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  • Mice  (597)
  • ASTROPHYSICS
  • Analytical Chemistry and Spectroscopy
  • 2005-2009  (597)
  • 1
    Publication Date: 2008-03-18
    Description: Identifying variations in DNA that increase susceptibility to disease is one of the primary aims of genetic studies using a forward genetics approach. However, identification of disease-susceptibility genes by means of such studies provides limited functional information on how genes lead to disease. In fact, in most cases there is an absence of functional information altogether, preventing a definitive identification of the susceptibility gene or genes. Here we develop an alternative to the classic forward genetics approach for dissecting complex disease traits where, instead of identifying susceptibility genes directly affected by variations in DNA, we identify gene networks that are perturbed by susceptibility loci and that in turn lead to disease. Application of this method to liver and adipose gene expression data generated from a segregating mouse population results in the identification of a macrophage-enriched network supported as having a causal relationship with disease traits associated with metabolic syndrome. Three genes in this network, lipoprotein lipase (Lpl), lactamase beta (Lactb) and protein phosphatase 1-like (Ppm1l), are validated as previously unknown obesity genes, strengthening the association between this network and metabolic disease traits. Our analysis provides direct experimental support that complex traits such as obesity are emergent properties of molecular networks that are modulated by complex genetic loci and environmental factors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841398/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841398/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Yanqing -- Zhu, Jun -- Lum, Pek Yee -- Yang, Xia -- Pinto, Shirly -- MacNeil, Douglas J -- Zhang, Chunsheng -- Lamb, John -- Edwards, Stephen -- Sieberts, Solveig K -- Leonardson, Amy -- Castellini, Lawrence W -- Wang, Susanna -- Champy, Marie-France -- Zhang, Bin -- Emilsson, Valur -- Doss, Sudheer -- Ghazalpour, Anatole -- Horvath, Steve -- Drake, Thomas A -- Lusis, Aldons J -- Schadt, Eric E -- P01 HL028481/HL/NHLBI NIH HHS/ -- P01 HL028481-24/HL/NHLBI NIH HHS/ -- P01 HL028481-240010/HL/NHLBI NIH HHS/ -- P01 HL030568/HL/NHLBI NIH HHS/ -- P01 HL030568-250011/HL/NHLBI NIH HHS/ -- R01 DK071673/DK/NIDDK NIH HHS/ -- R01 DK071673-03/DK/NIDDK NIH HHS/ -- England -- Nature. 2008 Mar 27;452(7186):429-35. doi: 10.1038/nature06757. Epub 2008 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18344982" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue/metabolism ; Animals ; Apolipoprotein A-II/genetics ; Chromosomes, Mammalian/genetics ; Female ; Gene Regulatory Networks/*genetics ; Genetic Predisposition to Disease/*genetics ; Genetic Variation/*genetics ; Linkage Disequilibrium ; Lipoprotein Lipase/genetics ; Liver/metabolism ; Lod Score ; Macrophages/metabolism ; Male ; Membrane Proteins/genetics ; Metabolic Syndrome X/enzymology/*genetics/metabolism ; Mice ; Obesity/enzymology/*genetics/metabolism ; Phenotype ; Phosphoprotein Phosphatases/deficiency/genetics/metabolism ; Quantitative Trait Loci ; Reproducibility of Results ; Ribosomal Proteins/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2009-11-13
    Description: The mucosal immune system forms the largest part of the entire immune system, containing about three-quarters of all lymphocytes and producing grams of secretory IgA daily to protect the mucosal surface from pathogens. To evoke the mucosal immune response, antigens on the mucosal surface must be transported across the epithelial barrier into organized lymphoid structures such as Peyer's patches. This function, called antigen transcytosis, is mediated by specialized epithelial M cells. The molecular mechanisms promoting this antigen uptake, however, are largely unknown. Here we report that glycoprotein 2 (GP2), specifically expressed on the apical plasma membrane of M cells among enterocytes, serves as a transcytotic receptor for mucosal antigens. Recombinant GP2 protein selectively bound a subset of commensal and pathogenic enterobacteria, including Escherichia coli and Salmonella enterica serovar Typhimurium (S. Typhimurium), by recognizing FimH, a component of type I pili on the bacterial outer membrane. Consistently, these bacteria were colocalized with endogenous GP2 on the apical plasma membrane as well as in cytoplasmic vesicles in M cells. Moreover, deficiency of bacterial FimH or host GP2 led to defects in transcytosis of type-I-piliated bacteria through M cells, resulting in an attenuation of antigen-specific immune responses in Peyer's patches. GP2 is therefore a previously unrecognized transcytotic receptor on M cells for type-I-piliated bacteria and is a prerequisite for the mucosal immune response to these bacteria. Given that M cells are considered a promising target for oral vaccination against various infectious diseases, the GP2-dependent transcytotic pathway could provide a new target for the development of M-cell-targeted mucosal vaccines.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hase, Koji -- Kawano, Kazuya -- Nochi, Tomonori -- Pontes, Gemilson Soares -- Fukuda, Shinji -- Ebisawa, Masashi -- Kadokura, Kazunori -- Tobe, Toru -- Fujimura, Yumiko -- Kawano, Sayaka -- Yabashi, Atsuko -- Waguri, Satoshi -- Nakato, Gaku -- Kimura, Shunsuke -- Murakami, Takaya -- Iimura, Mitsutoshi -- Hamura, Kimiyo -- Fukuoka, Shin-Ichi -- Lowe, Anson W -- Itoh, Kikuji -- Kiyono, Hiroshi -- Ohno, Hiroshi -- DK43294/DK/NIDDK NIH HHS/ -- DK56339/DK/NIDDK NIH HHS/ -- England -- Nature. 2009 Nov 12;462(7270):226-30. doi: 10.1038/nature08529.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory for Epithelial Immunobiology, Research Center for Allergy and Immunology, RIKEN, Kanagawa 230-0045, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19907495" target="_blank"〉PubMed〈/a〉
    Keywords: Adhesins, Escherichia coli/genetics/immunology/*metabolism ; Animals ; Antigens, Bacterial/genetics/immunology/*metabolism ; Cell Line ; Epithelial Cells/*immunology/metabolism ; Escherichia coli/immunology/metabolism ; Fimbriae Proteins/genetics/immunology/*metabolism ; GPI-Linked Proteins ; Glycoproteins ; HeLa Cells ; Humans ; Immunity, Mucosal/*immunology ; Intestines/cytology ; Membrane Glycoproteins/*metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Peyer's Patches/*cytology/immunology ; Salmonella typhimurium/genetics/immunology/metabolism ; Substrate Specificity
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2009-04-11
    Description: The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin-proteasome system might prove useful for the treatment of human malignancies. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Here we describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumour cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Soucy, Teresa A -- Smith, Peter G -- Milhollen, Michael A -- Berger, Allison J -- Gavin, James M -- Adhikari, Sharmila -- Brownell, James E -- Burke, Kristine E -- Cardin, David P -- Critchley, Stephen -- Cullis, Courtney A -- Doucette, Amanda -- Garnsey, James J -- Gaulin, Jeffrey L -- Gershman, Rachel E -- Lublinsky, Anna R -- McDonald, Alice -- Mizutani, Hirotake -- Narayanan, Usha -- Olhava, Edward J -- Peluso, Stephane -- Rezaei, Mansoureh -- Sintchak, Michael D -- Talreja, Tina -- Thomas, Michael P -- Traore, Tary -- Vyskocil, Stepan -- Weatherhead, Gabriel S -- Yu, Jie -- Zhang, Julie -- Dick, Lawrence R -- Claiborne, Christopher F -- Rolfe, Mark -- Bolen, Joseph B -- Langston, Steven P -- England -- Nature. 2009 Apr 9;458(7239):732-6. doi: 10.1038/nature07884.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA. teresa.soucy@mpi.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19360080" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/*pharmacology ; Cell Line, Tumor ; Cells, Cultured ; Cullin Proteins/metabolism ; Cyclopentanes/*pharmacology ; Enzyme Inhibitors/*pharmacology ; Female ; Humans ; Mice ; Neoplasms/*drug therapy ; Proteasome Inhibitors ; Pyrimidines/*pharmacology ; Transplantation, Heterologous ; Ubiquitin-Activating Enzymes/*metabolism ; Ubiquitins/metabolism
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  • 4
    Publication Date: 2007-10-13
    Description: Human cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes. To catalog the genetic changes that occur during tumorigenesis, we isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene "mountains" and a much larger number of gene "hills" that are mutated at low frequency. We describe statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. These results have implications for understanding the nature and heterogeneity of human cancers and for using personal genomics for tumor diagnosis and therapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wood, Laura D -- Parsons, D Williams -- Jones, Sian -- Lin, Jimmy -- Sjoblom, Tobias -- Leary, Rebecca J -- Shen, Dong -- Boca, Simina M -- Barber, Thomas -- Ptak, Janine -- Silliman, Natalie -- Szabo, Steve -- Dezso, Zoltan -- Ustyanksky, Vadim -- Nikolskaya, Tatiana -- Nikolsky, Yuri -- Karchin, Rachel -- Wilson, Paul A -- Kaminker, Joshua S -- Zhang, Zemin -- Croshaw, Randal -- Willis, Joseph -- Dawson, Dawn -- Shipitsin, Michail -- Willson, James K V -- Sukumar, Saraswati -- Polyak, Kornelia -- Park, Ben Ho -- Pethiyagoda, Charit L -- Pant, P V Krishna -- Ballinger, Dennis G -- Sparks, Andrew B -- Hartigan, James -- Smith, Douglas R -- Suh, Erick -- Papadopoulos, Nickolas -- Buckhaults, Phillip -- Markowitz, Sanford D -- Parmigiani, Giovanni -- Kinzler, Kenneth W -- Velculescu, Victor E -- Vogelstein, Bert -- CA 43460/CA/NCI NIH HHS/ -- CA 57345/CA/NCI NIH HHS/ -- CA109274/CA/NCI NIH HHS/ -- CA112828/CA/NCI NIH HHS/ -- CA121113/CA/NCI NIH HHS/ -- CA62924/CA/NCI NIH HHS/ -- GM070219/GM/NIGMS NIH HHS/ -- GM07309/GM/NIGMS NIH HHS/ -- P30-CA43703/CA/NCI NIH HHS/ -- RR017698/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2007 Nov 16;318(5853):1108-13. Epub 2007 Oct 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17932254" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/*genetics/metabolism ; Cell Line ; Chromosome Mapping ; Colorectal Neoplasms/*genetics/metabolism ; Computational Biology ; DNA, Neoplasm ; Databases, Genetic ; Genes, Neoplasm ; Genome, Human ; Humans ; Metabolic Networks and Pathways/genetics ; Mice ; Mutation ; Neoplasm Proteins/genetics/metabolism ; Sequence Analysis, DNA
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2009-03-21
    Description: New drugs are required to counter the tuberculosis (TB) pandemic. Here, we describe the synthesis and characterization of 1,3-benzothiazin-4-ones (BTZs), a new class of antimycobacterial agents that kill Mycobacterium tuberculosis in vitro, ex vivo, and in mouse models of TB. Using genetics and biochemistry, we identified the enzyme decaprenylphosphoryl-beta-d-ribose 2'-epimerase as a major BTZ target. Inhibition of this enzymatic activity abolishes the formation of decaprenylphosphoryl arabinose, a key precursor that is required for the synthesis of the cell-wall arabinans, thus provoking cell lysis and bacterial death. The most advanced compound, BTZ043, is a candidate for inclusion in combination therapies for both drug-sensitive and extensively drug-resistant TB.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128490/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128490/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Makarov, Vadim -- Manina, Giulia -- Mikusova, Katarina -- Mollmann, Ute -- Ryabova, Olga -- Saint-Joanis, Brigitte -- Dhar, Neeraj -- Pasca, Maria Rosalia -- Buroni, Silvia -- Lucarelli, Anna Paola -- Milano, Anna -- De Rossi, Edda -- Belanova, Martina -- Bobovska, Adela -- Dianiskova, Petronela -- Kordulakova, Jana -- Sala, Claudia -- Fullam, Elizabeth -- Schneider, Patricia -- McKinney, John D -- Brodin, Priscille -- Christophe, Thierry -- Waddell, Simon -- Butcher, Philip -- Albrethsen, Jakob -- Rosenkrands, Ida -- Brosch, Roland -- Nandi, Vrinda -- Bharath, Sowmya -- Gaonkar, Sheshagiri -- Shandil, Radha K -- Balasubramanian, Venkataraman -- Balganesh, Tanjore -- Tyagi, Sandeep -- Grosset, Jacques -- Riccardi, Giovanna -- Cole, Stewart T -- 062511/Wellcome Trust/United Kingdom -- 080039/Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2009 May 8;324(5928):801-4. doi: 10.1126/science.1171583. Epub 2009 Mar 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉A. N. Bakh Institute of Biochemistry, Russian Academy of Science, 119071 Moscow, Russia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19299584" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Antitubercular Agents/chemical synthesis/chemistry/*pharmacology/*therapeutic use ; Arabinose/metabolism ; Cell Wall/metabolism ; Drug Resistance, Bacterial ; Enzyme Inhibitors/cerebrospinal fluid/chemistry/pharmacology/therapeutic use ; Ethambutol/pharmacology ; Gene Expression Regulation, Bacterial/drug effects ; Genes, Bacterial ; Mice ; Mice, Inbred BALB C ; Microbial Sensitivity Tests ; Molecular Sequence Data ; Molecular Structure ; Mycobacterium/drug effects/genetics ; Mycobacterium tuberculosis/*drug effects/genetics/metabolism ; Polysaccharides/*biosynthesis ; Racemases and Epimerases/*antagonists & inhibitors/metabolism ; Spiro Compounds/chemical synthesis/chemistry/*pharmacology/*therapeutic use ; Thiazines/chemical synthesis/chemistry/*pharmacology/*therapeutic use ; Tuberculosis/*drug therapy/microbiology
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  • 6
    Publication Date: 2008-02-19
    Description: Cytosine DNA methylation is important in regulating gene expression and in silencing transposons and other repetitive sequences. Recent genomic studies in Arabidopsis thaliana have revealed that many endogenous genes are methylated either within their promoters or within their transcribed regions, and that gene methylation is highly correlated with transcription levels. However, plants have different types of methylation controlled by different genetic pathways, and detailed information on the methylation status of each cytosine in any given genome is lacking. To this end, we generated a map at single-base-pair resolution of methylated cytosines for Arabidopsis, by combining bisulphite treatment of genomic DNA with ultra-high-throughput sequencing using the Illumina 1G Genome Analyser and Solexa sequencing technology. This approach, termed BS-Seq, unlike previous microarray-based methods, allows one to sensitively measure cytosine methylation on a genome-wide scale within specific sequence contexts. Here we describe methylation on previously inaccessible components of the genome and analyse the DNA methylation sequence composition and distribution. We also describe the effect of various DNA methylation mutants on genome-wide methylation patterns, and demonstrate that our newly developed library construction and computational methods can be applied to large genomes such as that of mouse.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2377394/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2377394/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cokus, Shawn J -- Feng, Suhua -- Zhang, Xiaoyu -- Chen, Zugen -- Merriman, Barry -- Haudenschild, Christian D -- Pradhan, Sriharsa -- Nelson, Stanley F -- Pellegrini, Matteo -- Jacobsen, Steven E -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Mar 13;452(7184):215-9. doi: 10.1038/nature06745. Epub 2008 Feb 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular, Cell, and Developmental Biology, University of California at Los Angeles, Los Angeles, California 90095, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18278030" target="_blank"〉PubMed〈/a〉
    Keywords: 5-Methylcytosine/metabolism ; Animals ; Arabidopsis/*genetics ; Base Sequence ; Computational Biology ; Cytosine/metabolism ; *DNA Methylation ; Gene Expression Regulation, Plant/genetics ; Gene Library ; Genome, Plant/*genetics ; Mice ; Mutation/genetics ; Promoter Regions, Genetic/genetics ; Reproducibility of Results ; Sequence Analysis, DNA/*methods ; Sulfites/*metabolism ; Uracil/metabolism
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    Electronic ISSN: 1476-4687
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  • 7
    Publication Date: 2008-02-19
    Description: Understanding the neuropathology of multiple sclerosis (MS) is essential for improved therapies. Therefore, identification of targets specific to pathological types of MS may have therapeutic benefits. Here we identify, by laser-capture microdissection and proteomics, proteins unique to three major types of MS lesions: acute plaque, chronic active plaque and chronic plaque. Comparative proteomic profiles identified tissue factor and protein C inhibitor within chronic active plaque samples, suggesting dysregulation of molecules associated with coagulation. In vivo administration of hirudin or recombinant activated protein C reduced disease severity in experimental autoimmune encephalomyelitis and suppressed Th1 and Th17 cytokines in astrocytes and immune cells. Administration of mutant forms of recombinant activated protein C showed that both its anticoagulant and its signalling functions were essential for optimal amelioration of experimental autoimmune encephalomyelitis. A proteomic approach illuminated potential therapeutic targets selective for specific pathological stages of MS and implicated participation of the coagulation cascade.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Han, May H -- Hwang, Sun-Il -- Roy, Dolly B -- Lundgren, Deborah H -- Price, Jordan V -- Ousman, Shalina S -- Fernald, Guy Haskin -- Gerlitz, Bruce -- Robinson, William H -- Baranzini, Sergio E -- Grinnell, Brian W -- Raine, Cedric S -- Sobel, Raymond A -- Han, David K -- Steinman, Lawrence -- T32 AI007290/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Feb 28;451(7182):1076-81. doi: 10.1038/nature06559. Epub 2008 Feb 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18278032" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Animals ; Blood Coagulation ; Encephalomyelitis, Autoimmune, Experimental/immunology/metabolism/pathology ; Female ; *Gene Expression Profiling ; Humans ; Inflammation/metabolism/pathology ; Male ; Mice ; Middle Aged ; Multiple Sclerosis/classification/drug therapy/*metabolism/*pathology ; Protein C/genetics/metabolism/pharmacology ; *Proteomics ; Th1 Cells/immunology ; Th2 Cells/immunology ; Thrombin/antagonists & inhibitors/metabolism
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  • 8
    Publication Date: 2008-12-02
    Description: MicroRNAs comprise a broad class of small non-coding RNAs that control expression of complementary target messenger RNAs. Dysregulation of microRNAs by several mechanisms has been described in various disease states including cardiac disease. Whereas previous studies of cardiac disease have focused on microRNAs that are primarily expressed in cardiomyocytes, the role of microRNAs expressed in other cell types of the heart is unclear. Here we show that microRNA-21 (miR-21, also known as Mirn21) regulates the ERK-MAP kinase signalling pathway in cardiac fibroblasts, which has impacts on global cardiac structure and function. miR-21 levels are increased selectively in fibroblasts of the failing heart, augmenting ERK-MAP kinase activity through inhibition of sprouty homologue 1 (Spry1). This mechanism regulates fibroblast survival and growth factor secretion, apparently controlling the extent of interstitial fibrosis and cardiac hypertrophy. In vivo silencing of miR-21 by a specific antagomir in a mouse pressure-overload-induced disease model reduces cardiac ERK-MAP kinase activity, inhibits interstitial fibrosis and attenuates cardiac dysfunction. These findings reveal that microRNAs can contribute to myocardial disease by an effect in cardiac fibroblasts. Our results validate miR-21 as a disease target in heart failure and establish the therapeutic efficacy of microRNA therapeutic intervention in a cardiovascular disease setting.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thum, Thomas -- Gross, Carina -- Fiedler, Jan -- Fischer, Thomas -- Kissler, Stephan -- Bussen, Markus -- Galuppo, Paolo -- Just, Steffen -- Rottbauer, Wolfgang -- Frantz, Stefan -- Castoldi, Mirco -- Soutschek, Jurgen -- Koteliansky, Victor -- Rosenwald, Andreas -- Basson, M Albert -- Licht, Jonathan D -- Pena, John T R -- Rouhanifard, Sara H -- Muckenthaler, Martina U -- Tuschl, Thomas -- Martin, Gail R -- Bauersachs, Johann -- Engelhardt, Stefan -- R01 CA059998/CA/NCI NIH HHS/ -- R01 CA78711/CA/NCI NIH HHS/ -- England -- Nature. 2008 Dec 18;456(7224):980-4. doi: 10.1038/nature07511. Epub 2008 Nov 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine I, Interdisziplinares Zentrum fur Klinische Forschung (IZKF), University of Wuerzburg, 97080 Wuerzburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19043405" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cardiomyopathies/*genetics/*metabolism/pathology/therapy ; Cell Line ; Cell Survival ; Cells, Cultured ; Disease Models, Animal ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Fibroblasts/*metabolism ; Gene Silencing ; Humans ; *MAP Kinase Signaling System ; Male ; Mice ; Mice, Transgenic ; MicroRNAs/*genetics ; Myocytes, Cardiac/cytology/metabolism ; Rats
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  • 9
    Publication Date: 2009-11-27
    Description: Receptor-activator of NF-kappaB ligand (TNFSF11, also known as RANKL, OPGL, TRANCE and ODF) and its tumour necrosis factor (TNF)-family receptor RANK are essential regulators of bone remodelling, lymph node organogenesis and formation of a lactating mammary gland. RANKL and RANK are also expressed in the central nervous system. However, the functional relevance of RANKL/RANK in the brain was entirely unknown. Here we report that RANKL and RANK have an essential role in the brain. In both mice and rats, central RANKL injections trigger severe fever. Using tissue-specific Nestin-Cre and GFAP-Cre rank(floxed) deleter mice, the function of RANK in the fever response was genetically mapped to astrocytes. Importantly, Nestin-Cre and GFAP-Cre rank(floxed) deleter mice are resistant to lipopolysaccharide-induced fever as well as fever in response to the key inflammatory cytokines IL-1beta and TNFalpha. Mechanistically, RANKL activates brain regions involved in thermoregulation and induces fever via the COX2-PGE(2)/EP3R pathway. Moreover, female Nestin-Cre and GFAP-Cre rank(floxed) mice exhibit increased basal body temperatures, suggesting that RANKL and RANK control thermoregulation during normal female physiology. We also show that two children with RANK mutations exhibit impaired fever during pneumonia. These data identify an entirely novel and unexpected function for the key osteoclast differentiation factors RANKL/RANK in female thermoregulation and the central fever response in inflammation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hanada, Reiko -- Leibbrandt, Andreas -- Hanada, Toshikatsu -- Kitaoka, Shiho -- Furuyashiki, Tomoyuki -- Fujihara, Hiroaki -- Trichereau, Jean -- Paolino, Magdalena -- Qadri, Fatimunnisa -- Plehm, Ralph -- Klaere, Steffen -- Komnenovic, Vukoslav -- Mimata, Hiromitsu -- Yoshimatsu, Hironobu -- Takahashi, Naoyuki -- von Haeseler, Arndt -- Bader, Michael -- Kilic, Sara Sebnem -- Ueta, Yoichi -- Pifl, Christian -- Narumiya, Shuh -- Penninger, Josef M -- England -- Nature. 2009 Nov 26;462(7272):505-9. doi: 10.1038/nature08596.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19940926" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Astrocytes/drug effects/metabolism ; Body Temperature Regulation/*drug effects/*physiology ; Child ; Dinoprostone/metabolism ; Female ; Fever/*chemically induced/complications/*metabolism ; Gene Expression Profiling ; Humans ; Injections, Intraventricular ; Male ; Mice ; Mice, Inbred C57BL ; Pneumonia/complications/metabolism ; RANK Ligand/administration & dosage/antagonists & ; inhibitors/metabolism/*pharmacology ; Rats ; Rats, Wistar ; Receptor Activator of Nuclear Factor-kappa B/genetics/*metabolism ; Receptors, Prostaglandin E/metabolism ; Receptors, Prostaglandin E, EP3 Subtype ; *Sex Characteristics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2009-08-13
    Description: Influenza A viruses cause recurrent outbreaks at local or global scale with potentially severe consequences for human health and the global economy. Recently, a new strain of influenza A virus was detected that causes disease in and transmits among humans, probably owing to little or no pre-existing immunity to the new strain. On 11 June 2009 the World Health Organization declared that the infections caused by the new strain had reached pandemic proportion. Characterized as an influenza A virus of the H1N1 subtype, the genomic segments of the new strain were most closely related to swine viruses. Most human infections with swine-origin H1N1 influenza viruses (S-OIVs) seem to be mild; however, a substantial number of hospitalized individuals do not have underlying health issues, attesting to the pathogenic potential of S-OIVs. To achieve a better assessment of the risk posed by the new virus, we characterized one of the first US S-OIV isolates, A/California/04/09 (H1N1; hereafter referred to as CA04), as well as several other S-OIV isolates, in vitro and in vivo. In mice and ferrets, CA04 and other S-OIV isolates tested replicate more efficiently than a currently circulating human H1N1 virus. In addition, CA04 replicates efficiently in non-human primates, causes more severe pathological lesions in the lungs of infected mice, ferrets and non-human primates than a currently circulating human H1N1 virus, and transmits among ferrets. In specific-pathogen-free miniature pigs, CA04 replicates without clinical symptoms. The assessment of human sera from different age groups suggests that infection with human H1N1 viruses antigenically closely related to viruses circulating in 1918 confers neutralizing antibody activity to CA04. Finally, we show that CA04 is sensitive to approved and experimental antiviral drugs, suggesting that these compounds could function as a first line of defence against the recently declared S-OIV pandemic.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748827/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748827/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Itoh, Yasushi -- Shinya, Kyoko -- Kiso, Maki -- Watanabe, Tokiko -- Sakoda, Yoshihiro -- Hatta, Masato -- Muramoto, Yukiko -- Tamura, Daisuke -- Sakai-Tagawa, Yuko -- Noda, Takeshi -- Sakabe, Saori -- Imai, Masaki -- Hatta, Yasuko -- Watanabe, Shinji -- Li, Chengjun -- Yamada, Shinya -- Fujii, Ken -- Murakami, Shin -- Imai, Hirotaka -- Kakugawa, Satoshi -- Ito, Mutsumi -- Takano, Ryo -- Iwatsuki-Horimoto, Kiyoko -- Shimojima, Masayuki -- Horimoto, Taisuke -- Goto, Hideo -- Takahashi, Kei -- Makino, Akiko -- Ishigaki, Hirohito -- Nakayama, Misako -- Okamatsu, Masatoshi -- Takahashi, Kazuo -- Warshauer, David -- Shult, Peter A -- Saito, Reiko -- Suzuki, Hiroshi -- Furuta, Yousuke -- Yamashita, Makoto -- Mitamura, Keiko -- Nakano, Kunio -- Nakamura, Morio -- Brockman-Schneider, Rebecca -- Mitamura, Hiroshi -- Yamazaki, Masahiko -- Sugaya, Norio -- Suresh, M -- Ozawa, Makoto -- Neumann, Gabriele -- Gern, James -- Kida, Hiroshi -- Ogasawara, Kazumasa -- Kawaoka, Yoshihiro -- HHNSN266200700010C/NS/NINDS NIH HHS/ -- HHSN266200700010C/PHS HHS/ -- HHSN272200800060C/AI/NIAID NIH HHS/ -- R01 AI069274/AI/NIAID NIH HHS/ -- R01 AI069274-04/AI/NIAID NIH HHS/ -- U19 AI070503/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Aug 20;460(7258):1021-5. doi: 10.1038/nature08260.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Shiga University of Medical Science, Ohtsu, Shiga 520-2192, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19672242" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Viral/immunology ; Antiviral Agents/pharmacology ; Cell Line ; Dogs ; Female ; Ferrets/virology ; HN Protein/metabolism ; Humans ; Influenza A Virus, H1N1 Subtype/drug effects/enzymology/pathogenicity/*physiology ; Lung/immunology/pathology/virology ; Macaca fascicularis/immunology/virology ; Male ; Mice ; Mice, Inbred BALB C ; Neutralization Tests ; Orthomyxoviridae Infections/immunology/transmission/virology ; Primate Diseases/pathology/virology ; Swine/*virology ; Swine Diseases/pathology/virology ; Swine, Miniature/virology ; Virus Replication
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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