knockout mice

Summary

Summary: Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes.

Top Publications

  1. ncbi The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells
    Ivaylo I Ivanov
    Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA
    Cell 126:1121-33. 2006
  2. ncbi Toll-like receptor signalling
    Shizuo Akira
    Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, and ERATO, Japan Science and Technology Agency, 3 1 Yamada oka, Suita, Osaka 565 0871, Japan
    Nat Rev Immunol 4:499-511. 2004
  3. ncbi Interleukin-10 and the interleukin-10 receptor
    K W Moore
    Department of Molecular Biology, DNAX Research Institute of Molecular and Cellular Biology Inc, Palo Alto, California 94304, USA
    Annu Rev Immunol 19:683-765. 2001
  4. ncbi Initial sequencing and comparative analysis of the mouse genome
    Robert H Waterston
    Genome Sequencing Center, Washington University School of Medicine, Campus Box 8501, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA
    Nature 420:520-62. 2002
  5. ncbi Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product
    K Hoshino
    Department of Biochemistry, Hyogo College of Medicine, Japan
    J Immunol 162:3749-52. 1999
  6. ncbi IRF-7 is the master regulator of type-I interferon-dependent immune responses
    Kenya Honda
    Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7 3 1, Bunkyo ku, Tokyo 113 0033, Japan
    Nature 434:772-7. 2005
  7. ncbi Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis
    Seth Rakoff-Nahoum
    Howard Hughes Medical Institute and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA
    Cell 118:229-41. 2004
  8. pmc Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance
    Justin I Odegaard
    Division of Endocrinology, Metabolism and Gerontology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305 5103, USA
    Nature 447:1116-20. 2007
  9. ncbi Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function
    O Adachi
    Department of Biochemistry, Hyogo College of Medicine, Nishinomiya, Japan
    Immunity 9:143-50. 1998
  10. pmc Disseminated tuberculosis in interferon gamma gene-disrupted mice
    A M Cooper
    Department of Microbiology, Colorado State University, Fort Collins 80523
    J Exp Med 178:2243-7. 1993

Detail Information

Publications336 found, 100 shown here

  1. ncbi The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells
    Ivaylo I Ivanov
    Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA
    Cell 126:1121-33. 2006
    ..Together, these studies suggest that RORgammat is a key regulator of immune homeostasis and highlight its potential as a therapeutic target in inflammatory diseases...
  2. ncbi Toll-like receptor signalling
    Shizuo Akira
    Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, and ERATO, Japan Science and Technology Agency, 3 1 Yamada oka, Suita, Osaka 565 0871, Japan
    Nat Rev Immunol 4:499-511. 2004
  3. ncbi Interleukin-10 and the interleukin-10 receptor
    K W Moore
    Department of Molecular Biology, DNAX Research Institute of Molecular and Cellular Biology Inc, Palo Alto, California 94304, USA
    Annu Rev Immunol 19:683-765. 2001
    ..This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease...
  4. ncbi Initial sequencing and comparative analysis of the mouse genome
    Robert H Waterston
    Genome Sequencing Center, Washington University School of Medicine, Campus Box 8501, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA
    Nature 420:520-62. 2002
    ....
  5. ncbi Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product
    K Hoshino
    Department of Biochemistry, Hyogo College of Medicine, Japan
    J Immunol 162:3749-52. 1999
    ..Overexpression of wild-type TLR4 but not the mutant TLR4 from C3H/HeJ mice activated NF-kappaB. Taken together, the present study demonstrates that TLR4 is the gene product that regulates LPS response...
  6. ncbi IRF-7 is the master regulator of type-I interferon-dependent immune responses
    Kenya Honda
    Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7 3 1, Bunkyo ku, Tokyo 113 0033, Japan
    Nature 434:772-7. 2005
    ..Thus, all elements of IFN responses, whether the systemic production of IFN in innate immunity or the local action of IFN from plasmacytoid dendritic cells in adaptive immunity, are under the control of IRF-7...
  7. ncbi Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis
    Seth Rakoff-Nahoum
    Howard Hughes Medical Institute and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA
    Cell 118:229-41. 2004
    ..These findings reveal a novel function of TLRs-control of intestinal epithelial homeostasis and protection from injury-and provide a new perspective on the evolution of host-microbial interactions...
  8. pmc Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance
    Justin I Odegaard
    Division of Endocrinology, Metabolism and Gerontology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305 5103, USA
    Nature 447:1116-20. 2007
    ....
  9. ncbi Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function
    O Adachi
    Department of Biochemistry, Hyogo College of Medicine, Nishinomiya, Japan
    Immunity 9:143-50. 1998
    ..Taken together, these results demonstrate that MyD88 is a critical component in the signaling cascade that is mediated by IL-1 receptor as well as IL-18 receptor...
  10. pmc Disseminated tuberculosis in interferon gamma gene-disrupted mice
    A M Cooper
    Department of Microbiology, Colorado State University, Fort Collins 80523
    J Exp Med 178:2243-7. 1993
    ..These data, therefore, indicate that although IFN-gamma may not be needed for DTH expression, it plays a pivotal and essential role in protective cellular immunity to tuberculosis infection...
  11. pmc An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection
    J L Flynn
    Howard Hughes Medical Institute, Department of Microbiology, Albert Einstein College of Medicine, Bronx, New York 10461
    J Exp Med 178:2249-54. 1993
    ..In contrast to control mice, gko mice exhibit heightened tissue necrosis and succumb to a rapid and fatal course of tuberculosis that could be delayed, but not prevented, by treatment with exogenous recombinant IFN-gamma...
  12. pmc A highly efficient recombineering-based method for generating conditional knockout mutations
    Pentao Liu
    Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA
    Genome Res 13:476-84. 2003
    ..This method should also facilitate the generation of knock-in mutations and transgene constructs, as well as expedite the analysis of regulatory elements and functional domains in or near genes...
  13. ncbi Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components
    O Takeuchi
    Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Japan
    Immunity 11:443-51. 1999
    ..These results demonstrate that TLR2 and TLR4 recognize different bacterial cell wall components in vivo and TLR2 plays a major role in Gram-positive bacterial recognition...
  14. ncbi XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor
    H Yoshida
    Graduate School of Biostudies, Kyoto University, Kyoto 606 8304, Japan
    Cell 107:881-91. 2001
    ..Our results reveal features of the UPR conserved during evolution and clarify the relationship between IRE1- and ATF6-dependent pathways...
  15. ncbi IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge
    Shabaana A Khader
    Trudeau Institute, Saranac Lake, New York 12983, USA
    Nat Immunol 8:369-77. 2007
    ....
  16. ncbi Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1
    Mehrdad Matloubian
    Howard Hughes Medical Institute and Department of Microbiology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, California 94143 0414, USA
    Nature 427:355-60. 2004
    ..These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs...
  17. ncbi Pax7 is required for the specification of myogenic satellite cells
    P Seale
    Department of Biology, McMaster University, Hamilton, Ontario, Canada
    Cell 102:777-86. 2000
    ..Together these studies suggest that induction of Pax7 in muscle-derived stem cells induces satellite cell specification by restricting alternate developmental programs...
  18. pmc Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity
    Yueh Ming Loo
    Department of Immunology, University of Washington School of Medicine, Box 357650, Seattle, WA 98195 7650, USA
    J Virol 82:335-45. 2008
    ....
  19. pmc Mop3 is an essential component of the master circadian pacemaker in mammals
    M K Bunger
    The McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, WI 53706, USA
    Cell 103:1009-17. 2000
    ..These results provide genetic evidence that MOP3 is the bona fide heterodimeric partner of mCLOCK. Furthermore, these data demonstrate that MOP3 is a nonredundant and essential component of the circadian pacemaker in mammals...
  20. ncbi Prostanoid receptors: structures, properties, and functions
    S Narumiya
    Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto, Japan
    Physiol Rev 79:1193-226. 1999
    ..In this article, we summarize these findings and attempt to give an overview of the current status of research on the prostanoid receptors...
  21. ncbi FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress
    Zuzana Tothova
    Division of Hematology, Department of Medicine, Brigham and Women s Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
    Cell 128:325-39. 2007
    ..Thus, FoxO proteins play essential roles in the response to physiologic oxidative stress and thereby mediate quiescence and enhanced survival in the HSC compartment, a function that is required for its long-term regenerative potential...
  22. ncbi ATM and related protein kinases: safeguarding genome integrity
    Yosef Shiloh
    The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
    Nat Rev Cancer 3:155-68. 2003
    ..Understanding ATM's mode of action provides new insights into the association between defective responses to DNA damage and cancer, and brings us closer to resolving the issue of cancer predisposition in some A-T carriers...
  23. ncbi CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs
    R Forster
    Molecular Tumorgenetics and Immunogenetics, Max Delbruck Center for Molecular Medicine, Berlin, Germany
    Cell 99:23-33. 1999
    ..Thus, in order to bring together lymphocytes and dendritic cells to form the characteristic microarchitecture of secondary lymphoid organs, CCR7 is required to rapidly initiate an adoptive immune response...
  24. ncbi Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis
    Tian Wang
    Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, Connecticut 06520, USA
    Nat Med 10:1366-73. 2004
    ..Collectively, WNV infection leads to a Tlr3-dependent inflammatory response, which is involved in brain penetration of the virus and neuronal injury...
  25. ncbi Inactivation of the beta-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development
    V Brault
    Department of Molecular Embryology, Max Planck Institute of Immunobiology, Stuebeweg 51, D 79108 Freiburg, Germany
    Development 128:1253-64. 2001
    ..Our results demonstrate the pivotal role of beta-catenin in morphogenetic processes during brain and craniofacial development...
  26. ncbi The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells
    Kaoru Mitsui
    Laboratory of Animal Molecular Technology, Research and Education Center for Genetic Information, Nara Institute of Science and Technology, Nara 630 0192, Japan
    Cell 113:631-42. 2003
    ..nanog-deficient ES cells lost pluripotency and differentiated into extraembryonic endoderm lineage. These data demonstrate that Nanog is a critical factor underlying pluripotency in both ICM and ES cells...
  27. ncbi STAT3 regulates cytokine-mediated generation of inflammatory helper T cells
    Xuexian O Yang
    Department of Immunology, M D Anderson Cancer Center, Houston, Texas 77030, USA
    J Biol Chem 282:9358-63. 2007
    ..Our data thus demonstrate a pathway whereby cytokines regulate THi differentiation through a selective STAT transcription factor that functions to regulate lineage-specific gene expression...
  28. pmc Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense
    P Ye
    Louisiana State University Health Sciences Gene Therapy Program, Section of Pulmonary Critical Care Medicine, New Orleans, LA 70112, USA
    J Exp Med 194:519-27. 2001
    ..pneumoniae infection. These data support impaired IL-17R signaling as a potential mechanism by which deficiency of CD4 lymphocytes predisposes to bacterial pneumonia...
  29. ncbi A central role for JNK in obesity and insulin resistance
    Jiro Hirosumi
    Division of Biological Sciences and Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA
    Nature 420:333-6. 2002
    ..Thus, JNK is a crucial mediator of obesity and insulin resistance and a potential target for therapeutics...
  30. pmc neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas
    G Gradwohl
    Institut de Genetique et de Biologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique Institut National de la Santé et de la Recherche Médicale Université Louis Pasteur, F 67404 Illkirch, France
    Proc Natl Acad Sci U S A 97:1607-11. 2000
    ..Thus, ngn3 is required for the specification of a common precursor for the four pancreatic endocrine cell types...
  31. pmc CD4(+)CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis
    Charles F Anderson
    Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
    J Exp Med 204:285-97. 2007
    ....
  32. ncbi A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome
    J Guy
    Wellcome Centre for Cell Biology, Institute of Cell and Molecular Biology, University of Edinburgh, The King s Buildings, Edinburgh, UK
    Nat Genet 27:322-6. 2001
    ....
  33. ncbi Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses
    Susumu Nakae
    Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, 4 6 1 Shirokanedai, Minato ku, Tokyo, Japan
    Immunity 17:375-87. 2002
    ..Our findings indicate that IL-17 plays an important role in activating T cells in allergen-specific T cell-mediated immune responses...
  34. ncbi Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart
    Chen Leng Cai
    Institute of Molecular Medicine, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
    Dev Cell 5:877-89. 2003
    ..Our results have implications for the development of specific cardiac lineages, left-right asymmetry, cardiac evolution, and isolation of cardiac progenitor cells...
  35. pmc A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis
    Caroline Sutton
    Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland
    J Exp Med 203:1685-91. 2006
    ..Tumor necrosis factor alpha also synergized with IL-23 to enhance IL-17 production, and this was IL-1 dependent. Our findings demonstrate that IL-1 functions upstream of IL-17 to promote pathogenic ThIL-17 cells in EAE...
  36. pmc Increased adipose tissue in male and female estrogen receptor-alpha knockout mice
    P A Heine
    Departments of Veterinary Biosciences and Kinesiology, University of Illinois, Urbana, IL 61802, USA
    Proc Natl Acad Sci U S A 97:12729-34. 2000
    ..These results are evidence that estrogen/ERalpha signaling is critical in female and male WAT; obesity in alphaERKO males involves a mechanism of reduced energy expenditure rather than increased energy intake...
  37. pmc IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6
    David Yen
    Department of Discovery Research, Schering Plough Biopharma, Palo Alto, California 94304, USA
    J Clin Invest 116:1310-6. 2006
    ..This pathway may be responsible for chronic intestinal inflammation as well as other chronic autoimmune inflammatory diseases...
  38. ncbi Mammalian SIRT1 represses forkhead transcription factors
    Maria Carla Motta
    Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    Cell 116:551-63. 2004
    ..We speculate how down-regulating these two classes of damage-responsive mammalian factors may favor long lifespan under certain environmental conditions, such as calorie restriction...
  39. ncbi TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents
    Diana M Bautista
    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA
    Cell 124:1269-82. 2006
    ..Thus, TRPA1 is an important component of the transduction machinery through which environmental irritants and endogenous proalgesic agents depolarize nociceptors to elicit inflammatory pain...
  40. pmc Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting
    S Kersten
    Institut de Biologie Animale, Universite de Lausanne, CH 1015 Lausanne, Switzerland
    J Clin Invest 103:1489-98. 1999
    ..By modulating gene expression, PPARalpha stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues...
  41. pmc Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance
    Laura Bonifaz
    Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021, USA
    J Exp Med 196:1627-38. 2002
    ..Therefore, DEC-205 provides an efficient receptor-based mechanism for DCs to process proteins for MHC class I presentation in vivo, leading to tolerance in the steady state and immunity after DC maturation...
  42. ncbi beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin
    J Huelsken
    Max Delbrueck Center for Molecular Medicine, Robert Roessle Strasse 10, 13092, Berlin, Germany
    Cell 105:533-45. 2001
    ..Further analysis demonstrates that beta-catenin is essential for fate decisions of skin stem cells: in the absence of beta-catenin, stem cells fail to differentiate into follicular keratinocytes, but instead adopt an epidermal fate...
  43. pmc Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata
    Filip K Swirski
    Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Clin Invest 117:195-205. 2007
    ..Conversely, the number of Ly-6C(lo) cells remained unaffected. Thus, we believe that Ly-6C(hi) monocytes represent a newly recognized component of the inflammatory response in experimental atherosclerosis...
  44. pmc Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine
    Ivaylo I Ivanov
    Kimmel Center for Biology and Medicine of the Skirball Institute, Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA
    Cell Host Microbe 4:337-49. 2008
    ..Our results suggest that composition of intestinal microbiota regulates the Th17:Treg balance in the LP and may thus influence intestinal immunity, tolerance, and susceptibility to inflammatory bowel diseases...
  45. pmc Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes
    Jay D Horton
    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390 9046, USA
    Proc Natl Acad Sci U S A 100:12027-32. 2003
    ....
  46. pmc The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues
    T Lindsten
    Department of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
    Mol Cell 6:1389-99. 2000
    ..Thus, Bax and Bak have overlapping roles in the regulation of apoptosis during mammalian development and tissue homeostasis...
  47. pmc Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene
    N Harada
    Banyu Tsukuba Research Institute Merck, Tsukuba 300 2611, Japan
    EMBO J 18:5931-42. 1999
    ..in the offspring intestines, which caused adenomatous intestinal polyps resembling those in Apc(Delta716) knockout mice. Some nascent microadenomas were also found in the colon...
  48. ncbi IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis
    Yutaka Komiyama
    Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, 4 6 1 Shirokanedai, Minato ku, Tokyo 108 8639, Japan
    J Immunol 177:566-73. 2006
    ..These observations indicate that IL-17 rather than IFN-gamma plays a crucial role in the development of EAE...
  49. ncbi Transcriptional regulation by calcium, calcineurin, and NFAT
    Patrick G Hogan
    The Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115, USA
    Genes Dev 17:2205-32. 2003
  50. ncbi TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction
    Kelvin Y Kwan
    Department of Neurobiology and Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
    Neuron 50:277-89. 2006
    ..b>Knockout mice display behavioral deficits in response to mustard oil, to cold ( approximately 0 degrees C), and to punctate ..
  51. ncbi Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase
    C Postic
    Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
    J Biol Chem 274:305-15. 1999
    ..Interestingly, hepatic GK knock-out mice also have impaired insulin secretion in response to glucose. These studies indicate that deficiencies in both beta cell and hepatic GK contribute to the hyperglycemia of MODY-2...
  52. ncbi Projection of an immunological self shadow within the thymus by the aire protein
    Mark S Anderson
    Section on Immunology and Immunogenetics, Joslin Diabetes Center Department of Medicine, Brigham and Women s Hospital Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA
    Science 298:1395-401. 2002
    ..These findings highlight the importance of thymically imposed "central" tolerance in controlling autoimmunity...
  53. ncbi IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo
    M M Fort
    DNAX Research Institute, Palo Alto, CA 94304, USA
    Immunity 15:985-95. 2001
    ..These results suggest that IL-25, derived from Th2 T cells, is capable of amplifying allergic type inflammatory responses by its actions on other cell types...
  54. ncbi Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice
    M Drab
    Max Planck Institute for Molecular Cell Biology and Genetics, Pfotenhauer Strasse 108, D 01307 Dresden, Germany
    Science 293:2449-52. 2001
    ..Thus, caveolin-1 and caveolae play a fundamental role in organizing multiple signaling pathways in the cell...
  55. ncbi TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells
    Marc Veldhoen
    Division of Molecular Immunology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom
    Immunity 24:179-89. 2006
    ..Our data indicate that, in the presence of IL-6, TGFbeta1 subverts Th1 and Th2 differentiation for the generation of IL-17-producing T cells...
  56. ncbi Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation
    R M Chemelli
    Howard Hughes Medical Institute, Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, 75235 9050, USA
    Cell 98:437-51. 1999
    ..Here, we report that, by behavioral and electroencephalographic criteria, orexin knockout mice exhibit a phenotype strikingly similar to human narcolepsy patients, as well as canarc-1 mutant dogs, the only ..
  57. pmc Late developmental plasticity in the T helper 17 lineage
    Yun Kyung Lee
    Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    Immunity 30:92-107. 2009
    ..These results support a model of late Th17 developmental plasticity with implications for autoimmunity and host defense...
  58. pmc MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity
    Hajime Kanda
    Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
    J Clin Invest 116:1494-505. 2006
    ..These findings suggest that an increase in MCP-1 expression in adipose tissue contributes to the macrophage infiltration into this tissue, insulin resistance, and hepatic steatosis associated with obesity in mice...
  59. ncbi Cancer immunoediting: from immunosurveillance to tumor escape
    Gavin P Dunn
    Department of Pathology and Immunology, Center for Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA
    Nat Immunol 3:991-8. 2002
    ..In this review, we will summarize the historical and experimental basis of cancer immunoediting and discuss its dual roles in promoting host protection against cancer and facilitating tumor escape from immune destruction...
  60. ncbi Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene
    M Elchebly
    Department of Biochemistry, McGill University, 3655 Drummond Street, Montreal, Quebec, Canada, H3G 1Y6
    Science 283:1544-8. 1999
    ..These results demonstrate that PTP-1B has a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing it as a potential therapeutic target in the treatment of type 2 diabetes and obesity...
  61. pmc Alpha/beta interferon protects against lethal West Nile virus infection by restricting cellular tropism and enhancing neuronal survival
    Melanie A Samuel
    Department of Molecular Microbiology, Washington University School of Medicine, Campus Box 8051, 660 S Euclid Ave, St Louis, MO 63110, USA
    J Virol 79:13350-61. 2005
    ..Collectively, our data suggest that IFN-alpha/beta controls WNV infection by restricting tropism and viral burden and by preventing death of infected neurons...
  62. ncbi A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance
    J C Bruning
    Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA
    Mol Cell 2:559-69. 1998
    ..The muscle-specific insulin receptor knockout mice exhibit a muscle-specific > 95% reduction in receptor content and early signaling events...
  63. ncbi A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection
    H Suzuki
    Chugai Pharmaceutical Co Ltd, Shizuoka, Japan
    Nature 386:292-6. 1997
    ..In addition, MSR-A-knockout mice show an increased susceptibility to infection with Listeria monocytogenes or herpes simplex virus type-1, ..
  64. ncbi Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain
    Daniel J Cua
    Department of Immunology, DNAX Research Inc, Palo Alto, California 94304 1104, USA
    Nature 421:744-8. 2003
    ..In addition, we show that IL-23, unlike IL-12, acts more broadly as an end-stage effector cytokine through direct actions on macrophages...
  65. ncbi In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-gamma and TNF-alpha
    R T Gazzinelli
    Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA
    J Immunol 157:798-805. 1996
    ..Together the data suggest that endogenous IL-10 synthesis plays an important role in vivo in down-regulating monokine and IFN-gamma responses to acute intracellular infection, thereby preventing host immunopathology...
  66. pmc Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella
    G J Pazour
    Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA
    J Cell Biol 151:709-18. 2000
    ..This indicates that IFT is important for primary cilia assembly in mammals. It is likely that primary cilia have an important function in the kidney and that defects in their assembly can lead to polycystic kidney disease...
  67. pmc Requirement for hippocampal CA3 NMDA receptors in associative memory recall
    Kazu Nakazawa
    Picower Center for Learning and Memory, RIKEN MIT Neuroscience Research Center, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    Science 297:211-8. 2002
    ..These results provide direct evidence for CA3 NMDA receptor involvement in associative memory recall...
  68. ncbi Toll-like receptors control activation of adaptive immune responses
    M Schnare
    Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
    Nat Immunol 2:947-50. 2001
    ..These results suggest that distinct pathways of the innate immune system control activation of the two effector arms of adaptive immunity...
  69. pmc Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses
    Manish J Butte
    Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
    Immunity 27:111-22. 2007
    ..Our findings point to a substantial bidirectional inhibitory interaction between B7-1 and PD-L1 and add an additional dimension to immunoregulatory functions of the B7:CD28 family...
  70. ncbi Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock
    Thomas Vogl
    Institute of Experimental Dermatology, University of Munster, D 48129 Munster, Germany
    Nat Med 13:1042-9. 2007
    ..Therefore Mrp8-Mrp14 complexes are new inflammatory components that amplify phagocyte activation during sepsis upstream of TNFalpha-dependent effects...
  71. ncbi Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer
    Shunyou Wang
    Howard Hughes Medical Institute, University of California Los Angeles School of Medicine, 90095, Los Angeles, CA, USA
    Cancer Cell 4:209-21. 2003
    ..This murine prostate cancer model provides a unique tool for both exploring the molecular mechanism underlying prostate cancer and for development of new targeted therapies...
  72. ncbi TLR9 signals after translocating from the ER to CpG DNA in the lysosome
    Eicke Latz
    Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Lazare Research Building 308, 364 Plantation Street, Worcester, MA 01605, USA
    Nat Immunol 5:190-8. 2004
    ..Our data indicate a previously unknown mechanism of cellular activation involving the recruitment of TLR9 from the ER to sites of CpG DNA uptake, where signal transduction is initiated...
  73. ncbi Pten is essential for embryonic development and tumour suppression
    A Di Cristofano
    Department of Human Genetics, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, NY 10021, USA
    Nat Genet 19:348-55. 1998
    ..These results support the notion that PTEN haploinsufficiency plays a causal role in CD, LDD and BZS pathogenesis, and demonstrate that Pten is a tumour suppressor essential for embryonic development...
  74. ncbi The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis
    J S Munger
    Department of Medicine, and Kaplan Cancer Center, New York University School of Medicine, New York 10016 6402, USA
    Cell 96:319-28. 1999
    ..These data identify a novel mechanism for locally regulating TGF beta 1 function in vivo by regulating expression of the alpha v beta 6 integrin...
  75. pmc Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice
    Mikio Furuse
    Department of Cell Biology, Kyoto University Faculty of Medicine, Yoshida Konoe, Sakyo ku, Kyoto 606 8501, Japan
    J Cell Biol 156:1099-111. 2002
    ..These findings provide the first evidence that continuous claudin-based TJs occur in the epidermis and that these TJs are crucial for the barrier function of the mammalian skin...
  76. ncbi The mouse Spo11 gene is required for meiotic chromosome synapsis
    P J Romanienko
    Genetics and Biochemistry Branch National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health 20892, Bethesda, MD, USA
    Mol Cell 6:975-87. 2000
    ..We speculate that there is an additional role for Spo11, after it generates DSBs, in synapsis...
  77. ncbi A mechanosensory complex that mediates the endothelial cell response to fluid shear stress
    Eleni Tzima
    Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    Nature 437:426-31. 2005
    ..In support of the relevance of this pathway in vivo, PECAM-1-knockout mice do not activate NF-kappaB and downstream inflammatory genes in regions of disturbed flow...
  78. ncbi Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1
    J C Yoon
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nature 413:131-8. 2001
    ..These results implicate PGC-1 as a key modulator of hepatic gluconeogenesis and as a central target of the insulin-cAMP axis in liver...
  79. ncbi Role of brain insulin receptor in control of body weight and reproduction
    J C Bruning
    Klinik II und Poliklinik für Innere Medizin and Center of Molecular Medicine ZMMK der Universität zu Köln, Joseph Stelzmann Strasse 9, 50931 Cologne, Germany
    Science 289:2122-5. 2000
    ..Thus, IR signaling in the CNS plays an important role in regulation of energy disposal, fuel metabolism, and reproduction...
  80. pmc RANK is essential for osteoclast and lymph node development
    W C Dougall
    Immunex Corporation, Seattle, Washington 98101 USA
    Genes Dev 13:2412-24. 1999
    ..These experiments reveal that RANK provides critical signals necessary for lymph node organogenesis and osteoclast differentiation...
  81. ncbi Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme
    M Muramatsu
    Department of Medical Chemistry, Graduate School of Medicine, Institute for Virus Research, Kyoto University, Japan
    Cell 102:553-63. 2000
    ..These results suggest that AID may be involved in regulation or catalysis of the DNA modification step of both class switching and somatic hypermutation...
  82. pmc 11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress
    Y Kotelevtsev
    Centre for Genome Research, University of Edinburgh, Kings Buildings, West Mains Road, Edinburgh EH 9 3JQ, Scotland, UK
    Proc Natl Acad Sci U S A 94:14924-9. 1997
    ..The 11beta-HSD-1 -/- mice were found to resist hyperglycamia provoked by obesity or stress. Attenuation of hepatic 11beta-HSD-1 may provide a novel approach to the regulation of gluconeogenesis...
  83. ncbi A critical role for IL-21 in regulating immunoglobulin production
    Katsutoshi Ozaki
    Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892 1674, USA
    Science 298:1630-4. 2002
    ..This suggests that these gammac-dependent cytokines may be those whose inactivation is primarily responsible for the B cell defect in humans with XSCID...
  84. pmc Lessons from loricrin-deficient mice: compensatory mechanisms maintaining skin barrier function in the absence of a major cornified envelope protein
    P J Koch
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
    J Cell Biol 151:389-400. 2000
    ....
  85. ncbi Mitochondrial fusion protects against neurodegeneration in the cerebellum
    Hsiuchen Chen
    Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA
    Cell 130:548-62. 2007
    ....
  86. pmc Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy
    T Sullivan
    Advanced BioScience Laboratories Basic Research Program, National Cancer Institute Frederick Cancer Research and Development Center, Maryland 21702, USA
    J Cell Biol 147:913-20. 1999
    ..Mice lacking the A-type lamins exhibit tissue-specific alterations to their nuclear envelope integrity and emerin distribution. In skeletal and cardiac muscles, this is manifest as a dystrophic condition related to EDMD...
  87. ncbi Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin
    Andrew M Intlekofer
    Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Nat Immunol 6:1236-44. 2005
    ..Therefore, these key transcription factors link the long-term renewal of memory CD8(+) T cells to their characteristic effector potency...
  88. ncbi RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems
    Koichi Kobayashi
    Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Nature 416:194-9. 2002
    ..Rip2 is therefore a signal transducer and integrator of signals for both the innate and adaptive immune systems...
  89. pmc TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis
    Andre Bafica
    Immunobiology Section, Laboratory of Parasitic Diseases, National Institutes of Health, Bethesda, MD 20892, USA
    J Exp Med 202:1715-24. 2005
    ..by several major mycobacterial ligands, we analyzed the resistance of TLR9(-/-) as well as TLR2/9 double knockout mice to aerosol infection with Mycobacterium tuberculosis...
  90. pmc NF-kappaB is a negative regulator of IL-1beta secretion as revealed by genetic and pharmacological inhibition of IKKbeta
    Florian R Greten
    Second Department of Medicine, Klinikum rechts der Isar, Technical University Munich, 81675 Germany
    Cell 130:918-31. 2007
    ..These results unravel an unanticipated role for IKKbeta-dependent NF-kappaB signaling in the negative control of IL-1beta production and highlight potential complications of long-term IKKbeta inhibition...
  91. pmc The role of interleukin (IL)-10 in the persistence of Leishmania major in the skin after healing and the therapeutic potential of anti-IL-10 receptor antibody for sterile cure
    Y Belkaid
    Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg 4 Rm 126, Center Dr MSC 0425, Bethesda, MD 20892, USA
    J Exp Med 194:1497-506. 2001
    ....
  92. ncbi Identification of ubiquitin ligases required for skeletal muscle atrophy
    S C Bodine
    Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY, 10591 6707, USA
    Science 294:1704-8. 2001
    ..Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx or MuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy...
  93. ncbi Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2
    M Trommsdorff
    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235 9046, USA
    Cell 97:689-701. 1999
    ..mDab1 expression is upregulated in knockout mice that lack both VLDLR and ApoER2...
  94. ncbi Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis
    C J Sinal
    Laboratory of Metabolism, Division of Basic Sciences, National Institutes of Health, Bethesda, Maryland 20892, USA
    Cell 102:731-44. 2000
    ..These data demonstrate that FXR/BAR is critical for bile acid and lipid homeostasis by virtue of its role as an intracellular bile acid sensor...
  95. ncbi Natural regulatory T cells control the development of atherosclerosis in mice
    Hafid Ait-Oufella
    Institut National de la Sante et de la Recherche Medicale INSERM, Unit 689, Centre de Recherché Cardiovasculaire Lariboisière, 41, Bd de la Chapelle, 75010 Paris, France
    Nat Med 12:178-80. 2006
    ..These results provide new insights into the immunopathogenesis of atherosclerosis and could lead to new therapeutic approaches that involve immune modulation using regulatory T cells...
  96. pmc IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response
    Kyungho Lee
    Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
    Genes Dev 16:452-66. 2002
    ..Both processing of ATF6 and IRE1alpha-mediated splicing of XBP1 mRNA are required for full activation of the UPR...
  97. pmc Flagellin-deficient Legionella mutants evade caspase-1- and Naip5-mediated macrophage immunity
    Tao Ren
    Genetics Department, Harvard Medical School, Boston, Massachusetts, USA
    PLoS Pathog 2:e18. 2006
    ..It thus appears that macrophages sense cytosolic flagellin via a TLR5-independent pathway that leads to rapid caspase-1-dependent cell death and provides defense against intracellular bacterial pathogens...
  98. ncbi Dicer is essential for mouse development
    Emily Bernstein
    Cold Spring Harbor Laboratory, Watson School of Biological Sciences, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA
    Nat Genet 35:215-7. 2003
    ..Coupled with our inability to generate viable Dicer1-null embryonic stem (ES) cells, this suggests a role for Dicer, and, by implication, the RNAi machinery, in maintaining the stem cell population during early mouse development...
  99. pmc The knockout mouse project
    Christopher P Austin
    National Human Genome Research Institute, National Institutes of Health, Building 31, Room 4B09, 31 Center Drive, Bethesda, Maryland 20892, USA
    Nat Genet 36:921-4. 2004
    ..It is time to harness new technologies and efficiencies of production to mount a high-throughput international effort to produce and phenotype knockouts for all mouse genes, and place these resources into the public domain...
  100. ncbi Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice
    L Gu
    Department of Adult Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA
    Mol Cell 2:275-81. 1998
    ..Thus, MCP-1 plays a unique and crucial role in the initiation of atherosclerosis and may provide a new therapeutic target in this disorder...
  101. ncbi DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development
    M Okano
    Cardiovascular Research Center, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Charlestown 02129, USA
    Cell 99:247-57. 1999
    ..Our results indicate that both Dnmt3a and Dnmt3b function as de novo methyltransferases that play important roles in normal development and disease...

Research Grants72

  1. Discovery metabolite profiling of the prolyl peptidases
    Alan Saghatelian; Fiscal Year: 2009
    ..Furthermore, the application of DMP to peptidases will demonstrate the generality of this approach for the future characterization of medically relevant enzymes and signaling pathways. ..
  2. Transcription factors regulating sensory gene expression and pain pathways
    Eric E Turner; Fiscal Year: 2011
    ..genechips" to assay the entire program of pain-related genes expressed in maturing sensory neurons in Islet1 knockout mice and controls, and we will examine how Islet1 regulates its target genes by modifying gene structure in ..
  3. Mice Humanized with Hepatocytes and iPS Cells from Patients with Metabolic Diseas
    Stephen C Strom; Fiscal Year: 2010
    ..We propose these humanized mice will be a technology platform to better understand the human disease and it will aid in the development of gene or cellular therapy to correct these devastating diseases. ..
  4. Pyruvate Dehydrogenase kinase as Therapeutic Target for Hepatic Steatosis, Obesit
    Robert A Harris; Fiscal Year: 2012
    ..The immediate objective is to perform proof-of- principle studies with PDK knockout mice generated in my laboratory...
  5. Role of Chromogranin A in Metabolic Syndrome
    Sushil K Mahata; Fiscal Year: 2013
    ..To gain a better insight into the role of Chga in metabolic disorder, we have generated Chga knockout mice (Chga-KO), which display hypertension, high plasma catecholamines, increased hepatic sensitivity to insulin ..
  6. Gamma-Synuclein-Mediated Regulation of Norepinephrine Transporter
    Anita Sidhu; Fiscal Year: 2010
    ..This grant is also relevant for the ARRA in that it will immediately create 3 new professional jobs. ..
  7. Regulation of thyroid hormone levels by central and peripheral pathways
    KRISTEN RACHEL VELLA; Fiscal Year: 2013
    ..abstract_text> ..
  8. Role of Txnip in adapting fuel metabolism to nutritional state
    SIMON HUI; Fiscal Year: 2013
    ..Using tissue-specific Txnip knockout mice, we have identified that impaired mitochondrial oxidation in the muscle is the major contributor leading to ..
  9. Roles of Nitric Oxide and Superoxide in Cystitis
    ANTHONY JOHN KANAI; Fiscal Year: 2013
    ..will be tested in control and transient receptor potential ankyrin 1 and vanilloid 1 (TRPA1-/- and TRPV1-/-) knockout mice using optical mapping of UC, dorsal root ganglia (DRG) neurons and afferent nerve terminals in the bladder ..
  10. Cystathionine beta synthase (CBS) and angiogenesis
    Priyabrata Mukherjee; Fiscal Year: 2013
    ..In fact, heterozygous and homozygous deleted CBS knockout mice exhibit mild to severe HHcy, respectively...
  11. Response to and signals of caloric restriction and intermittent feeding regimens
    MARC KOPEL HELLERSTEIN; Fiscal Year: 2010
    ....
  12. Enterococcus faecalis, Colorectal Cancer, and Bystander Effects
    Mark M Huycke; Fiscal Year: 2012
    ..prostanoids, TNF1, malondialdehyde and 4- hydroxynonenal in the colonic mucosa of interleukin (IL)-10 knockout mice will be determined...
  13. THE ROLE OF ACETYLATION IN MITOCHONDRIAL FUNCTION
    Gary Cecchini; Fiscal Year: 2013
    ..Using the SIRT3 KO mouse model, it will be determined if the properties of cardiac tissue such as pre- and post-conditioning are altered by acetylation/deacetylation of proteins. ..
  14. Autonomic and Antihypertensive Actions of Neuronal CGRP/RAMP1 Receptors
    Mark W Chapleau; Fiscal Year: 2013
    ..responsible for autonomic and blood pressure phenotypes in the nervous system-targeted RAMP1 transgenic and knockout mice;and (3) Test the hypothesis that activation of nervous system CGRP/ RAMP1 receptors abrogates Ang-II induced ..
  15. 5-HT transporter function: Interaction of hormones and antidepressants
    Alan Frazer; Fiscal Year: 2013
    ..chronoamperometry, two approaches will be used, namely the use of specific estrogen receptor (ER1 or ER2) knockout mice and the effects of selective estrogen receptor agonists in rats, to study the role of these estrogen receptor ..
  16. Role and Regulation of INrf2
    ANIL KUMAR JAISWAL; Fiscal Year: 2013
    ..Aim 3 will continue with generation of INrf2 conditional knockout mice that do not express INrf2 protein in liver and epidermis of skin...
  17. INSULIN RECEPTORS AND THE GLUCOSE TRANSPORT SYSTEM
    JERROLD MICHAEL OLEFSKY; Fiscal Year: 2013
    ..Our previous work has shown that genetically disabling macrophage inflamma- tory pathways in knockout mice protects animals from obesity and high fat diet induced insulin resistance, lead- ing to the idea that the ..
  18. Regulation of epithelial cell homeostasis by actin microfilaments
    Seema Khurana; Fiscal Year: 2010
    ....
  19. Neuroprotection and Myelin Repair Mechanisms in Multiple Sclerosis
    Inderjit Singh; Fiscal Year: 2013
    ..Moreover, AMPK-11 gene knockout mice had more severe EAE than wild-type mice, suggesting a role for AMPK in EAE attenuation...
  20. MODULATION OF IFN ACTION VIA NOVEL REGULATORY FACTORS
    DHAN V KALVAKOLANU; Fiscal Year: 2013
    ..We will evaluate the critical relevance of these factors to DAPK1 and autophagy using RNAi, knockout mice, protein-interactions, ChIP assays, mutagenesis and transcriptional analyses...
  21. Targeting iNOS to inhibit myeloid-derived suppressor cells (MDSC) in melanoma
    ANDREW GREGORY SIKORA; Fiscal Year: 2013
    ..abstract_text> ..
  22. A novel peroxidase in vascular endothelium and the development of atherosclerosis
    Guangjie Cheng; Fiscal Year: 2012
    ..These studies are an essential prelude to (patho)physiological studies (e.g., in knockout mice) of the role of VPO in cardiovascular disease...
  23. ALTERED CARDIAC MYOCYTE SIGNALING IN DIABETIC MYOCARDIUM AND FUNCTIONAL SEQUELAE
    ANTHONY JUSTIN MUSLIN; Fiscal Year: 2010
    ..of diabetic cardiomyopathy will be investigated by use of cPLA2 -/- akt2-/- and iPLA2 -/- akt2-/- double knockout mice. Experimental results from this project will help to define specific signaling mechanisms involved in the ..
  24. ER stress: role in myocyte apoptosis and myocardial remodeling
    Krishna Singh; Fiscal Year: 2013
    ..Specific Aim 2 will use Gadd153 knockout mice to investigate the in vivo role of ER stress in apoptosis and myocardial remodeling following 2-AR stimulation ..
  25. The genetics and pathophysiology of impaired Wnt signaling in metabolic syndrome
    Arya Mani; Fiscal Year: 2012
    ..Preliminary results from IPGTT in heterozygote knockout mice on Western diet has demonstrated increased glucose stimulated insulin levels and reduced hepatic glycogen ..
  26. An Aldosterone-Endothelin Feedback Mechanism on Sodium Homeostasis
    Charles S Wingo; Fiscal Year: 2012
    ..Renal ET-1 is known to stimulate natriuresis and diuresis. Collecting-duct specific ET-1 knockout mice exhibit salt- sensitive hypertension...
  27. Arginine Availability and Metabolism in the Immune Evasion of H. pylori
    Keith T Wilson; Fiscal Year: 2013
    ..We will generate Arg2-/-iNOS-/- double knockout mice that will be compared to wild-type (WT), Arg2-/-, and iNOS-/- mice, and bone marrow chimeras will be used, to ..
  28. Role of stearoyl CoA desaturase-1 in TLR5 KO mice colitis and metabolic syndrome
    Matam Vijay Kumar; Fiscal Year: 2013
    ..study the role of SCD-1 in the development of colitis and metabolic syndrome by generating SCD-1/TLR5 double knockout mice. Overall, our research proposal may help in designing oleate-rich dietary formulations and also clarify ..
  29. Characterization of epsilon-sarcoglycan interacting proteins in mouse brain
    Yuqing Li; Fiscal Year: 2012
    ..We have established a Sgce knockout model of DYT11 dystonia. We found that the Sgce knockout mice showed myoclonus, motor deficits indicative of dystonia, anxiety, depression, and changes in the dopaminergic ..
  30. Lipid Binding Proteins in Obesity and Diabetes Syndromes
    David A Bernlohr; Fiscal Year: 2013
    ..When placed on high fat diets, FABP knockout mice exhibit attenuated characteristics of the metabolic syndrome including diminished adipocyte lipolysis, reduced ..
  31. Canonical Transient Receptor Potential (TRPC) subfamily function in Hippocampus.
    David E Clapham; Fiscal Year: 2013
    ..TRPC4, TRPC5, both TRPC4 and TRPC5 genes, obtained the TRPC1 knockout mouse, and are breeding TRPC1/4/5 triple knockout mice. Here we propose to use these mice to understand the function of these ion channels in the hippocampus using ..
  32. Inhibition of bone formation by Prx1
    Mark S Nanes; Fiscal Year: 2013
    ..2B. Determine if OB precursors cultured from Prx1 knockout mice are resistant to TNF inhibition of OB differentiation...
  33. DNA Repair Deficiency Associated with Obesity and the Metabolic Syndrome
    R Stephen Lloyd; Fiscal Year: 2013
    ..Disease manifestations in the neil1 knockout mice may include obesity, fatty liver disease, dyslipidemia and hyperinsulinemia, with male knockouts much more ..
  34. Undercarboxylated osteocalcin, body fat, and diabetes in older adults
    Ann V Schwartz; Fiscal Year: 2010
    ..This research project will determine if lower ucOC levels predict development of diabetes or increases in total body fat over nine years. ..
  35. Folate and S-adenosyimethionine in Methyl Group and One-carbon Metabolism
    Conrad Wagner; Fiscal Year: 2012
    ....
  36. DNA Damage Checkpoint and Cancer
    Toru Ouchi; Fiscal Year: 2012
    ....
  37. Mechanisms of Angiogenesis in Retinopathy of Prematurity
    Mary Elizabeth Hartnett; Fiscal Year: 2009
    ..To do this we will use knockout mice to p47phox, a subunit of NADPH oxidase, or pharmacologic inhibitors of NADPH oxidase...
  38. Regulation of vaccine-induced anti-fungal T17 cells
    MARCEL WUETHRICH; Fiscal Year: 2013
    ..TCR Tg mouse, we have established an in vitro screen with bone marrow derived dendritic cells from knockout mice and an in vivo adoptive transfer system to delineate the signaling adaptors, pathogen recognition receptors, ..
  39. Combined BAC Transgenic and Knock-Out Mouse Model of Lowe Syndrome Nephropathy
    Robert L Nussbaum; Fiscal Year: 2013
    ..We have shown that the lack of renal phenotype in Ocrl-knockout mice is due to complete compensation by another phosphatidylinositol(4,5)P2 5-phosphatase, Inpp5b, encoded by ..
  40. P38 MAP KINASE SIGNALING IN SKIN
    Tatiana Efimova; Fiscal Year: 2013
    ..Together, the data from chemical carcinogenesis studies, using global p384 knockout mice, and the results from skin graft studies using oncogenic ras-transformed p384-null keratinocytes, support our ..
  41. The Role of MYST Histone Acetyltransferase in Genome Stability
    M Mitchell Smith; Fiscal Year: 2013
    ..Finally, we will use our knowledge of ESA1 to construct conditional knockout mice carrying mutant Myst2 alleles that will reveal if it also has essential non-enzymatic functions during ..
  42. Mechanisms of Angiogenesis of Retinopathy of Prematurity
    MARY ELIZABETH RUTH HARTNETT; Fiscal Year: 2013
    ..To do this we will use knockout mice to p47phox, a subunit of NADPH oxidase or pharmacologic inhibitors of NADPH oxidase...
  43. Local Calcium Signaling in Pulmonary Arteries
    JAMES SK SHAM; Fiscal Year: 2012
    ..patch clamp, laser-scanning confocal microscopy, and UV-pulse laser flash photolysis, siRNA, and CD38 knockout mice to determine (1) the Ca2+ signals and physiological functions mediated by different RyR subtypes;(2) the ..
  44. Transcriptional control of pituitary gonadotropin genes
    Varykina G Thackray; Fiscal Year: 2013
    ..Funding of this proposal will also allow the PI, as an Early-Stage Investigator, to establish a fully-independent research program in the field of reproductive endocrinology. ..
  45. Role of murine induced pluripotent stem cells on the correction of cardiac and sk
    Diego Fraidenraich; Fiscal Year: 2010
    ..Using a mouse model of the "thin myocardial syndrome" (Id knockout mice), we have shown that secreted factors from ES cells normalize gene expression profiles in neighbor cells...
  46. Role of ALDH7A1 in Ethanol-Induced Oxidative Damage
    CHAD NICHOLAS BROCKER; Fiscal Year: 2011
    ..This long term goal of this project is to elucidate the protective functions of ALDH7A1 during excessive alcohol consumption. ..
  47. Regulatory Oxygenases in Vasculopathic Rickettsioses
    SANJEEV SAHNI; Fiscal Year: 2010
    ..or dominant- negative mutants, siRNA-based knockdown, tissue-targeted over-expression, and knockout mice, we will address the following thematically and mechanistically interrelated specific aims: Aim 1 will (i)...
  48. Vitamin D3 Regulation of the Hypothalamic-Pituitary-Gonadal Axis
    Genevieve S Neal-Perry; Fiscal Year: 2012
    ..Phenotypes in VDR and CYP27b1 knockout mice include hypogonadism, arrested ovarian follicular development and hypoplastic uteri...
  49. Role of poly (ADP-ribose) polymerase 1 (PARP-1) in experimental colitis
    Claire Larmonier; Fiscal Year: 2013
    ..A novel mouse model for conditional cell-type specific Parp1 targeting, Parp1/Rag1 double knockout mice, and bone marrow chimeras developed as part of this proposal will be used in the following specific aims: (1) ..
  50. Lipid Binding Proteins in Obesity and Diabetes Syndromes
    David A Bernlohr; Fiscal Year: 2011
    ..When placed on high fat diets, FABP knockout mice exhibit attenuated characteristics of the metabolic syndrome including diminished adipocyte lipolysis, reduced ..
  51. Regulation of Triglyceride Metabolism by the transcription factor CREB-H
    Ann Hwee Lee; Fiscal Year: 2013
    ....
  52. Molecular Pathological Mechanism & Potential Therapeutics of Lafora Disease
    YAN NONE LIU; Fiscal Year: 2010
    ..Knowledge gained from this project could greatly improve the care of Lafora patients and provide very important insight for developing therapeutic agents for the treatment of the so far incurable LD patients. ..
  53. Chemokine Decoy Receptor for Therapy of Autoimmune Arthritis
    Kanneganti Murthy; Fiscal Year: 2012
    ..We will test this agent in a clinically-relevant small animal model and determine the most effective dose, in anticipation of definitive large animal studies to confirm its efficacy and safety. ..
  54. Regulation of vasculature by estrogen receptors during aging in mouse models
    Margaret Markiewicz; Fiscal Year: 2013
    ..investigated the role of estrogen receptors in the process of new vessel formation using female ER?? and ER?? knockout mice. Our preliminary data have demonstrated an impairment of skin microvasculature in both ER?? -/- and ER?? -/- ..
  55. The Role of H6PDH and 11beta-HSD1 in Type 2 Diabetes and Obesity
    Yanjun Liu; Fiscal Year: 2013
    ..In support of this, H6PDH knockout mice are unable to regenerate tissue GCs and impaired 112- HSD1 activity...
  56. Adiponectin and fetal programming
    Jianhua Shao; Fiscal Year: 2013
    ..By using high fat diet-induced obese dams and adiponectin knockout mice, Specific Aim 3 will study the effects of maternal obesity and the role of fetal adiponectin on C/EBP2 ..
  57. Effects of periodontitis on insulin target organs and glucose homeostasis
    Keiko Watanabe; Fiscal Year: 2013
    ..as peripheral glucose uptake (AS160) by skeletal muscle and adipose tissue using whole body TLR4 and 2&4 knockout mice, 2) determine the pathways involved in periodontitis-induced hepatic IR and altered glucose homeostasis via ..
  58. Conditional Knockout of Calcium Receptors in Bone Cells
    Dolores M Shoback; Fiscal Year: 2013
    ....
  59. Myosin phosphatase autoinhibition in gastrointestinal smooth muscle contraction
    Avril V Somlyo; Fiscal Year: 2012
    ..The pCa-force relationship is left shifted in telokin knockout mice compared to wild type...
  60. Molecular Mechanism of Acrolein-Induced Vascular Toxicity: Role of PPAR gamma and
    Zivar Yousefipour; Fiscal Year: 2013
    ..Acrolein treated Sprague-Dawley rats, gp91phox and p47 phox knockout mice, and NOS knockout mice will be utilized to determine changes in blood pressure and vascular responses by ..
  61. Prostaglandin signaling following seizures
    Jianxiong Jiang; Fiscal Year: 2013
    ....
  62. Mechanism of eNOS Uncoupling in the Renal Microvasculature
    YVES CLAUDE GORIN; Fiscal Year: 2013
    ..of NO generation by eNOS in the kidney has been conclusively established by recent studies showing that eNOS knockout mice made diabetic develop advanced lesions and progressive DN...
  63. Role and Mechanisms of Prolactin on HPA Axis Activation Following Stress
    James Janik; Fiscal Year: 2009
    ..i) post- partum, female wild-type mice (physiologically hyperprolactinemic) or (ii) wild-type and PRL knockout mice treated with exogenous PRL to induce hyperprolactinemia for 1, 3 or 6 days to determine the time course and ..
  64. REGULATION OF CELLULAR RESPONSES TO NEUROPEPTIDES
    Nigel W Bunnett; Fiscal Year: 2010
    ..will be examined by expression of dominant negative mutants, and by studying neurons from p- arrestin knockout mice. The role of the cytoskeleton and of endosomal acidification and phosphatases will be examined using specific ..
  65. Role of G-gamma-7 in striatal cannabinoid and D2 dopamine
    Dana E Selley; Fiscal Year: 2010
    ..Our preliminary findings indicate that AC inhibition by striatal CB1 and D2 receptors is diminished in Gng7 knockout mice, suggesting a role for this G-gamma subunit in inhibitory Gi/o signaling...
  66. Anxiety development in 5-HT1A autoreceptor knockout mice, interaction with stress
    Rene Hen; Fiscal Year: 2010
    ....
  67. X-RAYS INDUCE EXOCYTOSIS OF ENDOTHELIAL P-SELECTIN
    Dennis Hallahan; Fiscal Year: 2002
    ..We will study the roles of calcium and calmodulin in the activation of motor proteins that are required for microtubule- dependent translocation of WPB to the cell membrane. ..
  68. PHYSICOCHEMICAL INVESTIGATION OF TASTE
    Vijay Lyall; Fiscal Year: 2010
    ..Preliminary data from NADPH oxidase knockout mice indicate that protons cross the apical membranes of taste cells through two hydrogen ion channels...
  69. Transgenic/Molecular Approaches for Ocular Albinism
    Debora Farber; Fiscal Year: 2006
    ..Three different Gi protein knockout mice will also be examined to define the Gi protein through which OA1 normally functions, and constitutively active ..
  70. GM-CSF is required for macrophage surfactant catabolism
    Tracey Bonfield; Fiscal Year: 2006
    ..abstract_text> ..
  71. MUCOSAL IMMUNOLOGY OF HELICOBACTER INDUCED GASTRITIS
    Steven Czinn; Fiscal Year: 2007
    ..we have demonstrated that IFNy is the dominant cytokine associated with protective immunity but that IFNy-knockout mice can still be protectively immunized...
  72. PAHs: Balance of Detoxication vs Metabolic Activation
    Daniel Nebert; Fiscal Year: 2009
    ..Using Cyp1a1(-/-) and Cyp1b1(-/-) knockout mice, we have shown that CYP1A1 is more important in detoxication than metabolic activation, whereas CYP1B1 causes ..