Pulmonary Surfactant Antagonists of Rhinovirus Infection and Inflammation

Information

  • Research Project
  • 10246164
  • ApplicationId
    10246164
  • Core Project Number
    P01HL132821
  • Full Project Number
    5P01HL132821-05
  • Serial Number
    132821
  • FOA Number
    PAR-16-402
  • Sub Project Id
    6270
  • Project Start Date
    9/1/2017 - 6 years ago
  • Project End Date
    8/31/2022 - a year ago
  • Program Officer Name
    NOEL, PATRICIA
  • Budget Start Date
    9/1/2021 - 2 years ago
  • Budget End Date
    8/31/2022 - a year ago
  • Fiscal Year
    2021
  • Support Year
    05
  • Suffix
  • Award Notice Date
    8/25/2021 - 2 years ago
Organizations

Pulmonary Surfactant Antagonists of Rhinovirus Infection and Inflammation

Viral exacerbations of asthma are responsible for 1.8 million emergency room visits and 0.4 million hospitalizations in the US each year, constituting a major public health problem and economic burden. Human rhinoviruses (HRV) are the dominant instigators of asthma exacerbations in children and adults. Currently, there are not preventives or therapeutics for HRV infection. Our recent work has identified three constituents of human pulmonary surfactant, the phospholipids, palmitoyl-oleoyl-phosphatidylglycerol (POPG) and phosphatidylinositol (PI), and surfactant protein A (SP-A), as potent inhibitors of HRV infection and inflammatory sequelae. This proposal is focused upon defining how POPG, PI and SP-A inhibit viral infection in primary cultures of human nasal epithelial cells; and testing the efficacy of these agents for preventing exacerbations in mouse models of asthma. We will address these issues in three Specific Aims. In Aim 1 we will investigate the molecular mechanisms of human SP-A inhibition of 3 types of HRV infection with special emphasis upon the isoforms of the protein that are most effective against each virus. We will examine the anti-viral activities of the three major expressed isoforms of human SP-A encoded by the SP-A1 gene, and the three major expressed isoforms encoded by the SP-A2 gene. In Aim 2 we will investigate the mechanisms of POPG and PI inhibition of three types of HRV infection and inflammation. In Aim 3 we will critically test the activities of PI and novel structural anaolgs of the lipid as inhibitors of HRV infection in mice. PI and structural analogs will also be examined for their activity as suppressors of asthma exacerbations, using a house dust mite model for asthma coupled with HRV infection in mice. The studies in this project will be integrated with 3 other Research Projects, a Clinical Core and a Biostatistics/Environmental Exposure Core that are essential elements of the entire Research Proposal. The Clinical Core will provide patient nasal epithelial cells from exacerbation-prone asthmatics and multiple control groups. Project 1 will provide detailed information regarding the environmental exposures that drive asthma exacerbations and influence the phenotypes of the epithelial cells, and ultimately the clinical outcome of patients. We will interface with Project 2 by determining how SP-A, POPG, PI and lipid analog antagonism of HRV infection influences the transcriptomic profiles of the epithelial cells and if there are any associations with environmental exposures and clinical outcomes. Our interactions with Project 3 will focus upon how the interactions between SP-A and lipids influence the production and secretion of factors from nasal epithelial cells that influence the epigenetic landscape and phenotypes of CD4+ T cells. In total, Project 4 will provide new information about the anti-viral properties of pulmonary surfactant constituents and their utility for preventing HRV-dependent asthma exacerbations in the context of known environmental exposures and nasal epithelial phenotypes.

IC Name
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
  • Activity
    P01
  • Administering IC
    HL
  • Application Type
    5
  • Direct Cost Amount
    260814
  • Indirect Cost Amount
    126877
  • Total Cost
  • Sub Project Total Cost
    387691
  • ARRA Funded
    False
  • CFDA Code
  • Ed Inst. Type
  • Funding ICs
    NHLBI:387691\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    HLBP
  • Study Section Name
    Heart, Lung, and Blood Initial Review Group
  • 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