Mechanistic relationships between IDO, GCN2, and mTOR signals in immunity to apoptotic cells

Information

  • Research Project
  • 9477939
  • ApplicationId
    9477939
  • Core Project Number
    R01AR067763
  • Full Project Number
    5R01AR067763-05
  • Serial Number
    067763
  • FOA Number
    PA-13-302
  • Sub Project Id
  • Project Start Date
    4/1/2015 - 9 years ago
  • Project End Date
    3/31/2020 - 4 years ago
  • Program Officer Name
    MANCINI, MARIE
  • Budget Start Date
    4/1/2018 - 6 years ago
  • Budget End Date
    3/31/2019 - 5 years ago
  • Fiscal Year
    2018
  • Support Year
    05
  • Suffix
  • Award Notice Date
    4/20/2018 - 6 years ago

Mechanistic relationships between IDO, GCN2, and mTOR signals in immunity to apoptotic cells

? DESCRIPTION (provided by applicant): The spleen is required for the generation of systemic tolerance to apoptotic cells. We have recently shown a specialized set of macrophages residing in the marginal zone region of the red pulp drive immunologic tolerance to apoptotic material and in their absence apoptotic cells induce inflammation and autoimmune reactivity. While it is not known how this occurs on a mechanistic level, we have found apoptotic cells provoke expression of a tryptophan-catabolizing enzyme, indoleamine 2, 3 dioxygenase (IDO), which is critical for immune suppression in a variety of inflammatory settings. Further we discovered blockade of IDO greatly altered the way macrophages and dendritic cells respond to apoptotic cells with increased inflammatory immunity and autoimmune disease activity in lupus-prone animals. Thus the data suggest a novel mechanism whereby IDO activity in macrophages controls both innate and adaptive immunity to apoptotic cells. Our proposed project will examine how apoptotic cells driven IDO activity impacts mTOR signals in marginal zone macrophages, how IDO-driven tryptophan metabolism impacts apoptotic cell-mediated tolerance, and mechanisms by which IDO may influence Treg activation; finally testing these mechanisms in an experimental model of systemic lupus erythematosus. Thus, the findings of this project could have enormous implications in diseases of hypo and hyper-immunity where modulation of the tolerogenic rheostat would provide significant clinical benefit.

IC Name
NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
  • Activity
    R01
  • Administering IC
    AR
  • Application Type
    5
  • Direct Cost Amount
    220000
  • Indirect Cost Amount
    17600
  • Total Cost
    237600
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    846
  • Ed Inst. Type
  • Funding ICs
    NIAMS:237600\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    HAI
  • Study Section Name
    Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section
  • Organization Name
    UNIVERSITY HEALTH NETWORK
  • Organization Department
  • Organization DUNS
    208469486
  • Organization City
    TORONTO
  • Organization State
    ON
  • Organization Country
    CANADA
  • Organization Zip Code
    M5G 2M9
  • Organization District
    CANADA