Novel Intervention for Colitis

Summary

Principal Investigator: MICHAEL VITEK
Abstract: [unreadable] DESCRIPTION (provided by applicant): Novel Intervention for Colitis The scope of the current proposal is to determine whether administration of an apoE mimetic peptide, COG112, improves clinical, histological and inflammatory outcomes in clinically relevant paradigms of colitis. Specifically, we will employ the acute Citrobacter rodentium (C. rodentium) model, an acute Dextran Sulfate Sodium (DSS) model and a chronic DSS model of colitis. We will also define whether there is a dose-dependent response to treatment with COG112 in these models of human disease. This course of experiments has the potential to represent a novel therapeutic strategy for a difficult gastrointestinal disease in which adequate treatment strategies do not currently exist. Specific Aim 1: Using a C. rodentium-infectious model of acute colitis, measure the response to treatment with different doses of COG112 using clinical outcome measures, histological outcome measures and measures of a panel of representative inflammatory mediators. Specific Aim 2: Using a DSS model of acute colitis, measure the response to treatment with different doses of COG112 using clinical outcome measures, histological outcome measures and measures of a panel of representative inflammatory mediators. Specific Aim 3: Using a DSS model of chronic colitis, measure the response to treatment with different doses of COG112 using clinical outcome measures, histological outcome measures and measures of a panel of representative inflammatory mediators. Novel Intervention for Colitis: Inflammatory Bowel Disease (IBD), more commonly known as Crohn's disease and ulcerative colitis, affects approximately 1 million Americans with inflammation of the intestines, abdominal pain, cramping and diarrhea. These symptoms vary in severity, but are often debilitating for patients to the extent that they greatly alter their quality of life. We have found that clinical and histological scores of IBD are less when the levels of small molecules known as polyamines are increased. To increase polyamine levels, one needs to increase the amount of arginine, an amino acid derived from our diets, that is converted to polyamines through the action of the arginase/ornithine decarboxylase pathway. We have found a novel drug, COG112, can stimulate this arginase activity. Thus, mouse models of colitis treated with COG112 should have less disease than their untreated counterparts. So we propose to directly measure whether COG112 will exacerbate or ameliorate colitis in mouse models. [unreadable] [unreadable] [unreadable]
Funding Period: 2007-02-05 - 2008-10-31
more information: NIH RePORT

Top Publications

  1. pmc The apolipoprotein E-mimetic peptide COG112 inhibits NF-kappaB signaling, proinflammatory cytokine expression, and disease activity in murine models of colitis
    Kshipra Singh
    Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
    J Biol Chem 286:3839-50. 2011
  2. ncbi Apolipoprotein E and peptide mimetics modulate inflammation by binding the SET protein and activating protein phosphatase 2A
    Dale J Christensen
    Cognosci, Inc, Research Triangle Park, NC 27709, USA
    J Immunol 186:2535-42. 2011
  3. ncbi Immunology of Helicobacter pylori: insights into the failure of the immune response and perspectives on vaccine studies
    Keith T Wilson
    Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0252, USA
    Gastroenterology 133:288-308. 2007
  4. pmc The apolipoprotein E-mimetic peptide COG112 inhibits the inflammatory response to Citrobacter rodentium in colonic epithelial cells by preventing NF-kappaB activation
    Kshipra Singh
    Department of Medicine, Division of Gastroenterology, Vandergilt University School of Medicine, Nashville, Tennessee 37232, USA
    J Biol Chem 283:16752-61. 2008
  5. pmc Matrix metalloproteinase-7 and premalignant host responses in Helicobacter pylori-infected mice
    Seth R Ogden
    Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232 2279, USA
    Cancer Res 70:30-5. 2010

Detail Information

Publications5

  1. pmc The apolipoprotein E-mimetic peptide COG112 inhibits NF-kappaB signaling, proinflammatory cytokine expression, and disease activity in murine models of colitis
    Kshipra Singh
    Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
    J Biol Chem 286:3839-50. 2011
    ..Isolated colonic epithelial cells exhibited marked attenuation of expression of iNOS and the CXC chemokines KC and MIP-2. These studies indicate that apoE-mimetic peptides such as COG112 are novel potential therapies for IBD...
  2. ncbi Apolipoprotein E and peptide mimetics modulate inflammation by binding the SET protein and activating protein phosphatase 2A
    Dale J Christensen
    Cognosci, Inc, Research Triangle Park, NC 27709, USA
    J Immunol 186:2535-42. 2011
    ....
  3. ncbi Immunology of Helicobacter pylori: insights into the failure of the immune response and perspectives on vaccine studies
    Keith T Wilson
    Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0252, USA
    Gastroenterology 133:288-308. 2007
    ..Understanding the mechanisms of immune evasion could lead to new opportunities for enhancing eradication and prevention of infection and associated disease...
  4. pmc The apolipoprotein E-mimetic peptide COG112 inhibits the inflammatory response to Citrobacter rodentium in colonic epithelial cells by preventing NF-kappaB activation
    Kshipra Singh
    Department of Medicine, Division of Gastroenterology, Vandergilt University School of Medicine, Nashville, Tennessee 37232, USA
    J Biol Chem 283:16752-61. 2008
    ..These studies indicate that apoE-mimetic peptides may have novel therapeutic potential by inhibiting NF-kappaB-driven proinflammatory epithelial responses to pathogenic colonic bacteria...
  5. pmc Matrix metalloproteinase-7 and premalignant host responses in Helicobacter pylori-infected mice
    Seth R Ogden
    Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232 2279, USA
    Cancer Res 70:30-5. 2010
    ..Collectively, these studies indicate that H. pylori-mediated induction of MMP-7 may serve to protect the gastric mucosa from pathophysiologic processes that promote carcinogenesis...