunology. The animals are smaller, lighter, with altered fat to lean ratio and have increased blood pressure and a slight bradycardia. The animals have reduced cholesterol and triglyceride levels in blood. At the immunological level a subtle phenotype is observed due to the effect and fine-tuning of the signaling network at the different levels of differentiation, proliferation and function of lymphocytes. Moreover, the importance of the proteolytic regulation of the Notch signaling network emphasized. Conclusions/Significance In conclusion, slight alterations in one player of Notch signaling alter the entire organism, emphasizing the fine-tuning character of this pathway in a high number of processes.
The Endocytic Adaptor Eps15 Controls Marginal Zone B Cell Numbers
Benedetta Pozzi, Stefania Amodio, Caterina Lucano, Anna Sciullo, Simona Ronzoni, Daniela Castelletti, Thure Adler, Irina Treise, Ingrid Holmberg Betsholtz, Birgit Rathkolb, Dirk H. Busch, Eckhard Wolf, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabě de Angelis, Christer Betsholtz, Stefano Casola, Pier Paolo Di Fiore, Nina Offenh?user
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0050818
Abstract: Eps15 is an endocytic adaptor protein involved in clathrin and non-clathrin mediated endocytosis. In Caenorhabditis elegans and Drosophila melanogaster lack of Eps15 leads to defects in synaptic vesicle recycling and synapse formation. We generated Eps15-KO mice to investigate its function in mammals. Eps15-KO mice are born at the expected Mendelian ratio and are fertile. Using a large-scale phenotype screen covering more than 300 parameters correlated to human disease, we found that Eps15-KO mice did not show any sign of disease or neural deficits. Instead, altered blood parameters pointed to an immunological defect. By competitive bone marrow transplantation we demonstrated that Eps15-KO hematopoietic precursor cells were more efficient than the WT counterparts in repopulating B220+ bone marrow cells, CD19? thymocytes and splenic marginal zone (MZ) B cells. Eps15-KO mice showed a 2-fold increase in MZ B cell numbers when compared with controls. Using reverse bone marrow transplantation, we found that Eps15 regulates MZ B cell numbers in a cell autonomous manner. FACS analysis showed that although MZ B cells were increased in Eps15-KO mice, transitional and pre-MZ B cell numbers were unaffected. The increase in MZ B cell numbers in Eps15 KO mice was not dependent on altered BCR signaling or Notch activity. In conclusion, in mammals, the endocytic adaptor protein Eps15 is a regulator of B-cell lymphopoiesis.
Standardized, Systemic Phenotypic Analysis of UmodC93F and UmodA227T Mutant Mice
Elisabeth Kemter, Petra Prückl, Birgit Rathkolb, Kateryna Micklich, Thure Adler, Lore Becker, Johannes Beckers, Dirk H. Busch, Alexander A. G?tz, Wolfgang Hans, Marion Horsch, Boris Ivandic, Martin Klingenspor, Thomas Klopstock, Jan Rozman, Anja Schrewe, Holger Schulz, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabé de Angelis, Eckhard Wolf, Bernhard Aigner
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078337
Abstract: Uromodulin-associated kidney disease (UAKD) summarizes different clinical features of an autosomal dominant heritable disease syndrome in humans with a proven uromodulin (UMOD) mutation involved. It is often characterized by hyperuricemia, gout, alteration of urine concentrating ability, as well as a variable rate of disease progression inconstantly leading to renal failure and histological alterations of the kidneys. We recently established the two Umod mutant mouse lines UmodC93F and UmodA227T on the C3H inbred genetic background both showing kidney defects analogous to those found in human UAKD patients. In addition, disease symptoms were revealed that were not yet described in other published mouse models of UAKD. To examine if further organ systems and/or metabolic pathways are affected by Umod mutations as primary or secondary effects, we describe a standardized, systemic phenotypic analysis of the two mutant mouse lines UmodA227T and UmodC93F in the German Mouse Clinic. Different genotypes as well as different ages were tested. Beside the already published changes in body weight, body composition and bone metabolism, the influence of the Umod mutation on energy metabolism was confirmed. Hematological analysis revealed a moderate microcytic and erythropenic anemia in older Umod mutant mice. Data of the other analyses in 7-10 month-old mutant mice showed single small additional effects.
Mouse Nuclear Myosin I Knock-Out Shows Interchangeability and Redundancy of Myosin Isoforms in the Cell Nucleus
Tomá? Venit, Rastislav Dzijak, Al?běta Kalendová, Michal Kahle, Jana Roho?ková, Volker Schmidt, Thomas Rülicke, Birgit Rathkolb, Wolfgang Hans, Alexander Bohla, Oliver Eickelberg, Tobias Stoeger, Eckhard Wolf, Ali ?nder Yildirim, Valérie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Pavel Hozák
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061406
Abstract: Background Nuclear myosin I (NM1) is a nuclear isoform of the well-known “cytoplasmic” Myosin 1c protein (Myo1c). Located on the 11th chromosome in mice, NM1 results from an alternative start of transcription of the Myo1c gene adding an extra 16 amino acids at the N-terminus. Previous studies revealed its roles in RNA Polymerase I and RNA Polymerase II transcription, chromatin remodeling, and chromosomal movements. Its nuclear localization signal is localized in the middle of the molecule and therefore directs both Myosin 1c isoforms to the nucleus. Methodology/Principal Findings In order to trace specific functions of the NM1 isoform, we generated mice lacking the NM1 start codon without affecting the cytoplasmic Myo1c protein. Mutant mice were analyzed in a comprehensive phenotypic screen in cooperation with the German Mouse Clinic. Strikingly, no obvious phenotype related to previously described functions has been observed. However, we found minor changes in bone mineral density and the number and size of red blood cells in knock-out mice, which are most probably not related to previously described functions of NM1 in the nucleus. In Myo1c/NM1 depleted U2OS cells, the level of Pol I transcription was restored by overexpression of shRNA-resistant mouse Myo1c. Moreover, we found Myo1c interacting with Pol II. The ratio between Myo1c and NM1 proteins were similar in the nucleus and deletion of NM1 did not cause any compensatory overexpression of Myo1c protein. Conclusion/Significance We observed that Myo1c can replace NM1 in its nuclear functions. Amount of both proteins is nearly equal and NM1 knock-out does not cause any compensatory overexpression of Myo1c. We therefore suggest that both isoforms can substitute each other in nuclear processes.
Neurobeachin, a Regulator of Synaptic Protein Targeting, Is Associated with Body Fat Mass and Feeding Behavior in Mice and Body-Mass Index in Humans
Pawel K. Olszewski,Jan Rozman,Josefin A. Jacobsson,Birgit Rathkolb,Siv Str?mberg,Wolfgang Hans,Anica Klockars,Johan Alsi?,Ulf Risérus,Lore Becker,Sabine M. H?lter,Ralf Elvert,Nicole Ehrhardt,Valérie Gailus-Durner,Helmut Fuchs,Robert Fredriksson,Eckhard Wolf,Thomas Klopstock,Wolfgang Wurst,Allen S. Levine,Claude Marcus,Martin Hrabě de Angelis,Martin Klingenspor,Helgi B. Schi?th ?,Manfred W. Kilimann ?
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002568
Abstract: Neurobeachin (Nbea) regulates neuronal membrane protein trafficking and is required for the development and functioning of central and neuromuscular synapses. In homozygous knockout (KO) mice, Nbea deficiency causes perinatal death. Here, we report that heterozygous KO mice haploinsufficient for Nbea have higher body weight due to increased adipose tissue mass. In several feeding paradigms, heterozygous KO mice consumed more food than wild-type (WT) controls, and this consumption was primarily driven by calories rather than palatability. Expression analysis of feeding-related genes in the hypothalamus and brainstem with real-time PCR showed differential expression of a subset of neuropeptide or neuropeptide receptor mRNAs between WT and Nbea+/? mice in the sated state and in response to food deprivation, but not to feeding reward. In humans, we identified two intronic NBEA single-nucleotide polymorphisms (SNPs) that are significantly associated with body-mass index (BMI) in adult and juvenile cohorts. Overall, data obtained in mice and humans suggest that variation of Nbea abundance or activity critically affects body weight, presumably by influencing the activity of feeding-related neural circuits. Our study emphasizes the importance of neural mechanisms in body weight control and points out NBEA as a potential risk gene in human obesity.

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