Macrophage Metabolism After Target Cell Ingestion Regulates Anti-Inflammatory Reprogramming

Information

  • Research Project
  • 10239261
  • ApplicationId
    10239261
  • Core Project Number
    R00HL141658
  • Full Project Number
    5R00HL141658-04
  • Serial Number
    141658
  • FOA Number
    PA-16-193
  • Sub Project Id
  • Project Start Date
    8/15/2020 - 3 years ago
  • Project End Date
    7/31/2023 - 10 months ago
  • Program Officer Name
    KALANTARI, ROYA
  • Budget Start Date
    8/1/2021 - 2 years ago
  • Budget End Date
    7/31/2022 - a year ago
  • Fiscal Year
    2021
  • Support Year
    04
  • Suffix
  • Award Notice Date
    8/2/2021 - 2 years ago
Organizations

Macrophage Metabolism After Target Cell Ingestion Regulates Anti-Inflammatory Reprogramming

ABSTRACT Inflammation is a ubiquitous component of lung disease involving accumulation of leukocytes in the airspaces. In order for inflammation to resolve, dead and dying leukocytes must be removed and production of inflammatory cytokines must be turned off. Macrophages (M?) are key orchestrators of these processes, however the triggers that reprogram inflammatory M? to perform these roles remain incompletely understood. Clearance of dead cells has been shown to provide an important reprogramming signal, but we have limited knowledge of the precise mechanisms by which dead cell ingestion facilitates redirection of M? function. Recent work has demonstrated a key role for cellular metabolism in determining M? function. Ingested target cells provide a clear source of varied macromolecules that must be digested by M?. However, little research has been done to assess intracellular metabolites produced by this process or to consider the subsequent immune consequence. We propose the first comprehensive study of M? metabolism following target cell ingestion and degradation, and hypothesize that changes in the levels of intracellular metabolites control ingestion-driven M? reprogramming. Our preliminary studies have identified a promising molecular target, polyamines, which are dramatically increased in M? following the ingestion of apoptotic target cells. Polyamines have a known anti- inflammatory function including suppression of numerous pro-inflammatory cytokines. We propose to test the hypothesis that upregulation of polyamine synthesis by M? following target cell ingestion is critical to suppress a key M? cytokine IL-1?, and important for the resolution of lung inflammation in vivo. During the K99 mentored phase, I will build upon my experience studying M? biology and target cell clearance by learning techniques related to cellular metabolism including unbiased metabolomics and the use of isotope metabolites to measure metabolic flux. During this phase, I will: 1) complete a comprehensive, integrated assessment of the metabolites produced following ingestion of target cells, focusing on polyamines, and assess whether these metabolites derive from digested target cell material, and 2) specifically assess the role of arginase-1 in regulating polyamine synthesis by inflammatory M?. Simultaneously, I will enrich my professional development by participating in journal clubs, seminars, national conferences, coursework, and having semi-annual evaluations by a trainee advisory committee. The R00 independent phase will allow me to establish my laboratory as I continue investigation into: 3) how M? polyamines affect cytokine production after target cell ingestion, and 4) the effects of M? polyamines on resolution of inflammation and lung repair. Collectively, this proposal will enhance my current expertise, address a critical unknown in the field of target cell clearance, and provide the necessary foundation to establish myself as an independent research scientist.

IC Name
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
  • Activity
    R00
  • Administering IC
    HL
  • Application Type
    5
  • Direct Cost Amount
    151829
  • Indirect Cost Amount
    97171
  • Total Cost
    249000
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    838
  • Ed Inst. Type
  • Funding ICs
    NHLBI:249000\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    NSS
  • 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