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49 results on '"Moreth, Kristin"'

1. Creld1 regulates myocardial development and function

Author

Beckert, Vera, Rassmann, Sebastian, Kayvanjoo, Amir Hossein, Klausen, Christina, Bonaguro, Lorenzo, Botermann, Dominik Simon, Krause, Melanie, Moreth, Kristin, Spielmann, Nadine, da Silva-Buttkus, Patricia, Fuchs, Helmut, Gailus-Durner, Valerie, de Angelis, Martin Hrabě, Händler, Kristian, Ulas, Thomas, Aschenbrenner, Anna C., Mass, Elvira, and Wachten, Dagmar

Published
2021
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2. A mouse model for intellectual disability caused by mutations in the X-linked 2′‑O‑methyltransferase Ftsj1 gene

Author

Jensen, Lars R., Garrett, Lillian, Hölter, Sabine M., Rathkolb, Birgit, Rácz, Ildikó, Adler, Thure, Prehn, Cornelia, Hans, Wolfgang, Rozman, Jan, Becker, Lore, Aguilar-Pimentel, Juan Antonio, Puk, Oliver, Moreth, Kristin, Dopatka, Monika, Walther, Diego J., von Bohlen und Halbach, Viola, Rath, Matthias, Delatycki, Martin, Bert, Bettina, Fink, Heidrun, Blümlein, Katharina, Ralser, Markus, Van Dijck, Anke, Kooy, Frank, Stark, Zornitza, Müller, Sabine, Scherthan, Harry, Gecz, Jozef, Wurst, Wolfgang, Wolf, Eckhard, Zimmer, Andreas, Klingenspor, Martin, Graw, Jochen, Klopstock, Thomas, Busch, Dirk, Adamski, Jerzy, Fuchs, Helmut, Gailus-Durner, Valérie, de Angelis, Martin Hrabě, von Bohlen und Halbach, Oliver, Ropers, Hans-Hilger, and Kuss, Andreas W.

Published
2019
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4. Understanding gene functions and disease mechanisms: Phenotyping pipelines in the German Mouse Clinic

Author

Fuchs, Helmut, Aguilar-Pimentel, Juan Antonio, Amarie, Oana V., Becker, Lore, Calzada-Wack, Julia, Cho, Yi-Li, Garrett, Lillian, Hölter, Sabine M., Irmler, Martin, Kistler, Martin, Kraiger, Markus, Mayer-Kuckuk, Philipp, Moreth, Kristin, Rathkolb, Birgit, Rozman, Jan, da Silva Buttkus, Patricia, Treise, Irina, Zimprich, Annemarie, Gampe, Kristine, Hutterer, Christine, Stöger, Claudia, Leuchtenberger, Stefanie, Maier, Holger, Miller, Manuel, Scheideler, Angelika, Wu, Moya, Beckers, Johannes, Bekeredjian, Raffi, Brielmeier, Markus, Busch, Dirk H., Klingenspor, Martin, Klopstock, Thomas, Ollert, Markus, Schmidt-Weber, Carsten, Stöger, Tobias, Wolf, Eckhard, Wurst, Wolfgang, Yildirim, Ali Önder, Zimmer, Andreas, Gailus-Durner, Valérie, and Hrabě de Angelis, Martin

Published
2018
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5. The Role of Fibroblast Growth Factor-Binding Protein 1 in Skin Carcinogenesis and Inflammation

Author

Becker, Lore, Vernaleken, Alexandra, Klopstock, Thomas, Adler, Thure, Treise, Irina, Horsch, Marion, Moreth, Kristin, Brommage, Robert, Hans, Wolfgang, Östereicher, Manuela, Steinkamp, Ralph, Lengger, Christoph, Maier, Holger, Stoeger, Claudia, Leuchtenberger, Stefanie, Busch, Dirk H., Beckers, Johannes, Bekeredjian, Raffi, Garrett, Lillian, Hölter, Sabine M., Zimprich, Annemarie, Amarie, Oana, Wurst, Wolfgang, Graw, Jochen, Rozman, Jan, Calzada-Wack, Julia, da Silva-Buttkus, Patricia, Neff, Frauke, Klingenspor, Martin, Racz, Ildiko, Zimmer, Andreas, Rathkolb, Birgit, Wolf, Eckhard, Schmidt, Marcel Oliver, Garman, Khalid Ammar, Lee, Yong Gu, Zuo, Chong, Beck, Patrick James, Tan, Mingjun, Aguilar-Pimentel, Juan Antonio, Ollert, Markus, Schmidt-Weber, Carsten, Fuchs, Helmut, Gailus-Durner, Valerie, Hrabe de Angelis, Martin, Tassi, Elena, Riegel, Anna Tate, and Wellstein, Anton

Published
2018
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6. Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease

Author

Finan, Brian, Clemmensen, Christoffer, Zhu, Zhimeng, Stemmer, Kerstin, Gauthier, Karine, Müller, Luisa, De Angelis, Meri, Moreth, Kristin, Neff, Frauke, Perez-Tilve, Diego, Fischer, Katrin, Lutter, Dominik, Sánchez-Garrido, Miguel A., Liu, Peng, Tuckermann, Jan, Malehmir, Mohsen, Healy, Marc E., Weber, Achim, Heikenwalder, Mathias, Jastroch, Martin, Kleinert, Maximilian, Jall, Sigrid, Brandt, Sara, Flamant, Frédéric, Schramm, Karl-Werner, Biebermann, Heike, Döring, Yvonne, Weber, Christian, Habegger, Kirk M., Keuper, Michaela, Gelfanov, Vasily, Liu, Fa, Köhrle, Josef, Rozman, Jan, Fuchs, Helmut, Gailus-Durner, Valerie, Hrabě de Angelis, Martin, Hofmann, Susanna M., Yang, Bin, Tschöp, Matthias H., DiMarchi, Richard, and Müller, Timo D.

Published
2016
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9. RNA editing of Filamin A pre‐mRNA regulates vascular contraction and diastolic blood pressure

Author

Jain, Mamta, Mann, Tomer D, Stulić, Maja, Rao, Shailaja P, Kirsch, Andrijana, Pullirsch, Dieter, Strobl, Xué, Rath, Claus, Reissig, Lukas, Moreth, Kristin, Klein‐Rodewald, Tanja, Bekeredjian, Raffi, Gailus‐Durner, Valerie, Fuchs, Helmut, Hrabě de Angelis, Martin, Pablik, Eleonore, Cimatti, Laura, Martin, David, Zinnanti, Jelena, Graier, Wolfgang F, Sibilia, Maria, Frank, Saša, Levanon, Erez Y, and Jantsch, Michael F

Published
2018
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10. Cardioprotection and lifespan extension by the natural polyamine spermidine

Author

Eisenberg, Tobias, Abdellatif, Mahmoud, Schroeder, Sabrina, Primessnig, Uwe, Stekovic, Slaven, Pendl, Tobias, Harger, Alexandra, Schipke, Julia, Zimmermann, Andreas, Schmidt, Albrecht, Tong, Mingming, Ruckenstuhl, Christoph, Dammbrueck, Christopher, Gross, Angelina S, Herbst, Viktoria, Magnes, Christoph, Trausinger, Gert, Narath, Sophie, Meinitzer, Andreas, Hu, Zehan, Kirsch, Alexander, Eller, Kathrin, Carmona-Gutierrez, Didac, Büttner, Sabrina, Pietrocola, Federico, Knittelfelder, Oskar, Schrepfer, Emilie, Rockenfeller, Patrick, Simonini, Corinna, Rahn, Alexandros, Horsch, Marion, Moreth, Kristin, Beckers, Johannes, Fuchs, Helmut, Gailus-Durner, Valerie, Neff, Frauke, Janik, Dirk, Rathkolb, Birgit, Rozman, Jan, de Angelis, Martin Hrabe, Moustafa, Tarek, Haemmerle, Guenter, Mayr, Manuel, Willeit, Peter, von Frieling-Salewsky, Marion, Pieske, Burkert, Scorrano, Luca, Pieber, Thomas, Pechlaner, Raimund, Willeit, Johann, Sigrist, Stephan J, Linke, Wolfgang A, Mühlfeld, Christian, Sadoshima, Junichi, Dengjel, Joern, Kiechl, Stefan, Kroemer, Guido, Sedej, Simon, and Madeo, Frank

Subjects
Polyamines -- Research, Cardiovascular diseases -- Research, Biological sciences, Health
Abstract

Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease., Author(s): Tobias Eisenberg [1, 2]; Mahmoud Abdellatif [3]; Sabrina Schroeder [1]; Uwe Primessnig [3, 4]; Slaven Stekovic [1]; Tobias Pendl [1]; Alexandra Harger [1, 5]; Julia Schipke [6, 7]; Andreas [...]

Published
2016
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11. Serum Response Factor (SRF) Ablation Interferes with Acute Stress-Associated Immediate and Long-Term Coping Mechanisms

Author

Zimprich, Annemarie, Mroz, Gabi, Meyer zu Reckendorf, Christopher, Anastasiadou, Sofia, Förstner, Philip, Garrett, Lillian, Hölter, Sabine M., Becker, Lore, Rozman, Jan, Prehn, Cornelia, Rathkolb, Birgit, Moreth, Kristin, Wurst, Wolfgang, Klopstock, Thomas, Klingenspor, Martin, Adamski, Jerzy, Wolf, Eckhard, Bekeredjian, Raffi, Fuchs, Helmut, Gailus-Durner, Valerie, de Angelis, Martin Hrabe, and Knöll, Bernd

Published
2016
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13. Every-other-day feeding extends lifespan but fails to delay many symptoms of aging in mice

Author

Xie, Kan, Neff, Frauke, Markert, Astrid, Rozman, Jan, Aguilar-Pimentel, Juan Antonio, Amarie, Oana Veronica, Becker, Lore, Brommage, Robert, Garrett, Lillian, Henzel, Kristin S., Hölter, Sabine M., Janik, Dirk, Lehmann, Isabelle, Moreth, Kristin, Pearson, Brandon L., Racz, Ildiko, Rathkolb, Birgit, Ryan, Devon P., Schröder, Susanne, Treise, Irina, Bekeredjian, Raffi, Busch, Dirk H., Graw, Jochen, Ehninger, Gerhard, Klingenspor, Martin, Klopstock, Thomas, Ollert, Markus, Sandholzer, Michael, Schmidt-Weber, Carsten, Weiergräber, Marco, Wolf, Eckhard, Wurst, Wolfgang, Zimmer, Andreas, Gailus-Durner, Valerie, Fuchs, Helmut, Hrabě de Angelis, Martin, and Ehninger, Dan

Published
2017
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17. Rapamycin extends murine lifespan but has limited effects on aging

Author

Neff, Frauke, Flores-Dominguez, Diana, Ryan, Devon P., Horsch, Marion, Schroder, Susanne, Adler, Thure, Afonso, Luciana Caminha, Aguilar-Pimentel, Juan Antonio, Becker, Lore, Garrett, Lillian, Hans, Wolfgang, Hettich, Moritz M., Holtmeier, Richard, Holter, Sabine M., Moreth, Kristin, Prehn, Cornelia, Puk, Oliver, Racz, Ildiko, Rathkolb, Birgit, Rozman, Jan, Naton, Beatrix, Ordemann, Rainer, Adamski, Jerzy, Beckers, Johannes, Bekeredjian, Raffi, Busch, Dirk H., Ehninger, Gerhard, Graw, Jochen, Hofler, Heinz, Klingenspor, Martin, Klopstock, Thomas, Ollert, Markus, Stypmann, Jorg, Wolf, Eckhard, Wurst, Wolfgang, Zimmer, Andreas, Fuchs, Helmut, Gailus-Durner, Valerie, de Angelis, Martin Hrabe, and Ehninger, Dan

Subjects
Aging -- Research, Rapamycin -- Dosage and administration -- Physiological aspects, Life spans (Biology) -- Research, Health care industry
Abstract

Aging is a major risk factor for a large number of disorders and functional impairments. Therapeutic targeting of the aging process may therefore represent an innovative strategy in the quest [...]

Published
2013
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18. The proteoglycan biglycan regulates expression of the B cell chemoattractant CXCL13 and aggravates murine lupus nephritis

Author

Moreth, Kristin, Brodbeck, Rebekka, Babelova, Andrea, Gretz, Norbert, Spieker, Tilmann, Zeng-Brouwers, Jinyang, Pfeilschifter, Josef, Young, Marian F., Schaefer, Roland M., and Schaefer, Liliana

Subjects
Gene expression -- Physiological aspects, Nephritis -- Genetic aspects, Proteoglycans -- Properties, B cells -- Genetic aspects, Health care industry
Abstract

CXCL13 is a key B cell chemoattractant and marker of disease activity in patients with SLE; however, the mechanism of its induction has not been identified yet. Here, we have shown that the proteoglycan biglycan triggers CXCL13 expression via TLR2/4 in macrophages and dendritic cells. In vivo, levels of biglycan were markedly elevated in the plasma and kidneys of human SLE patients and lupus-prone (MRL/lpr) mice. Overexpression of soluble biglycan in MRL/lpr mice raised plasma and renal levels of CXCL13 and caused accumulation of B cells with an enhanced B1/B cell ratio in the kidney, worsening of organ damage, and albuminuria. Importantly, biglycan also triggered CXCL13 expression and B cell infiltration in the healthy kidney. Conversely, biglycan deficiency improved systemic and renal outcome in lupus-prone mice, with lower levels of autoantibodies, less enlargement of the spleen and lymph nodes, and reduction in renal damage and albuminuria. This correlated with a marked decline in circulating and renal CXCL13 and a reduction in the number of B cells in the kidney. Collectively, our results describe what we believe to be a novel mechanism for the regulation of CXCL13 by biglycan, a host-derived ligand for TLR2/4. Blocking biglycan-TLR2/4 interactions might be a promising strategy for the management of SLE and other B cell-mediated inflammatory disease entities., Introduction There is growing evidence that extracellular matrix components, commonly thought to function purely as structural components, also act as signaling molecules and directly regulate inflammatory processes (1). Biglycan, a [...]

Published
2010
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20. Claudin-12 is not required for blood–brain barrier tight junction function

Author

Castro Dias, Mariana, Coisne, Caroline, Engelhardt, Britta, Aguilar-Pimentel, Antonio, Adler, Thure, Busch, Dirk H, Spielmann, Nadine, Moreth, Kristin, Hans, Wolfgang, Amarie, Oana, Graw, Jochen, Rozman, Jan, Baden, Pascale, Radc, Ildiko, Neff, Frauke, Calzada-Wack, Julia, Rathkolb, Birgit, Wolf, Eckhard, Klopstock, Thomas, Wurst, Wolfgang, Beckers, Johannes, Östereicher, Manuela, Miller, Gregor, Enzmann, Gaby, Maier, Holger, Stoeger, Claudia, Leuchtenberger, Stefanie, Gailus-Durner, Valérie, Fuchs, Helmut, Garrett, Lillian, Becker, Lore, Hölter, Sabine M, Consortium, German Mouse Clinic, Hrabě de Angelis, Martin, and Deutsch, Urban

Subjects
Male, 0301 basic medicine, endocrine system diseases, urologic and male genital diseases, lcsh:RC346-429, 0302 clinical medicine, Claudin-12, Gene Knock-In Techniques, Experimental autoimmune encephalomyelitis, Tight junction, General Medicine, ddc, 3. Good health, Cell biology, medicine.anatomical_structure, Neurology, Blood-Brain Barrier, Paracellular transport, Female, tissues, Cell type, Encephalomyelitis, Autoimmune, Experimental, Central nervous system, 610 Medicine & health, Mice, Transgenic, Biology, Blood–brain barrier, digestive system, Tight Junctions, 03 medical and health sciences, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Animals, ddc:610, Claudin, lcsh:Neurology. Diseases of the nervous system, Neuroinflammation, Blood–brain Barrier, Experimental Autoimmune Encephalomyelitis, Research, Endothelial Cells, medicine.disease, digestive system diseases, Mice, Inbred C57BL, 030104 developmental biology, Claudins, 570 Life sciences, biology, 030217 neurology & neurosurgery
Abstract

Background The blood–brain barrier (BBB) ensures central nervous system (CNS) homeostasis by strictly controlling the passage of molecules and solutes from the bloodstream into the CNS. Complex and continuous tight junctions (TJs) between brain endothelial cells block uncontrolled paracellular diffusion of molecules across the BBB, with claudin-5 being its dominant TJs protein. However, claudin-5 deficient mice still display ultrastructurally normal TJs, suggesting the contribution of other claudins or tight-junction associated proteins in establishing BBB junctional complexes. Expression of claudin-12 at the BBB has been reported, however the exact function and subcellular localization of this atypical claudin remains unknown. Methods We created claudin-12-lacZ-knock-in C57BL/6J mice to explore expression of claudin-12 and its role in establishing BBB TJs function during health and neuroinflammation. We furthermore performed a broad standardized phenotypic check-up of the mouse mutant. Results Making use of the lacZ reporter allele, we found claudin-12 to be broadly expressed in numerous organs. In the CNS, expression of claudin-12 was detected in many cell types with very low expression in brain endothelium. Claudin-12lacZ/lacZ C57BL/6J mice lacking claudin-12 expression displayed an intact BBB and did not show any signs of BBB dysfunction or aggravated neuroinflammation in an animal model for multiple sclerosis. Determining the precise localization of claudin-12 at the BBB was prohibited by the fact that available anti-claudin-12 antibodies showed comparable detection and staining patterns in tissues from wild-type and claudin-12lacZ/lacZ C57BL/6J mice. Conclusions Our present study thus shows that claudin-12 is not essential in establishing or maintaining BBB TJs integrity. Claudin-12 is rather expressed in cells that typically lack TJs suggesting that claudin-12 plays a role other than forming classical TJs. At the same time, in depth phenotypic screening of clinically relevant organ functions of claudin-12lacZ/lacZ C57BL/6J mice suggested the involvement of claudin-12 in some neurological but, more prominently, in cardiovascular functions.

Published
2019
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21. CRN2 binds to TIMP4 and MMP14 and promotes perivascular invasion of glioblastoma cells

Author

Solga, Roxana, Behrens, Juliane, Ziemann, Anja, Riou, Adrien, Berwanger, Carolin, Becker, Lore, Garrett, Lillian, de Angelis, Martin Hrabe, Fischer, Lisa, Coras, Roland, Barkovits, Katalin, Marcus, Katrin, Mahabir, Esther, Eichinger, Ludwig, Schroeder, Rolf, Noegel, Angelika A., Clemen, Christoph S., Aguilar-Pimentel, Antonio, Schmidt-Weber, Carsten, Klopstock, Thomas, Adler, Thure, Treisel, Irina, Busch, Dirk H., Moreth, Kristin, Hoelter, Sabine M., Zimprich, Annemarie, Wurst, Wolfgang, Amarie, Oana, Graw, Jochen, Rozman, Jan, Calzada-Wack, Julia, Racz, Ildiko, Rathkolb, Birgit, Wolf, Eckhard, Oestereicher, Manuela, Miller, Gregor, Lengger, Christoph, Maier, Holger, Stoeger, Claudia, Leuchtenberger, Stefanie, Gallus-Durner, Valerie, Fuchs, Helmut, Solga, Roxana, Behrens, Juliane, Ziemann, Anja, Riou, Adrien, Berwanger, Carolin, Becker, Lore, Garrett, Lillian, de Angelis, Martin Hrabe, Fischer, Lisa, Coras, Roland, Barkovits, Katalin, Marcus, Katrin, Mahabir, Esther, Eichinger, Ludwig, Schroeder, Rolf, Noegel, Angelika A., Clemen, Christoph S., Aguilar-Pimentel, Antonio, Schmidt-Weber, Carsten, Klopstock, Thomas, Adler, Thure, Treisel, Irina, Busch, Dirk H., Moreth, Kristin, Hoelter, Sabine M., Zimprich, Annemarie, Wurst, Wolfgang, Amarie, Oana, Graw, Jochen, Rozman, Jan, Calzada-Wack, Julia, Racz, Ildiko, Rathkolb, Birgit, Wolf, Eckhard, Oestereicher, Manuela, Miller, Gregor, Lengger, Christoph, Maier, Holger, Stoeger, Claudia, Leuchtenberger, Stefanie, Gallus-Durner, Valerie, and Fuchs, Helmut

Abstract

CRN2 is an actin filament binding protein involved in the regulation of various cellular processes including cell migration and invasion. CRN2 has been implicated in the malignant progression of different types of human cancer. We used CRN2 knock-out mice for analyses as well as for crossbreeding with a Tp53/Pten knock-out glioblastoma mouse model. CRN2 knock-out mice were subjected to a phenotyping screen at the German Mouse Clinic. Murine glioblastoma tissue specimens as well as cultured murine brain slices and glioblastoma cell lines were investigated by immunohistochemistry, immunofluorescence, and cell biological experiments. Protein interactions were studied by immunoprecipitation, pull-down, and enzyme activity assays. CRN2 knock-out mice displayed neurological and behavioural alterations, e.g. reduced hearing sensitivity, reduced acoustic startle response, hypoactivity, and less frequent urination. While glioblastoma mice with or without the additional CRN2 knock-out allele exhibited no significant difference in their survival rates, the increased levels of CRN2 in transplanted glioblastoma cells caused a higher tumour cell encasement of murine brain slice capillaries. We identified two important factors of the tumour microenvironment, the tissue inhibitor of matrix metalloproteinase 4 (TIMP4) and the matrix metalloproteinase 14 (MMP14, synonym: MT1-MMP), as novel binding partners of CRN2. All three proteins mutually interacted and co-localised at the front of lamellipodia, and CRN2 was newly detected in exosomes. On the functional level, we demonstrate that CRN2 increased the secretion of TIMP4 as well as the catalytic activity of MMP14. Our results imply that CRN2 represents a pro-invasive effector within the tumour cell microenvironment of glioblastoma multiforme.

Published
2019

22. The heterozygous R155C VCP mutation: Toxic in humans! Harmless in mice?

Author

Clemen, Christoph S., Winter, Lilli, Strucksberg, Karl-Heinz, Berwanger, Carolin, Türk, Matthias, Kornblum, Cornelia, Florin, Alexandra, Aguilar-Pimentel, Juan Antonio, Amarie, Oana Veronica, Becker, Lore, Garrett, Lillian, Hans, Wolfgang, Moreth, Kristin, Neff, Frauke, Pingen, Laura, Rathkolb, Birgit, Rácz, Ildikó, Rozman, Jan, Treise, Irina, Fuchs, Helmut, Gailus-Durner, Valerie, de Angelis, Martin Hrabe, Vorgerd, Matthias, Eichinger, Ludwig, and Schröder, Rolf

Published
2018
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24. Streptozotocin-induced β-cell damage, high fat diet, and metformin administration regulate Hes3 expression in the adult mouse brain

Author

Nikolakopoulou, Polyxeni, Chatzigeorgiou, Antonios, Consortium, German Mouse Clinic, Wolf, Eckhard, Klingenspor, Martin, Ollert, Markus, Schmidt-Weber, Carsten, Fuchs, Helmut, Gailus-Durner, Valerie, Hrabe de Angelis, Martin, Tsata, Vasiliki, Monasor, Laura Sebastian, Kourtzelis, Ioannis, Troullinaki, Maria, Witt, Anke, Anastasiou, Vivian, Chrousos, George, Yi, Chun-Xia, García-Cáceres, Cristina, Tschöp, Matthias H, Bornstein, Stefan R, Androutsellis-Theotokis, Andreas, Becker, Lore, Toutouna, Louiza, Klopstock, Thomas, Treise, Irina, Busch, Dirk H, Beckers, Johannes, Moreth, Kristin, Bekeredjian, Raffi, Garrett, Lillian, Hölter, Sabine M, Zimprich, Annemarie, Wurst, Wolfgang, Masjkur, Jimmy, Brommage, Robert, Amarie, Oana, Graw, Jochen, Calzada-Wack, Julia, Neff, Frauke, Zimmer, Andreas, Östereicher, Manuela, Steinkamp, Ralph, Lengger, Christoph, Maier, Holger, Arps-Forker, Carina, Stoeger, Claudia, Leuchtenberger, Stefanie, Poser, Steven W, Rozman, Jan, Rathkolb, Birgit, Aguilar-Pimentel, Juan Antonio, University of Zurich, Androutsellis-Theotokis, Andreas, APH - Aging & Later Life, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Laboratory for Endocrinology, AGEM - Endocrinology, metabolism and nutrition, and ACS - Diabetes & metabolism

Subjects
Male, 0301 basic medicine, Aging, medicine.medical_treatment, 10265 Clinic for Endocrinology and Diabetology, lcsh:Medicine, drug effects [Gene Expression Regulation], Type 2 diabetes, Insulin-Secreting Cells, pathology [Insulin-Secreting Cells], Basic Helix-Loop-Helix Transcription Factors, Medicine, lcsh:Science, genetics [Nerve Tissue Proteins], Multidisciplinary, Brain, toxicity [Streptozocin], Metformin, Phenotype, Hes3 protein, mouse, medicine.drug, medicine.medical_specialty, genetics [Basic Helix-Loop-Helix Transcription Factors], Nerve Tissue Proteins, 610 Medicine & health, Diet, High-Fat, Article, Streptozocin, 03 medical and health sciences, Insulin resistance, Diabetes mellitus, Internal medicine, Animals, metabolism [Aging], Progenitor cell, 1000 Multidisciplinary, Type 1 diabetes, metabolism [Nerve Tissue Proteins], deficiency [Nerve Tissue Proteins], business.industry, Insulin, lcsh:R, administration & dosage [Metformin], metabolism [Insulin-Secreting Cells], medicine.disease, Streptozotocin, Repressor Proteins, Mice, Inbred C57BL, metabolism [Basic Helix-Loop-Helix Transcription Factors], 030104 developmental biology, Endocrinology, Gene Expression Regulation, deficiency [Basic Helix-Loop-Helix Transcription Factors], metabolism [Brain], lcsh:Q, business, ddc:600, drug effects [Insulin-Secreting Cells]
Abstract

Diabetes mellitus is a group of disorders characterized by prolonged high levels of circulating blood glucose. Type 1 diabetes is caused by decreased insulin production in the pancreas whereas type 2 diabetes may develop due to obesity and lack of exercise; it begins with insulin resistance whereby cells fail to respond properly to insulin and it may also progress to decreased insulin levels. The brain is an important target for insulin, and there is great interest in understanding how diabetes affects the brain. In addition to the direct effects of insulin on the brain, diabetes may also impact the brain through modulation of the inflammatory system. Here we investigate how perturbation of circulating insulin levels affects the expression of Hes3, a transcription factor expressed in neural stem and progenitor cells that is involved in tissue regeneration. Our data show that streptozotocin-induced β-cell damage, high fat diet, as well as metformin, a common type 2 diabetes medication, regulate Hes3 levels in the brain. This work suggests that Hes3 is a valuable biomarker helping to monitor the state of endogenous neural stem and progenitor cells in the context of diabetes mellitus.

Published
2018
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25. Identification of genetic elements in metabolism by high-throughput mouse phenotyping

Author

Rozman, Jan, Rathkolb, Birgit, Meehan, Terrence F, Codner, Gemma F, Fiegel, Tanja, Ring, Natalie, Westerberg, Henrik, Greenaway, Simon, Sneddon, Duncan, Morgan, Hugh, Loeffler, Jorik, Stewart, Michelle E, Ramirez-Solis, Ramiro, Mason, Jeremy, Bradley, Allan, Skarnes, William C, Steel, Karen P, Maguire, Simon A, Dench, Joshua, Lafont, David, Vancollie, Valerie E, Pearson, Selina A, Gates, Amy S, Sanderson, Mark, Haselimashhadi, Hamed, Shannon, Carl, Anthony, Lauren F E, Sumowski, Maksymilian T, McLaren, Robbie S B, Doe, Brendan, Wardle-Jones, Hannah, Griffiths, Mark N D, Galli, Antonella, Swiatkowska, Agnieszka, Isherwood, Christopher M, Consortium, IMPC, Speak, Anneliese O, Cambridge, Emma L, Wilson, Heather M, Caetano, Susana S, Maguire, Anna Karin B, Adams, David J, Bottomley, Joanna, Ryder, Ed, Gleeson, Diane, Pouilly, Laurent, Hough, Tertius, Rousseau, Stephane, Auburtin, Aurélie, Reilly, Patrick, Ayadi, Abdel, Selloum, Mohammed, Wood, Joshua A, Clary, Dave, Havel, Peter, Tolentino, Todd, Tolentino, Heather, Mallon, Ann-Marie, Schuchbauer, Mike, Pedroia, Sheryl, Trainor, Amanda, Djan, Esi, Pham, Milton, Huynh, Alison, De Vera, Vincent, Seavitt, John, Gallegos, Juan, Garza, Arturo, Wells, Sara, Mangin, Elise, Senderstrom, Joel, Lazo, Iride, Mowrey, Kate, Bohat, Ritu, Samaco, Rodney, Veeraragavan, Surabi, Beeton, Christine, Kalaga, Sowmya, Kelsey, Lois, Santos, Luis, Vukobradovic, Igor, Berberovic, Zorana, Owen, Celeste, Qu, Dawei, Guo, Ruolin, Newbigging, Susan, Morikawa, Lily, Law, Napoleon, Shang, Xueyuan, Feugas, Patricia, Lelliott, Christopher J, Wang, Yanchun, Eskandarian, Mohammad, Zhu, Yingchun, Penton, Patricia, Laurin, Valerie, Clarke, Shannon, Lan, Qing, Sleep, Gillian, Creighton, Amie, Jacob, Elsa, White, Jacqueline K, Danisment, Ozge, Gertsenstein, Marina, Pereira, Monica, MacMaster, Suzanne, Tondat, Sandra, Carroll, Tracy, Cabezas, Jorge, Hunter, Jane, Clark, Greg, Bubshait, Mohammed, Oestereicher, Manuela A, Sorg, Tania, Miller, David, Sohel, Khondoker, Adissu, Hibret, Ganguly, Milan, Bezginov, Alexandr, Chiani, Francesco, Di Pietro, Chiara, Di Segni, Gianfranco, Ermakova, Olga, Ferrara, Filomena, Champy, Marie-France, Fruscoloni, Paolo, Gambadoro, Aalessia, Gastaldi, Serena, Golini, Elisabetta, La Sala, Gina, Mandillo, Silvia, Marazziti, Daniela, Massimi, Marzia, Matteoni, Rafaele, Orsini, Tiziana, Bower, Lynette R, Pasquini, Miriam, Raspa, Marcello, Rauch, Aline, Rossi, Gianfranco, Rossi, Nicoletta, Putti, Sabrina, Scavizzi, Ferdinando, Tocchini-Valentini, Giuseppe D, Wakana, Shigeharu, Suzuki, Tomohiro, Reynolds, Corey L, Tamura, Masaru, Kaneda, Hideki, Furuse, Tamio, Kobayashi, Kimio, Miura, Ikuo, Yamada, Ikuko, Obata, Yuichi, Yoshiki, Atsushi, Ayabe, Shinya, Chambers, J Nicole, Flenniken, Ann M, Chalupsky, Karel, Seisenberger, Claudia, Bürger, Antje, Beig, Joachim, Kühn, Ralf, Hörlein, Andreas, Schick, Joel, Oritz, Oskar, Giesert, Florian, Graw, Jochen, Murray, Stephen A, Ollert, Markus, Schmidt-Weber, Carsten, Stoeger, Tobias, Önder Yildirim, Ali, Eickelberg, Oliver, Klopstock, Thomas, Busch, Dirk H, Bekeredjian, Raffi, Zimmer, Andreas, Jacobsen, Jules O, Nutter, Lauryl M J, Smedley, Damian, Dickinson, Mary E, Benso, Frank, Morse, Iva, Kim, Hyoung-Chin, Lee, Ho, Cho, Soo Young, Svenson, Karen L, West, David, Tocchini-Valentini, Glauco P, Schütt, Christine, Beaudet, Arthur L, Bosch, Fatima, Braun, Robert B, Dobbie, Michael S, Gao, Xiang, Herault, Yann, Moshiri, Ala, Moore, Bret A, Kent Lloyd, K. C., McKerlie, Colin, Ravindranath, Aakash Chavan, Masuya, Hiroshi, Tanaka, Nobuhiko, Flicek, Paul, Parkinson, Helen E, Sedlacek, Radislav, Seong, Je Kyung, Wang, Chi-Kuang Leo, Moore, Mark, Brown, Steve D, Tschöp, Matthias H, Leuchtenberger, Stefanie, Wurst, Wolfgang, Klingenspor, Martin, Wolf, Eckhard, Beckers, Johannes, Machicao, Fausto, Peter, Andreas, Staiger, Harald, Häring, Hans-Ulrich, Grallert, Harald, Campillos, Monica, Sharma, Sapna, Maier, Holger, Fuchs, Helmut, Gailus-Durner, Valerie, Werner, Thomas, Hrabe de Angelis, Martin, Aguilar-Pimentel, Antonio, Becker, Lore, Treise, Irina, Moreth, Kristin, Garrett, Lillian, Kistler, Martin, Hölter, Sabine M, Zimprich, Annemarie, Marschall, Susan, Amarie, Oana V, Calzada-Wack, Julia, Neff, Frauke, Brachthäuser, Laura, Lengger, Christoph, Stoeger, Claudia, Zapf, Lilly, Willershäuser, Monja, Cho, Yi-Li, da Silva-Buttkus, Patricia, Kraiger, Markus J, Mayer-Kuckuk, Philipp, Gampe, Karen Kristine, Wu, Moya, Conte, Nathalie, Warren, Jonathan, Chen, Chao-Kung, Tudose, Ilinca, Brommage, Robert, Relac, Mike, Matthews, Peter, Cater, Heather L, Natukunda, Helen P, Cleak, James, Teboul, Lydia M, Clementson-Mobbs, Sharon, Szoke-Kovacs, Zsombor, Walling, Alison P, Johnson, Sara J, Rozman, Jan [0000-0002-8035-8904], Kistler, Martin [0000-0003-0116-7761], Mason, Jeremy [0000-0002-2796-5123], Lelliott, Christopher J [0000-0001-8087-4530], Herault, Yann [0000-0001-7049-6900], Kent Lloyd, KC [0000-0002-5318-4144], McKerlie, Colin [0000-0002-2232-0967], Flicek, Paul [0000-0002-3897-7955], Maier, Holger [0000-0003-2514-8290], Fuchs, Helmut [0000-0002-5143-2677], Hrabe de Angelis, Martin [0000-0002-7898-2353], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Blood Glucose, Candidate gene, Cancer Research, Basal Metabolism/genetics, Gene regulatory network, Obesity/genetics, genetics [Metabolic Diseases], General Physics and Astronomy, Genome-wide association study, Genome, Mice, genetics [Obesity], Triglycerides/metabolism, 2.1 Biological and endogenous factors, Gene Regulatory Networks, Aetiology, lcsh:Science, metabolism [Blood Glucose], Mice, Knockout, Multidisciplinary, genetics [Basal Metabolism], Phenotype, Area Under Curve, Diabetes Mellitus, Type 2/genetics, ddc:500, Technology Platforms, Type 2, metabolism [Triglycerides], Knockout, Science, Computational biology, Biology, genetics [Diabetes Mellitus, Type 2], General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Oxygen Consumption, Metabolic Diseases, Body Weight/genetics, Diabetes Mellitus, Genetics, Animals, Humans, Metabolic Diseases/genetics, Obesity, Gene, Gene knockout, Triglycerides, Oxygen Consumption/genetics, Blood Glucose/metabolism, genetics [Body Weight], Human Genome, Body Weight, Promoter, General Chemistry, genetics [Oxygen Consumption], High-Throughput Screening Assays, 030104 developmental biology, Diabetes Mellitus, Type 2, IMPC Consortium, lcsh:Q, Basal Metabolism, Genome-Wide Association Study
Abstract

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome., The genetic basis of metabolic diseases is incompletely understood. Here, by high-throughput phenotyping of 2,016 knockout mouse strains, Rozman and colleagues identify candidate metabolic genes, many of which are associated with unexplored regulatory gene networks and metabolic traits in human GWAS.

Published
2018
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26. Additional file 1: of Standardized, systemic phenotypic analysis reveals kidney dysfunction as main alteration of Kctd1 I27N mutant mice

Author

Kumar, Sudhir, Rathkolb, Birgit, Sabrautzki, Sibylle, Krebs, Stefan, Kemter, Elisabeth, Becker, Lore, Beckers, Johannes, Bekeredjian, Raffi, Brommage, Robert, Calzada-Wack, Julia, Garrett, Lillian, HĂślter, Sabine, Horsch, Marion, Klingenspor, Martin, Klopstock, Thomas, Moreth, Kristin, Neff, Frauke, Rozman, Jan, Fuchs, Helmut, ValĂŠrie Gailus-Durner, Angelis, Martin Hrabe De, Wolf, Eckhard, and Aigner, Bernhard

Subjects
education
Abstract

Time points of the phenotypic analyses for line Kctd1 I27N in the German Mouse Clinic (GMC) (DOCX 32 kb)

Published
2017
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27. A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

Author

Bowl, Michael R., Simon, Michelle M., Ingham, Neil J., Greenaway, Simon, Santos, Luis, Cater, Heather, Taylor, Sarah, Mason, Jeremy, Kurbatova, Natalja, Pearson, Selina, Bower, Lynette R., Clary, Dave A., Meziane, Hamid, Reilly, Patrick, Minowa, Osamu, Kelsey, Lois, Allen, Sue, Clementson-Mobbs, Sharon, Codner, Gemma, Fray, Martin, Gardiner, Wendy, Joynson, Russell, Kenyon, Janet, Loeffler, Jorik, Nell, Barbara, Parker, Andrew, Quwailid, Deen, Stewart, Michelle, Walling, Alison, Zaman, Rumana, Chen, Chao Kung, Conte, Nathalie, Matthews, Peter, Relac, Mike, Tudose, Ilinca, Warren, Jonathan, Le Marchand, Elise, El Amri, Amal, El Fertak, Leila, Ennah, Hamid, Ali-Hadji, Dalila, Ayadi, Abdel, Wattenhofer-Donze, Marie, Moulaert, David, Jacquot, Sylvie, André, Philippe, Birling, Marie Christine, Pavlovic, Guillaume, Lalanne, Valérie, Lux, Aline, Riet, Fabrice, Mittelhaeuser, Christophe, Bour, Raphael, Guimond, Alain, Bam'Hamed, Chaouki, Leblanc, Sophie, Vasseur, Laurent, Selloum, Mohammed, Sorg, Tania, Ayabe, Shinya, Furuse, Tamio, Kaneda, Hideki, Kobayashi, Kimio, Masuya, Hiroshi, Miura, Ikuo, Obata, Yuichi, Suzuki, Tomohiro, Tamura, Masaru, Tanaka, Nobuhiko, Yamada, Ikuko, Yoshiki, Atsushi, Berberovic, Zorana, Bubshait, Mohammed, Cabezas, Jorge, Carroll, Tracy, Clark, Greg, Clarke, Shannon, Creighton, Amie, Danisment, Ozge, Eskandarian, Mohammad, Feugas, Patricia, Gertsenstein, Marina, Guo, Ruolin, Hunter, Jane, Jacob, Elsa, Lan, Qing, Laurin, Valerie, Law, Napoleon, MacMaster, Sue, Miller, David, Morikawa, Lily, Newbigging, Susan, Owen, Celeste, Penton, Patricia, Pereira, Monica, Qu, Dawei, Shang, Xueyuan, Sleep, Gillian, Sohel, Khondoker, Tondat, Sandra, Wang, Yanchun, Vukobradovic, Igor, Zhu, Yingchun, Chiani, Francesco, Di Pietro, Chiara, Di Segni, Gianfranco, Ermakova, Olga, Ferrara, Filomena, Fruscoloni, Paolo, Gambadoro, Aalessia, Gastaldi, Serena, Golini, Elisabetta, Sala, Gina La, Mandillo, Silvia, Marazziti, Daniela, Massimi, Marzia, Matteoni, Rafaele, Orsini, Tiziana, Pasquini, Miriam, Raspa, Marcello, Rauch, Aline, Rossi, Gianfranco, Rossi, Nicoletta, Putti, Sabrina, Scavizzi, Ferdinando, Tocchini-Valentini, Giuseppe D., Beig, Joachim, Bürger, Antje, Giesert, Florian, Graw, Jochen, Kühn, Ralf, Oritz, Oskar, Schick, Joel, Seisenberger, Claudia, Amarie, Oana, Garrett, Lillian, Hölter, Sabine M., Zimprich, Annemarie, Aguilar-Pimentel, Antonio, Beckers, Johannes, Brommage, Robert, Calzada-Wack, Julia, Fuchs, Helmut, Gailus-Durner, Valérie, Lengger, Christoph, Leuchtenberger, Stefanie, Maier, Holger, Marschall, Susan, Moreth, Kristin, Neff, Frauke, Östereicher, Manuela A., Rozman, Jan, Steinkamp, Ralph, Stoeger, Claudia, Treise, Irina, Stoeger, Tobias, Yildrim, Ali Önder, Eickelberg, Oliver, Becker, Lore, Klopstock, Thomas, Ollert, Markus, Busch, Dirk H., Schmidt-Weber, Carsten, Bekeredjian, Raffi, Zimmer, Andreas, Rathkolb, Birgit, Wolf, Eckhard, Klingenspor, Martin, Tocchini-Valentini, Glauco P., Gao, Xiang, Bradley, Allan, Skarnes, William C., Moore, Mark, Beaudet, Arthur L., Justice, Monica J., Seavitt, John, Dickinson, Mary E., Wurst, Wolfgang, De Angelis, Martin Hrabe, Herault, Yann, Wakana, Shigeharu, Nutter, Lauryl M.J., Flenniken, Ann M., McKerlie, Colin, Murray, Stephen A., Svenson, Karen L., Braun, Robert E., West, David B., Lloyd, K. C.Kent, Adams, David J., White, Jacqui, Karp, Natasha, Flicek, Paul, Smedley, Damian, Meehan, Terrence F., Parkinson, Helen E., Teboul, Lydia M., Wells, Sara, Steel, Karen P., Mallon, Ann Marie, Brown, Steve D.M., Mason, Jeremy [0000-0002-2796-5123], de Angelis, Martin Hrabe [0000-0002-7898-2353], Herault, Yann [0000-0001-7049-6900], Wakana, Shigeharu [0000-0001-8532-0924], McKerlie, Colin [0000-0002-2232-0967], Lloyd, KC Kent [0000-0002-5318-4144], Flicek, Paul [0000-0002-3897-7955], Smedley, Damian [0000-0002-5836-9850], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Cancer Research, Candidate gene, General Physics and Astronomy, Datasets as Topic, Mice, 2.1 Biological and endogenous factors, Protein Interaction Maps, Aetiology, lcsh:Science, Pediatric, Genetics, Mice, Knockout, Multidisciplinary, medicine.diagnostic_test, Hearing Tests, Ear, Phenotype, medicine.anatomical_structure, Technology Platforms, International Mouse Phenotyping Consortium, medicine.symptom, Biotechnology, Hearing Loss/epidemiology, Hearing loss, Knockout, 1.1 Normal biological development and functioning, Science, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Clinical Research, Underpinning research, medicine, otorhinolaryngologic diseases, Auditory system, Animals, Genetic Testing, IMPC, mouse, auditory dysfunction, Set (psychology), Hearing Loss, Gene, Genetic testing, Auditory dysfunction, Human Genome, General Chemistry, 030104 developmental biology, Protein Interaction Maps/genetics, lcsh:Q
Abstract

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function., The full extent of the genetic basis for hearing impairment is unknown. Here, as part of the International Mouse Phenotyping Consortium, the authors perform a hearing loss screen in 3006 mouse knockout strains and identify 52 new candidate genes for genetic hearing loss.

Published
2017
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28. Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema

Author

Egaña, Isabel, Kaito, Hiroshi, Klopstock, Thomas, Fuchs, Helmut, Gailus-Durner, Valerie, Hrabe de Angelis, Martin, Rask-Andersen, Helge, Johansson, Henrik J, Lehtiö, Janne, He, Liqun, Yildirim, Ali Ö, Hellström, Mats, Nitzsche, Anja, Consortium, German Mouse Clinic, Aguilar-Pimentel, Antonio, Ollert, Markus, Schmidt-Weber, Carsten, Amarie, Oana, Graw, Jochen, Beckers, Johannes, Garrett, Lillian, Hölter, Sabine M, Zimprich, Annemarie, Becker, Lore, Wurst, Wolfgang, Moreth, Kristin, Bekeredjian, Raffi, Neff, Frauke, Calzada-Wack, Julia, Rácz, Ildikó, Zimmer, Andreas, Rathkolb, Birgit, Wolf, Eckhard, Rozman, Jan, Ballester-Lopez, Carolina, Klingenspor, Martin, Stoeger, Tobias, Eickelberg, Oliver, Treise, Irina, Busch, Dirk H, Östereicher, Manuela, Steinkamp, Ralph, Lengger, Christoph, Maier, Holger, Stoeger, Claudia, Niaudet, Colin, Leuchtenberger, Stefanie, Petkova, Milena, Liu, Wei, Vanlandewijck, Michael, and Vernaleken, Alexandra

Subjects
Male, Heterozygote, lcsh:Medicine, Apoptosis, genetics [Emphysema], pathology [Endothelial Cells], Article, genetics [Phosphoprotein Phosphatases], Mice, Sex Factors, Phosphoprotein Phosphatases, Animals, Humans, lcsh:Science, Pald1 protein, mouse, Lung, pathology [Emphysema], metabolism [Phosphoprotein Phosphatases], Emphysema, Mice, Knockout, lcsh:R, growth & development [Endothelium, Vascular], Endothelial Cells, Embryo, Mammalian, Mice, Inbred C57BL, Disease Models, Animal, physiology [Apoptosis], lcsh:Q, Female, Endothelium, Vascular, blood supply [Lung], ddc:600
Abstract

Paladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular-specific genes and is a putative phosphatase. Paladin has also been proposed to be involved in various biological processes such as insulin signaling, innate immunity and neural crest migration. To determine the role of paladin we have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice display an emphysema-like histology with increased alveolar air spaces and impaired lung function with an obstructive phenotype. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that Pald1 is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis.

Published
2017
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29. Laboratory mouse housing conditions can be improved using common environmental enrichment without compromising data

Author

André, Viola, primary, Gau, Christine, additional, Scheideler, Angelika, additional, Aguilar-Pimentel, Juan A., additional, Amarie, Oana V., additional, Becker, Lore, additional, Garrett, Lillian, additional, Hans, Wolfgang, additional, Hölter, Sabine M., additional, Janik, Dirk, additional, Moreth, Kristin, additional, Neff, Frauke, additional, Östereicher, Manuela, additional, Racz, Ildiko, additional, Rathkolb, Birgit, additional, Rozman, Jan, additional, Bekeredjian, Raffi, additional, Graw, Jochen, additional, Klingenspor, Martin, additional, Klopstock, Thomas, additional, Ollert, Markus, additional, Schmidt-Weber, Carsten, additional, Wolf, Eckhard, additional, Wurst, Wolfgang, additional, Gailus-Durner, Valérie, additional, Brielmeier, Markus, additional, Fuchs, Helmut, additional, and Hrabé de Angelis, Martin, additional

Published
2018
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31. The Role of Fibroblast Growth Factor-Binding Protein 1 in Skin Carcinogenesis and Inflammation

Author

Schmidt, Marcel Oliver, primary, Garman, Khalid Ammar, additional, Lee, Yong Gu, additional, Zuo, Chong, additional, Beck, Patrick James, additional, Tan, Mingjun, additional, Aguilar-Pimentel, Juan Antonio, additional, Ollert, Markus, additional, Schmidt-Weber, Carsten, additional, Fuchs, Helmut, additional, Gailus-Durner, Valerie, additional, Hrabe de Angelis, Martin, additional, Tassi, Elena, additional, Riegel, Anna Tate, additional, Wellstein, Anton, additional, Becker, Lore, additional, Vernaleken, Alexandra, additional, Klopstock, Thomas, additional, Adler, Thure, additional, Treise, Irina, additional, Horsch, Marion, additional, Moreth, Kristin, additional, Brommage, Robert, additional, Hans, Wolfgang, additional, Östereicher, Manuela, additional, Steinkamp, Ralph, additional, Lengger, Christoph, additional, Maier, Holger, additional, Stoeger, Claudia, additional, Leuchtenberger, Stefanie, additional, Busch, Dirk H., additional, Beckers, Johannes, additional, Bekeredjian, Raffi, additional, Garrett, Lillian, additional, Hölter, Sabine M., additional, Zimprich, Annemarie, additional, Amarie, Oana, additional, Wurst, Wolfgang, additional, Graw, Jochen, additional, Rozman, Jan, additional, Calzada-Wack, Julia, additional, da Silva-Buttkus, Patricia, additional, Neff, Frauke, additional, Klingenspor, Martin, additional, Racz, Ildiko, additional, Zimmer, Andreas, additional, Rathkolb, Birgit, additional, and Wolf, Eckhard, additional

Published
2018
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32. The First Scube3 Mutant Mouse Line with Pleiotropic Phenotypic Alterations

Author

Fuchs, Helmut, Sabrautzki, Sibylle, Przemeck, Gerhard K. H., Leuchtenberger, Stefanie, Lorenz-Depiereux, Bettina, Becker, Lore, Rathkolb, Birgit, Horsch, Marion, Garrett, Lillian, Östereicher, Manuela A., Hans, Wolfgang, Abe, Koichiro, Sagawa, Nobuho, Rozman, Jan, Vargas-Panesso, Ingrid L., Sandholzer, Michael, Lisse, Thomas S., Adler, Thure, Aguilar-Pimentel, Juan Antonio, Calzada-Wack, Julia, Ehrhard, Nicole, Elvert, Ralf, Gau, Christine, Hölter, Sabine M., Micklich, Katja, Moreth, Kristin, Prehn, Cornelia, Puk, Oliver, Racz, Ildiko, Stoeger, Claudia, Vernaleken, Alexandra, Michel, Dian, Diener, Susanne, Wieland, Thomas, Adamski, Jerzy, Bekeredjian, Raffi, Busch, Dirk H., Favor, John, Graw, Jochen, Klingenspor, Martin, Lengger, Christoph, Maier, Holger, Neff, Frauke, Ollert, Markus, Stoeger, Tobias, Yildirim, Ali Önder, Strom, Tim M., Zimmer, Andreas, Wolf, Eckhard, Wurst, Wolfgang, Klopstock, Thomas, Beckers, Johannes, Gailus-Durner, Valerie, and Hrabé de Angelis, Martin

Subjects
Male, mouse model, genetics [Energy Metabolism], QH426-470, Investigations, pleitropy, Kidney, Kidney Function Tests, Bone and Bones, metabolism [Bone and Bones], Mice, systemic phenotype, ddc:570, pathology [Osteitis Deformans], Genetics, Animals, physiopathology [Kidney], Exome, Genetic Association Studies, Skeleton, Glycoproteins, Mice, Knockout, metabolism [Osteitis Deformans], SCUBE3, Gene Expression Profiling, Calcium-Binding Proteins, metabolism [Kidney], Chromosome Mapping, High-Throughput Nucleotide Sequencing, Osteitis Deformans, abnormalities [Skeleton], Disease Models, Animal, genetics [Osteitis Deformans], Phenotype, Mutation, Scube3 protein, mouse, Female, genetics [Glycoproteins], Paget disease of bone (PDB), Energy Metabolism
Abstract

The vertebrate Scube (Signal peptide, CUB, and EGF-like domain-containing protein) family consists of three independent members, Scube1-3, which encode secreted cell surface-associated membrane glycoproteins. Limited information about the general function of this gene family is available, and their roles during adulthood. Here, we present the first Scube3 mutant mouse line (Scube3(N294K/N294K)), which clearly shows phenotypic alterations by carrying a missense mutation in exon 8, and thus contributes to our understanding of SCUBE3 functions. We performed a detailed phenotypic characterization in the German Mouse Clinic (GMC). Scube3(N294K/N294K) mutants showed morphological abnormalities of the skeleton, alterations of parameters relevant for bone metabolism, changes in renal function, and hearing impairments. These findings correlate with characteristics of the rare metabolic bone disorder Paget disease of bone (PDB), associated with the chromosomal region of human SCUBE3 In addition, alterations in energy metabolism, behavior, and neurological functions were detected in Scube3(N294K/N294K) mice. The Scube3(N294K/N294K) mutant mouse line may serve as a new model for further studying the effect of impaired SCUBE3 gene function.

Published
2016
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33. Standardized, systemic phenotypic analysis reveals kidney dysfunction as main alteration of Kctd1 I27N mutant mice

Author

Kumar, Sudhir, primary, Rathkolb, Birgit, additional, Sabrautzki, Sibylle, additional, Krebs, Stefan, additional, Kemter, Elisabeth, additional, Becker, Lore, additional, Beckers, Johannes, additional, Bekeredjian, Raffi, additional, Brommage, Robert, additional, Calzada-Wack, Julia, additional, Garrett, Lillian, additional, Hölter, Sabine M., additional, Horsch, Marion, additional, Klingenspor, Martin, additional, Klopstock, Thomas, additional, Moreth, Kristin, additional, Neff, Frauke, additional, Rozman, Jan, additional, Fuchs, Helmut, additional, Gailus-Durner, Valérie, additional, Hrabe de Angelis, Martin, additional, Wolf, Eckhard, additional, and Aigner, Bernhard, additional

Published
2017
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34. Generation of mice lacking DUF1220 protein domains: effects on fecundity and hyperactivity

Author

Keeney, J. G., O'Bleness, M. S., Horsch, M., Consortium, German Mouse Clinic, Beckers, J., Wurst, W., Klingenspor, M., Restrepo, D., de Angelis, M Hrabě, Sikela, J. M., Adler, Thure, Aguilar-Pimentel, Antonio, Anderson, N., Amarie, Oana, Becker, Lore, Beckers, Johannes, Bekeredjian, Raffi, Busch, Dirk H, Eickelberg, Oliver, Garrett, Lillian, Graw, Jochen, Hans, Wolfgang, Hölter, Sabine M, Davis, J. M., Horsch, Marion, Janik, Dirk, Klingenspor, Martin, Klopstock, Thomas, Moreth, Kristin, Neff, Frauke, Ollert, Markus, Puk, Oliver, Rácz, Ildikó, Rathkolb, Birgit, Arevalo, N., Rozman, Jan, Stöger, Tobias, Wolf, Eckhard, Yildrim, Ali Önder, Zimmer, Andreas, de Angelis, Martin Hrabe, Gailus-Durner, Valérie, Fuchs, Helmut, Busquet, N., Chick, W., Rozman, J., Hölter, S. M., and Garrett, L.

Subjects
Blood Glucose, Male, medicine.medical_specialty, Protein domain, Gene Dosage, Mice, Transgenic, Biology, Hyperkinesis, Gene dosage, genetics [Hyperkinesis], Article, Gene Knockout Techniques, Mice, ddc:570, Internal medicine, Genetics, medicine, Animals, genetics [DNA Primers], DNA Primers, metabolism [Blood Glucose], Gene Expression Profiling, growth & development [Brain], Brain, Calorimetry, Indirect, genetics [Fertility], Human brain, Organ Size, Phenotype, Biological Evolution, DUF1220, Protein Structure, Tertiary, Gene expression profiling, medicine.anatomical_structure, Endocrinology, Fertility, Liver, Area Under Curve, Brain size, Liver function, genetics [Mice, Transgenic], metabolism [Liver]
Abstract

Sequences encoding DUF1220 protein domains show the most extreme human lineage-specific copy number increase of any coding region in the genome and have been linked to human brain evolution. In addition, DUF1220 copy number (dosage) has been implicated in influencing brain size within the human species, both in normal populations and in individuals associated with brain size pathologies (1q21-associated microcephaly and macrocephaly). More recently, increasing dosage of a subtype of DUF1220 has been linked with increasing severity of the primary symptoms of autism. Despite these intriguing associations, a function for these domains has not been described. As a first step in addressing this question, we have developed the first transgenic model of DUF1220 function by removing the single DUF1220 domain (the ancestral form) encoded in the mouse genome. In a hypothesis generating exercise, these mice were evaluated by 197 different phenotype measurements. While resulting DUF1220-minus (KO) mice show no obvious anatomical peculiarities, they exhibit a significantly reduced fecundity (χ 2 = 19.1, df = 2, p = 7.0 × 10−5). Further extensive phenotypic analyses suggest hyperactivity (p

Published
2014
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36. Serum Response Factor (SRF) Ablation Interferes with Acute Stress-Associated Immediate and Long-Term Coping Mechanisms.

Author

Zimprich, Annemarie, Mroz, Gabi, Meyer zu Reckendorf, Christopher, Anastasiadou, Sofia, Förstner, Philip, Garrett, Lillian, Hölter, Sabine, Becker, Lore, Rozman, Jan, Prehn, Cornelia, Rathkolb, Birgit, Moreth, Kristin, Wurst, Wolfgang, Klopstock, Thomas, Klingenspor, Martin, Adamski, Jerzy, Wolf, Eckhard, Bekeredjian, Raffi, Fuchs, Helmut, and Gailus-Durner, Valerie

Abstract

Stress experience modulates behavior, metabolism, and energy expenditure of organisms. One molecular hallmark of an acute stress response is a rapid induction of immediate early genes (IEGs) such as c-Fos and Egr family members. IEG transcription in neurons is mediated by the neuronal activity-driven gene regulator serum response factor (SRF). We show a first role of SRF in immediate and long-lasting acute restraint stress (AS) responses. For this, we employed a standardized mouse phenotyping protocol at the German Mouse Clinic (GMC) including behavioral, metabolic, and cardiologic tests as well as gene expression profiling to analyze the consequences of forebrain-specific SRF deletion in mice exposed to AS. Adult mice with an SRF deletion in glutamatergic neurons ( Srf; ) showed hyperactivity, decreased anxiety, and impaired working memory. In response to restraint AS, instant stress reactivity including locomotor behavior and corticosterone induction was impaired in Srf mutant mice. Interestingly, even several weeks after previous AS exposure, SRF-deficient mice showed long-lasting AS-associated changes including altered locomotion, metabolism, energy expenditure, and cardiovascular changes. This suggests a requirement of SRF for mediating long-term stress coping mechanisms in wild-type mice. SRF ablation decreased AS-mediated IEG induction and activity of the actin severing protein cofilin. In summary, our data suggest an SRF function in immediate AS reactions and long-term post-stress-associated coping mechanisms. [ABSTRACT FROM AUTHOR]

Published
2017
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37. Standardized, systemic phenotypic analysis reveals kidney dysfunction as main alteration of Kctd1 mutant mice.

Author

Kumar, Sudhir, Rathkolb, Birgit, Sabrautzki, Sibylle, Krebs, Stefan, Kemter, Elisabeth, Becker, Lore, Beckers, Johannes, Bekeredjian, Raffi, Brommage, Robert, Calzada-Wack, Julia, Garrett, Lillian, Hölter, Sabine, Horsch, Marion, Klingenspor, Martin, Klopstock, Thomas, Moreth, Kristin, Neff, Frauke, Rozman, Jan, Fuchs, Helmut, and Gailus-Durner, Valérie

Subjects
PHENOTYPES, KIDNEY diseases, BLOOD plasma, ANIMAL models in research, ANIMAL genetics
Abstract

Background: Increased levels of blood plasma urea were used as phenotypic parameter for establishing novel mouse models for kidney diseases on the genetic background of C3H inbred mice in the phenotype-driven Munich ENU mouse mutagenesis project. The phenotypically dominant mutant line HST014 was established and further analyzed. Methods: Analysis of the causative mutation as well as the standardized, systemic phenotypic analysis of the mutant line was carried out. Results: The causative mutation was detected in the potassium channel tetramerization domain containing 1 ( Kctd1) gene which leads to the amino acid exchange Kctd1 thereby affecting the functional BTB domain of the protein. This line is the first mouse model harboring a Kctd1 mutation. Kctd1 homozygous mutant mice die perinatally. Standardized, systemic phenotypic analysis of Kctd1 heterozygous mutants was carried out in the German Mouse Clinic (GMC). Systematic morphological investigation of the external physical appearance did not detect the specific alterations that are described in KCTD1 mutant human patients affected by the scalp-ear-nipple (SEN) syndrome. The main pathological phenotype of the Kctd1 heterozygous mutant mice consists of kidney dysfunction and secondary effects thereof, without gross additional primary alterations in the other phenotypic parameters analyzed. Genome-wide transcriptome profiling analysis at the age of 4 months revealed about 100 differentially expressed genes (DEGs) in kidneys of Kctd1 heterozygous mutants as compared to wild-type controls. Conclusions: In summary, the main alteration of the Kctd1 heterozygous mutants consists in kidney dysfunction. Additional analyses in 9-21 week-old heterozygous mutants revealed only few minor effects. [ABSTRACT FROM AUTHOR]

Published
2017
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38. Every-other-day feeding extends lifespan but fails to delay many symptoms of aging in mice.

Author

Kan Xie, Neff, Frauke, Markert, Astrid, Rozman, Jan, Aguilar-Pimentel, Juan Antonio, Amarie, Oana Veronica, Becker, Lore, Brommage, Robert, Garrett, Lillian, Henzel, Kristin S., Hölter, Sabine M., Janik, Dirk, Lehmann, Isabelle, Moreth, Kristin, Pearson, Brandon L., Racz, Ildiko, Rathkolb, Birgit, Ryan, Devon P., Schröder, Susanne, and Treise, Irina

Abstract

Dietary restriction regimes extend lifespan in various animal models. Here we show that longevity in male C57BL/6J mice subjected to every-other-day feeding is associated with a delayed onset of neoplastic disease that naturally limits lifespan in these animals. We compare more than 200 phenotypes in over 20 tissues in aged animals fed with a lifelong every-other-day feeding or ad libitum access to food diet to determine whether molecular, cellular, physiological and histopathological aging features develop more slowly in everyother- day feeding mice than in controls. We also analyze the effects of every-other-day feeding on young mice on shorter-term every-other-day feeding or ad libitum to account for possible aging-independent restriction effects. Our large-scale analysis reveals overall only limited evidence for a retardation of the aging rate in every-other-day feeding mice. The data indicate that every-other-day feeding-induced longevity is sufficiently explained by delays in life-limiting neoplastic disorders and is not associated with a more general slowing of the aging process in mice. [ABSTRACT FROM AUTHOR]

Published
2017
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39. Pleiotropic Functions for Transcription Factor Zscan10

Author

Kraus, Petra, primary, V, Sivakamasundari, additional, Yu, Hong Bing, additional, Xing, Xing, additional, Lim, Siew Lan, additional, Adler, Thure, additional, Pimentel, Juan Antonio Aguilar, additional, Becker, Lore, additional, Bohla, Alexander, additional, Garrett, Lillian, additional, Hans, Wolfgang, additional, Hölter, Sabine M., additional, Janas, Eva, additional, Moreth, Kristin, additional, Prehn, Cornelia, additional, Puk, Oliver, additional, Rathkolb, Birgit, additional, Rozman, Jan, additional, Adamski, Jerzy, additional, Bekeredjian, Raffi, additional, Busch, Dirk H., additional, Graw, Jochen, additional, Klingenspor, Martin, additional, Klopstock, Thomas, additional, Neff, Frauke, additional, Ollert, Markus, additional, Stoeger, Tobias, additional, Yildrim, Ali Önder, additional, Eickelberg, Oliver, additional, Wolf, Eckhard, additional, Wurst, Wolfgang, additional, Fuchs, Helmut, additional, Gailus-Durner, Valérie, additional, de Angelis, Martin Hrabě, additional, Lufkin, Thomas, additional, and Stanton, Lawrence W., additional

Published
2014
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40. Die Bedeutung des Matrix-Proteoglykans Biglycan bei der Regulation von Entzündungsreaktionen

Author

Moreth, Kristin and Moreth, Kristin

Abstract

Die vorliegende Arbeit beschäftigt sich mit der Charakterisierung des Proteoglykans Biglycan und seiner Funktion als Signalmolekül in inflammatorischen und autoimmunen Prozessen. Die biologische Bedeutung der in vitro gewonnenen Ergebnisse in primären Makrophagen und dendritischen Zellen wurde durch in vivo Modelle der Pathogenvermittelten-und nicht-Pathogen-vermittelten Inflammation und der Autoimmun-Erkrankung Lupus Nephritis bestätigt. In primären Makrophagen und dendritischen Zellen induziert Biglycan die Produktion proinflammatorischer Zytokine und Chemokine durch Interaktion mit Toll-like Rezeptor (TLR) 2 und 4. Mit nucleotide-binding oligomerization like Rezeptorprotein3 (NLRP3)-,apoptosisassociated speck-like protein containing a CARD (ASC)- , Caspase-1- und TLR2/4- defizienten Mäusen und verschiedenen pharmakologischen Inhibitoren war es möglich in primären murinen peritonealen und Knochenmark-Makrophagen nachzuweisen, dass Biglycan die Caspase-1 NLRP3/ASC-abhängig aktivierte und damit die Prozessierung der Proform und Sekretion von reifem IL-1β induzierte. Durch Bindung an TLR2/TLR4 aktivierte Biglycan die NFκB, Erk und p38 mitogen-activated protein kinase (MAPK) Signalwege und stimulierte die Expression von Interleukin-1 beta (IL-1β). Biglycan aktivierte zudem den P2X7 Rezeptor (P2X7R) in Makrophagen und ist somit in der Lage auch ohne zusätzliche Ko-Stimulation, beispielsweise durch ATP, das NLRP3 Inflammasom zu stimulieren und die Prozessierung von aktivem IL-1β anzuregen. In einem Pathogenvermittelten (Lipopolysaccharid (LPS)-induzierte Sepsis) wie auch –nicht-athogenvermittelten (unilaterale Uretherobstruktion, UUO) Mausmodell der Inflammation wurde die biologische Relevanz dieser Prozesses gezeigt. Die Defizienz von Biglycan ging in diesen Modellen mit verminderter Aktivierung des NLRP3/Caspase-1 Inflammasomes, geringeren Spiegeln von reifem IL-1β und geringerer Organschädigung einher. Nachdem aufgezeigt werden konnte, dass d

Published
2010

41. Knock-out of nexilin in mice leads to dilated cardiomyopathy and endomyocardial fibroelastosis.

Author

Aherrahrou, Zouhair, Schlossarek, Saskia, Stoelting, Stephanie, Klinger, Matthias, Geertz, Birgit, Weinberger, Florian, Kessler, Thorsten, Aherrahrou, Redouane, Moreth, Kristin, Bekeredjian, Raffi, de Angelis, Martin Hrabě, Just, Steffen, Rottbauer, Wolfgang, Eschenhagen, Thomas, Schunkert, Heribert, Carrier, Lucie, and Erdmann, Jeanette

Abstract

Cardiomyopathy is one of the most common causes of chronic heart failure worldwide. Mutations in the gene encoding nexilin (NEXN) occur in patients with both hypertrophic and dilated cardiomyopathy (DCM); however, little is known about the pathophysiological mechanisms and relevance of NEXN to these disorders. Here, we evaluated the functional role of NEXN using a constitutive Nexn knock-out (KO) mouse model. Heterozygous (Het) mice were inter-crossed to produce wild-type (WT), Het, and homozygous KO mice. At birth, 32, 46, and 22 % of the mice were WT, Het, and KO, respectively, which is close to the expected Mendelian ratio. After postnatal day 6, the survival of the Nexn KO mice decreased dramatically and all of the animals died by day 8. Phenotypic characterizations of the WT and KO mice were performed at postnatal days 1, 2, 4, and 6. At birth, the relative heart weights of the WT and KO mice were similar; however, at day 4, the relative heart weight of the KO group was 2.3-fold higher than of the WT group. In addition, the KO mice developed rapidly progressive cardiomyopathy with left ventricular dilation and wall thinning and decreased cardiac function. At day 6, the KO mice developed a fulminant DCM phenotype characterized by dilated ventricular chambers and systolic dysfunction. At this stage, collagen deposits and some elastin deposits were observed within the left ventricle cavity, which resembles the features of endomyocardial fibroelastosis (EFE). Overall, these results further emphasize the role of NEXN in DCM and suggest a novel role in EFE. [ABSTRACT FROM AUTHOR]

Published
2016
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42. Histones from Dying Renal Cells Aggravate Kidney Injury via TLR2 and TLR4

Author

Allam, Ramanjaneyulu, primary, Scherbaum, Christina Rebecca, additional, Darisipudi, Murthy Narayana, additional, Mulay, Shrikant R., additional, Hägele, Holger, additional, Lichtnekert, Julia, additional, Hagemann, Jan Henrik, additional, Rupanagudi, Khader Valli, additional, Ryu, Mi, additional, Schwarzenberger, Claudia, additional, Hohenstein, Bernd, additional, Hugo, Christian, additional, Uhl, Bernd, additional, Reichel, Christoph A., additional, Krombach, Fritz, additional, Monestier, Marc, additional, Liapis, Helen, additional, Moreth, Kristin, additional, Schaefer, Liliana, additional, and Anders, Hans-Joachim, additional

Published
2012
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44. Signaling by the Matrix Proteoglycan Decorin Controls Inflammation and Cancer Through PDCD4 and MicroRNA-21

Author

Merline, Rosetta, primary, Moreth, Kristin, additional, Beckmann, Janet, additional, Nastase, Madalina V., additional, Zeng-Brouwers, Jinyang, additional, Tralhão, José Guilherme, additional, Lemarchand, Patricia, additional, Pfeilschifter, Josef, additional, Schaefer, Roland M., additional, Iozzo, Renato V., additional, and Schaefer, Liliana, additional

Published
2011
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47. Transforming growth factor-β2 upregulates sphingosine kinase-1 activity, which in turn attenuates the fibrotic response to TGF-β2 by impeding CTGF expression.

Author

Shuyu Ren, Babelova, Andrea, Moreth, Kristin, Cuiyan Xin, Eberhardt, Wolfgang, Doller, Anke, Pavenstädt, Hermann, Schaefer, Liliana, Pfeilschifter, Josef, and Huwiler, Andrea

Subjects
*TRANSFORMING growth factors-beta, *SPHINGOSINE, *FOCAL adhesion kinase, *CONNECTIVE tissue development, *FIBROSIS, *KIDNEY diseases, *GENE expression, *MESSENGER RNA
Abstract

Transforming growth factor-β2 (TGF-β2) stimulates the expression of pro-fibrotic connective tissue growth factor (CTGF) during the course of renal disease. Because sphingosine kinase-1 (SK-1) activity is also upregulated by TGF-β, we studied its effect on CTGF expression and on the development of renal fibrosis. When TGF-β2 was added to an immortalized human podocyte cell line we found that it activated the promoter of SK-1, resulting in upregulation of its mRNA and protein expression. Further, depletion of SK-1 by small interfering RNA or its pharmacological inhibition led to accelerated CTGF expression in the podocytes. Over-expression of SK-1 reduced CTGF induction, an effect mediated by intracellular sphingosine-1-phosphate. In vivo, SK-1 expression was also increased in the podocytes of kidney sections of patients with diabetic nephropathy when compared to normal sections of kidney obtained from patients with renal cancer. Similarly, in a mouse model of streptozotocin-induced diabetic nephropathy, SK-1 and CTGF were upregulated in podocytes. In SK-1 deficient mice, exacerbation of disease was detected by increased albuminuria and CTGF expression when compared to wild-type mice. Thus, SK-1 activity has a protective role in the fibrotic process and its deletion or inhibition aggravates fibrotic disease. [ABSTRACT FROM AUTHOR]

Published
2009
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48. A comprehensive and comparative phenotypic analysis of the collaborative founder strains identifies new and known phenotypes.

Author

Kollmus H, Fuchs H, Lengger C, Haselimashhadi H, Bogue MA, Östereicher MA, Horsch M, Adler T, Aguilar-Pimentel JA, Amarie OV, Becker L, Beckers J, Calzada-Wack J, Garrett L, Hans W, Hölter SM, Klein-Rodewald T, Maier H, Mayer-Kuckuk P, Miller G, Moreth K, Neff F, Rathkolb B, Rácz I, Rozman J, Spielmann N, Treise I, Busch D, Graw J, Klopstock T, Wolf E, Wurst W, Yildirim AÖ, Mason J, Torres A, Balling R, Mehaan T, Gailus-Durner V, Schughart K, and Hrabě de Angelis M

Subjects
Animals, Collaborative Cross Mice genetics, Databases, Genetic, Female, Genetic Association Studies, Genotype, Male, Mice, Quantitative Trait Loci, Species Specificity, Mice, Inbred Strains genetics, Phenotype
Abstract

The collaborative cross (CC) is a large panel of mouse-inbred lines derived from eight founder strains (NOD/ShiLtJ, NZO/HILtJ, A/J, C57BL/6J, 129S1/SvImJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Here, we performed a comprehensive and comparative phenotyping screening to identify phenotypic differences and similarities between the eight founder strains. In total, more than 300 parameters including allergy, behavior, cardiovascular, clinical blood chemistry, dysmorphology, bone and cartilage, energy metabolism, eye and vision, immunology, lung function, neurology, nociception, and pathology were analyzed; in most traits from sixteen females and sixteen males. We identified over 270 parameters that were significantly different between strains. This study highlights the value of the founder and CC strains for phenotype-genotype associations of many genetic traits that are highly relevant to human diseases. All data described here are publicly available from the mouse phenome database for analyses and downloads.

Published
2020
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49. Molecular mechanisms of TGF beta receptor-triggered signaling cascades rapidly induced by the calcineurin inhibitors cyclosporin A and FK506.

Author

Akool el-S, Doller A, Babelova A, Tsalastra W, Moreth K, Schaefer L, Pfeilschifter J, and Eberhardt W

Subjects
Animals, Cells, Cultured, Fibrosis, Humans, Injections, Intraperitoneal, Male, Mesangial Cells drug effects, Mesangial Cells enzymology, Mesangial Cells pathology, Phosphorylation drug effects, Protein Serine-Threonine Kinases antagonists & inhibitors, Rats, Rats, Wistar, Receptor, Transforming Growth Factor-beta Type I, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta antagonists & inhibitors, Signal Transduction immunology, Smad2 Protein metabolism, Smad2 Protein physiology, Tacrolimus pharmacology, Transforming Growth Factor beta1 biosynthesis, Transforming Growth Factor beta1 metabolism, Calcineurin Inhibitors, Cyclosporine pharmacology, Protein Serine-Threonine Kinases physiology, Receptors, Transforming Growth Factor beta physiology, Signal Transduction drug effects, Tacrolimus administration & dosage
Abstract

The calcineurin inhibitor (CNI)-induced renal fibrosis is attributed to an exaggerated deposition of extracellular matrix, which is mainly due to an increased expression of TGFbeta. Herein we demonstrate that the CNI cyclosporin A and tacrolimus (FK506), independent of TGFbeta synthesis, rapidly activate TGFbeta/Smad signaling in cultured mesangial cells and in whole kidney samples from CNI-treated rats. By EMSA, we demonstrate increased DNA binding of Smad-2, -3, and -4 to a cognate Smad-binding promoter element (SBE) accompanied by CNI-triggered activation of Smad-dependent expression of tissue inhibitor of metalloprotease-1 (TIMP-1) and connective tissue growth factor. Using an activin receptor-like kinase-5 (ALK-5) inhibitor and by small interfering RNA we depict a critical involvement of both types of TGFbeta receptors in CNI-triggered Smad signaling and fibrogenic gene expression, respectively. Mechanistically, CNI cause a rapid activation of latent TGFbeta, which is prevented in the presence of the antioxidant N-acetyl cysteine. A convergent activation of p38 MAPK is indicated by the partial blockade of CNI-induced Smad-2 activation by SB203580; conversely, both TGFbeta-RII and TGFbeta are critically involved in p38 MAPK activation by CNI. Activation of both signaling pathways is similarly triggered by reactive oxygen species. Finally, we show that neutralization of TGFbeta markedly reduced the CNI-dependent Smad activation in vitro and in vivo. Collectively, this study demonstrates that CNI via reactive oxygen species generation activate latent TGFbeta and thereby initiate the canonical Smad pathway by simultaneously activating p38 MAPK, which both synergistically induce Smad-driven gene expression.

Published
2008
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