Maternal programming of the stem cell-basophil axis for asthma

Information

  • Research Project
  • 10219912
  • ApplicationId
    10219912
  • Core Project Number
    R01AI143837
  • Full Project Number
    5R01AI143837-02
  • Serial Number
    143837
  • FOA Number
    PA-19-056
  • Sub Project Id
  • Project Start Date
    7/20/2020 - 3 years ago
  • Project End Date
    6/30/2024 - 13 days from now
  • Program Officer Name
    DONG, GANG
  • Budget Start Date
    7/1/2021 - 2 years ago
  • Budget End Date
    6/30/2022 - a year ago
  • Fiscal Year
    2021
  • Support Year
    02
  • Suffix
  • Award Notice Date
    6/30/2021 - 2 years ago
Organizations

Maternal programming of the stem cell-basophil axis for asthma

Project Summary/Abstract A growing number of epidemiological studies link childhood asthma with maternal environmental exposures with the strongest evidence provided for diesel exhaust and cigarette smoke. How maternal exposures lead to asthma in offspring is unknown. To address this, we developed a mouse model of asthma susceptibility in pups by exposing their mothers to diesel exhaust particles (DEP). Our data suggests that in this DEP-driven model, asthma-predisposing information is transmitted in part by a subset of offspring long-term hematopoietic stem cells (LT-HSCs), in the form of a stem cell memory. This subset distinguishes itself by expression of the IL3 receptor and is programmed for enhanced generation of basophils by the synergistic action of DEP-induced IL1b and IL3. One key mechanism of the synergism between IL1b and IL3 is the ability of IL1b to increase stem cell sensitivity to IL3 which is in part due to IL1b-mediated upregulation of IL3R b chain. In addition to expanding the basophil lineage, IL3 and IL1b are likely to enhance its capacity to promote asthma. Previous studies show that IL1b potentiates basophil histamine release and IL3 potently stimulates their IL4 production, sowing the seed for type-2 immune response. Consistent with this, in DEP offspring, basophils overexpress IL4. The IL3/IL1b-primed, expanded, IL4-overexpressing basophil population becomes a key driver of the type- 2 immune response and asthma upon allergen challenge. Basophil depletion in DEP pups prevents generation of allergen-specific IgE and development of asthma. This is in contrast with data obtained in plain allergen- based models in which basophils are redundant for production of IgE and asthma. Our overarching hypothesis is that maternal exposure to DEP induces asthma susceptibility in offspring through IL1b and IL3 driven programming of the hematopoietic stem cell-basophil axis. In Aim 1, by performing stem cell transplantation experiments, we will establish links between DEP IL3R+ LT-HSCs, increased basopoiesis and predisposition to asthma. We will define molecular basis of DEP IL3R+ LT-HSC programming by analyzing their transcriptomes (RNA-seq) and chromatin remodeling at gene regulatory sites (ATAC-seq). In Aim 2 we will study importance of IL1b and IL3 in programming of the HSC-basophil axis for asthma induction. In our model, IL1b and IL3 are increased in offspring and maternal tissues, including maternal serum. We propose that maternal IL1b and IL3 are important at early stages of embryonic hematopoiesis, when HSCs undergo their initial divisions and embryonic sources of IL1b and IL3 are scarce. Offspring-derived IL1b and IL3 complete the HSC programming process, sustain basopoiesis at a high level, and contribute to basophil activation after maternal cytokines fade away. To define how maternal IL1b and IL3 are transferred to embryos, study their roles and roles of offspring- encoded IL1b and IL3, we will perform serum transfers, injections with radiolabeled cytokines, and combine IL1b or IL3 KO strategies with embryo transfers. In Aim 3 we will use human blood samples to study IL1b and IL3 guided basophil development in childhood asthma.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R01
  • Administering IC
    AI
  • Application Type
    5
  • Direct Cost Amount
    396552
  • Indirect Cost Amount
    235254
  • Total Cost
    631806
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
  • Funding ICs
    NIAID:631806\
  • 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