Regulation of ChemR23 in Resolution of Inflammation

Summary

Principal Investigator: MARCELO DE OLIVEIRA FREIRE
Abstract: DESCRIPTION (provided by applicant): Loss of inflammation regulation is a biological event common to many human chronic inflammatory diseases including Type II diabetes mellitus, and periodontitis. A return to homeostasis (resolution of inflammation) requires cellular activation of a well-coordinated process mediated by endogenous lipids, including, resolvin E1 (RvE1), derived from the [unreadable]-3 fatty acid, eicosapentaenoic acid (EPA). Activation of the G protein-coupled receptor, ChemR23, by the agonist ligand RvE1 is known to lead to attenuation of NF-KB mediated pro-inflammatory cytokines, dictating cellular fate and consequently resolution of inflammation. However, how ChemR23 in innate cells fails to activate resolution in chronic inflammatory diseases remains unclear. This proposal will test the hypothesis that ChemR23 expression and function are altered in chronic inflammatory diseases and that engineered agonist biomimetic antibodies to chemR23 can impact the inflammatory phenotype. To that end, four distinct but complementary specific aims are proposed. The mentored phase of the proposal will be carried out under Prof. Van Dyke at The Forsyth Institute. The goal of the K99 mentored phase is to: 1) characterize the expression of ChemR23 receptors on inflammatory cells (neutrophils and monocyte/macrophages) of subjects with Type II diabetes and/or periodontitis;2) characterize the molecular pathways that are regulated by ChemR23 in disease. This training will provide expertise in inflammation biology, clinical pathology and proteomics. The understanding of ChemR23 in dictating the path chronic inflammation diseases investigated during the mentored phase will provide the foundation for transition to independent phase. Inflammation resolution is a rapidly emerging field of interest that would greatly benefit from unexplored biomimetic approaches to therapeutically regulate cell fate. Building on previous experience, the goal of R00 independent phase is to: 3) engineer agonist monoclonal antibody for ChemR23, and 4) to characterize the cellular and molecular mechanisms by which therapeutic antibodies regulate inflammation through ChemR23 activation. This award includes a well-structured training program that provides course work and seminar learning experiences as well as ensuring protected research time during concurrent specialty training in Periodontology at Harvard School of Dental Medicine. Successful completion of this project will lead to better understanding of the molecular and cellular role of ChemR23, and to translate this knowledge for the development of agonist biomimetics to modulate inflammatory diseases clinically.
Funding Period: 2013-07-01 - 2015-06-30
more information: NIH RePORT

Research Grants

  1. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
  2. Identification and Analysis of the Physiological Ligand for TLT2
    Louis B Justement; Fiscal Year: 2013
  3. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
  4. Primary Immune Deficiency Treatment Consortium
    Morton Cowan; Fiscal Year: 2013
  5. B Cells in Health and Disease
    IGNACIO E SANZ; Fiscal Year: 2013
  6. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
  7. MUSC Center for Oral Health Research
    Keith L Kirkwood; Fiscal Year: 2013
  8. Roles of Sphingolipids in the Pathophysiology of Obesity and Diabetes
    LAUREN ASHLEY COWART; Fiscal Year: 2013
  9. Specialized Program of Research Excellence
    Jennifer Rubin Grandis; Fiscal Year: 2013
  10. Bastyr/UW Oncomycology Translational Research Center
    Leanna J Standish; Fiscal Year: 2013

Detail Information

Research Grants30

  1. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  2. Identification and Analysis of the Physiological Ligand for TLT2
    Louis B Justement; Fiscal Year: 2013
    ..e. the TLT2 ligand) for the development of therapeutic interventions to modulate the acute inflammatory response. ..
  3. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  4. Primary Immune Deficiency Treatment Consortium
    Morton Cowan; Fiscal Year: 2013
    ..These studies will resolve critical questions concerning HCT for these disorders and form the basis for future prospective clinical trials. ..
  5. B Cells in Health and Disease
    IGNACIO E SANZ; Fiscal Year: 2013
    ..Finally, and central to this PPG, our results will greatly enhance our ability to design better and safer BCDT therapies and to develop biomarkers of B cell targeted treatments efficacy and safety. ..
  6. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
    ..This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship. ..
  7. MUSC Center for Oral Health Research
    Keith L Kirkwood; Fiscal Year: 2013
    ..abstract_text> ..
  8. Roles of Sphingolipids in the Pathophysiology of Obesity and Diabetes
    LAUREN ASHLEY COWART; Fiscal Year: 2013
    ....
  9. Specialized Program of Research Excellence
    Jennifer Rubin Grandis; Fiscal Year: 2013
    ..abstract_text> ..
  10. Bastyr/UW Oncomycology Translational Research Center
    Leanna J Standish; Fiscal Year: 2013
    ..We will investigate the effect of oral doses of PSK, a T. versicolor extract prescribed in Japan as a cancer drug, in augmenting the anticancer immune response in advanced breast cancer. ..
  11. Center of Research on Obesity and Cardiovascular Diseases
    Lisa A Cassis; Fiscal Year: 2013
    ....
  12. Role of Eicosanoids in Renal Function
    NANCY JOAN BROWN; Fiscal Year: 2013
    ..These are needed for the development of meaningful approaches for: a) the unequivocal definition of human pathophysiological significance, and b) future pharmacological targeting, and clinical diagnosis and intervention. ..
  13. BIOLOGY OF NEUROENDOCRINE PEPTIDES
    Marc R Montminy; Fiscal Year: 2013
    ..Specifying the contributions of the CRF family of ligands and receptors to the maintenance of homeostasis and to stress-linked allostasis may improve our ability to manage diseases, including mood and metabolic disorders ..
  14. Southeast Regional Centers of Excellence for Biodefense &Emerging Infectious Di
    Philip Frederick Sparling; Fiscal Year: 2013
    ..SERCEB brings new investigators to the biodefense effort through a combination of educational programs, support of innovative new projects, and the synergistic interactions among its world-class investigators. ..
  15. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  16. MOLECULAR GENETICS OF COAGULATION DISORDERS
    David Ginsburg; Fiscal Year: 2013
    ..This Project will identify key genes in this system that should provide valuable new diagnostic tools as well as suggest novel approaches to treatment. ..
  17. Structural bases of the functions of RNA-protein machines
    THOMAS ARTHUR STEITZ; Fiscal Year: 2013
    ..Also of interest will be the ways in which the structures and properties of RNA molecules can be utilized to carry out various biological functions often analogous to those performed by proteins. ..
  18. Normal &Neoplastic Growth in the Brain
    Suzanne J Baker; Fiscal Year: 2013
    ..Integrated analyses within the group will identify common and unique signal transduction pathways in pediatric brain tumorigenesis. ..
  19. Oral Mucosal Immunity in Vulnerable HIV Infected Populations
    Aaron Weinberg; Fiscal Year: 2013
    ..All the data will be subjected to rigorous scientific scrutiny through meetings between the PIs and an External Advisory Panel that will be organized through the Administrative Core (Core A). ..
  20. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  21. Mechanisms of Microvascular Control and Coordination in Health and Disease
    Gerald A Meininger; Fiscal Year: 2013
    ..End of Abstract) ..
  22. DEVELOPMENT OF NOVEL THERAPIES FOR NIDDM
    Christopher B Newgard; Fiscal Year: 2013
    ..abstract_text> ..
  23. Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers
    Augustine M Choi; Fiscal Year: 2013
    ..4) Clinical Outcomes and Molecular Phenotypes in Smokers with Parenchymal Lung Disease Cores: 1) Administrative Core 2) Respiratory Computational Discovery Core 3) Clinical Biorepository Core 4) Murine Models and Molecular Analysis Core ..
  24. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..