Neutrophil Nox2 controls mononuclear cell functions in inflammation; role in CGD

Information

  • Research Project
  • 10228694
  • ApplicationId
    10228694
  • Core Project Number
    R01AI141389
  • Full Project Number
    5R01AI141389-04
  • Serial Number
    141389
  • FOA Number
    PAR-15-130
  • Sub Project Id
  • Project Start Date
    9/18/2018 - 5 years ago
  • Project End Date
    8/31/2023 - 9 months ago
  • Program Officer Name
    VOULGAROPOULOU, FROSSO
  • Budget Start Date
    9/1/2021 - 2 years ago
  • Budget End Date
    8/31/2022 - a year ago
  • Fiscal Year
    2021
  • Support Year
    04
  • Suffix
  • Award Notice Date
    7/23/2021 - 2 years ago
Organizations

Neutrophil Nox2 controls mononuclear cell functions in inflammation; role in CGD

Project Summary / Abstract Chronic granulomatous disease (CGD) is a rare, but devastating, disease with known genetic abnormalities in the phagocyte (white blood cell) oxidase. In addition to immunodeficiency (the inability to fight certain bacteria and fungi), patients with this disease often have complex and poorly understood abnormalities in inflammatory processes manifest as colitis, poor wound healing, obstructing granuloma, and autoimmunity. Importantly, there is a lack of clearly applicable and effective treatments for many of these inflammatory consequences. Our studies in an animal model of human X-linked CGD clearly point to abnormal crosstalk during inflammatory processes between two different types of phagocytes, both with the mutated oxidase: neutrophils (or granulocytes) and mononuclear phagocytes. Specifically, we have shown that whereas CGD neutrophils were unable control the recruitment, maturation, inflammatory programming and disposal of the mononuclear phagocytes at sites of inflammation, the direct introduction of normal neutrophils was able to restore these activities and events in vivo. As such, signals from normal neutrophils orchestrate the activities of the mononuclear phagocytes at each step in the normal development and resolution of inflammation. It is hypothesized that identifying these signals provided by normal neutrophils could provide new therapeutic strategies. Using the murine model and adoptive transfers of neutrophils and their products as well as cell co- culture experiments (ex vivo), this proposal aims to define the mechanisms underlying the abnormal mononuclear phagocyte behavior in CGD and the precise processes lacking in CGD neutrophils that are overcome by the addition of normal neutrophils. Defining these is expected to lead to novel approaches to treatment of CGD and possibly other chronic inflammatory conditions. .

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R01
  • Administering IC
    AI
  • Application Type
    5
  • Direct Cost Amount
    381994
  • Indirect Cost Amount
    244476
  • Total Cost
    626470
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
  • Funding ICs
    NIAID:626470\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    NATIONAL JEWISH HEALTH
  • Organization Department
  • Organization DUNS
    076443019
  • Organization City
    DENVER
  • Organization State
    CO
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    802062761
  • Organization District
    UNITED STATES