Systemic First-Line Phenotyping

Gailus‐Durner, Valérie; Fuchs, Helmut; Adler, Thure; Pimentel, Antonio Aguilar; Becker, Lore; Bolle, Ines; Calzada‐Wack, Julia; Dalke, Claudia; Ehrhardt, Nicole; Ferwagner, Barbara; Hans, Wolfgang; Hölter, Sabine M.; Hölzlwimmer, Gabriele; Horsch, Marion; Javaheri, Anahita; Kallnik, Magdalena; Kling, Eva; Lengger, Christoph; Morth, C.; Moßbrugger, Ilona; Naton, Beatrix; Prehn, Cornelia; Puk, Oliver; Rathkolb, Birgit; Rozman, Jan; Schrewe, Anja; Thiele, F. A. J.; Adamski, Jerzy; Aigner, Bernhard; Behrendt, Heidrun; Busch, Dirk H.; Favor, Jack; Graw, Jochen; Heldmaier, Gerhard; Ivandic, Boris; Katus, Hugo A.; Klingenspor, Martin; Kremmer, Thomas Klopstock Elisabeth; Ollert, Markus; Quintanilla-Martı́nez, Leticia; Schulz, Holger; Wolf, Eckhard; Wurst, Wolfgang; Angelis, Martin Hrabé de

doi:10.1007/978-1-59745-471-1_25

Cited by 71 publications

(66 citation statements)

References 137 publications

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“…1). Systemic phenotypic screening of these mice at the German Mouse Clinic (29,30) revealed that they were healthy and showed no significant phenotype under nonstimulated conditions (the data can be accessed at: http://www.europhenome.org/).…”

Section: Resultsmentioning

confidence: 99%

IFIT2 Is an Effector Protein of Type I IFN–Mediated Amplification of Lipopolysaccharide (LPS)-Induced TNF-α Secretion and LPS-Induced Endotoxin Shock

Siegfried

Berchtold

Manncke

et al. 2013

The Journal of Immunology

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Type I IFN signaling amplifies the secretion of LPS-induced proinflammatory cytokines such as TNF-α or IL-6 and might thus contribute to the high mortality associated with Gram-negative septic shock in humans. The underlying molecular mechanism, however, is ill defined. In this study, we report the generation of mice deficient in IFN-induced protein with tetratricopeptide repeats 2 (Ifit2) and demonstrate that Ifit2 is a critical signaling intermediate for LPS-induced septic shock. Ifit2 expression was significantly upregulated in response to LPS challenge in an IFN-α receptor– and IFN regulatory factor (Irf)9–dependent manner. Also, LPS induced secretion of IL-6 and TNF-α by bone marrow–derived macrophages (BMDMs) was significantly enhanced in the presence of Ifit2. In accordance, Ifit2-deficient mice exhibited significantly reduced serum levels of IL-6 and TNF-α and reduced mortality in an endotoxin shock model. Investigation of the underlying signal transduction events revealed that Ifit2 upregulates Irf3 phosphorylation. In the absence of Irf3, reduced Ifn-β mRNA expression and Ifit2 protein expression after LPS stimulation was found. Also, Tnf-α and Il-6 secretion but not Tnf-α and Il-6 mRNA expression levels were reduced. Thus, IFN-stimulated Ifit2 via enhanced Irf3 phosphorylation upregulates the secretion of proinflammatory cytokines. It thereby amplifies LPS-induced cytokine production and critically influences the outcome of endotoxin shock.

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Section: Resultsmentioning

confidence: 99%

IFIT2 Is an Effector Protein of Type I IFN–Mediated Amplification of Lipopolysaccharide (LPS)-Induced TNF-α Secretion and LPS-Induced Endotoxin Shock

Siegfried

Berchtold

Manncke

et al. 2013

The Journal of Immunology

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“…The analysis of total IgE plasma levels by ELISA (18) in ADAR2 KO mice at the age of 14 weeks revealed statistically significant differences in females between mutants and controls (p ϭ 0.012; ϩ183.2%; Fig. 2).…”

Section: Morphological and Histological Examination Of Adar2 Komentioning

confidence: 93%

“…In the immunology screen, leukocyte populations and antibody isotype levels in peripheral blood were measured by flow cytometry and Luminex bead array technology (18). No differences in leukocyte subsets, such as T cells (CD3…”

Section: Morphological and Histological Examination Of Adar2 Komentioning

confidence: 99%

Requirement of the RNA-editing Enzyme ADAR2 for Normal Physiology in Mice

Horsch

Seeburg

Adler

et al. 2011

Journal of Biological Chemistry

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ADAR2, an RNA editing enzyme that converts specific adenosines to inosines in certain pre-mRNAs, often leading to amino acid substitutions in the encoded proteins, is mainly expressed in brain. Of all ADAR2-mediated edits, a single one in the pre-mRNA of the AMPA receptor subunit GluA2 is essential for survival. Hence, early postnatal death of mice lacking ADAR2 is averted when the critical edit is engineered into both GluA2 encoding Gria2 alleles. Adar2 ؊/؊ /Gria2 R/R mice display normal appearance and life span, but the general phenotypic effects of global lack of ADAR2 have remained unexplored. Here we have employed the Adar2 ؊/؊ /Gria2 R/R mouse line, and Gria2 R/R mice as controls, to study the phenotypic consequences of loss of all ADAR2-mediated edits except the critical one in GluA2. Our extended phenotypic analysis covering ϳ320 parameters identified significant changes related to absence of ADAR2 in behavior, hearing ability, allergy parameters and transcript profiles of brain.The most common RNA modification in higher organisms is the enzymatic deamination of specific adenosines to inosine (A-to-I editing), wrought by members of the ADAR protein family (1). ADARs, short for adenosine deaminases acting on RNA, were discovered by their ability to convert in vitro in double-stranded RNA ϳ50% of the adenosines to inosines, thus destabilizing the double-stranded structure (2). Occurring in worms, flies and mammals, these enigmatic enzymes are now known to switch specific adenosines to inosine in mostly primary nuclear transcripts (3-6). A-to-I editing often recodes amino acids within the gene-encoded protein, based on reading inosine as guanosine by the translational machinery, and can remove or create splice acceptor sites (7), thus altering the pattern of RNA splicing. Moreover, editing in 5Ј and 3ЈUTRs and intronic sequence may lead to altered translational efficiency,

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“…Animals were subsequently shipped to the German Mouse Clinic (46,47) for additional analyses (16-month vehicle, n = 19; 16-month rapamycin, n = 20; 25-month vehicle, n = 12; 25-month rapamycin, n = 16; 34-month vehicle, n = 11; 34-month rapamycin, n = 16). Cohorts were analyzed separately, each side by side with a group of young adult (3-6 months old) male C57BL/6J Rj mice (Janvier) kept on vehicle control diet (n = 10).…”

Section: Methodsmentioning

confidence: 99%

“…We used a modification of the SHIRPA screen (49) to assess 23 parameters related to neurological functions and general health as previously described (http://www.har.mrc.ac.uk/services/phenotyping/ neurology/shirpa.html) (46,47).…”

Section: Figure 10mentioning

confidence: 99%

Rapamycin extends murine lifespan but has limited effects on aging

Neff

Flores-Dominguez²,

Ryan³

et al. 2013

J. Clin. Invest.

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329

408

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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 for novel and broadly effective treatments against age-related diseases. The recent report of lifespan extension in mice treated with the FDA-approved mTOR inhibitor rapamycin represented the first demonstration of pharmacological extension of maximal lifespan in mammals. Longevity effects of rapamycin may, however, be due to rapamycin's effects on specific life-limiting pathologies, such as cancers, and it remains unclear if this compound actually slows the rate of aging in mammals. Here, we present results from a comprehensive, large-scale assessment of a wide range of structural and functional aging phenotypes, which we performed to determine whether rapamycin slows the rate of aging in male C57BL/6J mice. While rapamycin did extend lifespan, it ameliorated few studied aging phenotypes. A subset of aging traits appeared to be rescued by rapamycin. Rapamycin, however, had similar effects on many of these traits in young animals, indicating that these effects were not due to a modulation of aging, but rather related to aging-independent drug effects. Therefore, our data largely dissociate rapamycin's longevity effects from effects on aging itself.

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Systemic First-Line Phenotyping

Cited by 71 publications

References 137 publications

IFIT2 Is an Effector Protein of Type I IFN–Mediated Amplification of Lipopolysaccharide (LPS)-Induced TNF-α Secretion and LPS-Induced Endotoxin Shock

IFIT2 Is an Effector Protein of Type I IFN–Mediated Amplification of Lipopolysaccharide (LPS)-Induced TNF-α Secretion and LPS-Induced Endotoxin Shock

Requirement of the RNA-editing Enzyme ADAR2 for Normal Physiology in Mice

Rapamycin extends murine lifespan but has limited effects on aging

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