Combining genome, function, and phenotype to define the cell type specific gene regulatory architecture of idiopathic pulmonary fibrosis

Information

  • Research Project
  • 10071087
  • ApplicationId
    10071087
  • Core Project Number
    R01HL145372
  • Full Project Number
    5R01HL145372-03
  • Serial Number
    145372
  • FOA Number
    PA-18-484
  • Sub Project Id
  • Project Start Date
    1/1/2019 - 5 years ago
  • Project End Date
    12/31/2023 - 5 months ago
  • Program Officer Name
    VUGA, LOUIS J
  • Budget Start Date
    1/1/2021 - 3 years ago
  • Budget End Date
    12/31/2021 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    03
  • Suffix
  • Award Notice Date
    12/31/2020 - 3 years ago

Combining genome, function, and phenotype to define the cell type specific gene regulatory architecture of idiopathic pulmonary fibrosis

Project Summary Idiopathic pulmonary fibrosis (IPF) is the most common and severe form of interstitial lung disease. IPF occurs in middle-aged and older adults and affects over 50,000 Americans each year. Most IPF patients die from respiratory failure within five years of diagnosis. The current therapies target downstream disease mechanisms, and while they modestly slow the decline in lung function, they have not been shown to improve survival or quality of life for IPF patients. There is considerable heterogeneity of clinical outcomes among IPF patients, and we believe this heterogeneity is due to distinct mechanisms and programs involved in disease initiation that culminate in a common a pathology of end-stage lung fibrosis. As such, the development of transformative treatments hinges on our ability to better understand and target ?upstream? disease mechanisms. However, progress to this end has been held back by the limited study of the cell types and molecular changes initiating IPF pathogenesis. Novel technologies have recently been developed that enable quantification of mRNA levels in individual cells to be performed in a parallel, high throughput manner (scRNA- seq). Our proposed studies will leverage these technologies and the heterogeneity of the disease within the IPF lung to determine the mechanisms and mediators that underlie the early pathogenesis of IPF. We will use scRNA-seq to determine the gene expression profiles and programs in non-fibrotic control lungs (n=50), and paired, differentially affected regions of IPF lungs (n=100, paired distal, more fibrotic, vs. proximal, less fibrotic samples). We will use computational methods to group cells into putative cell types based on transcriptional similarity and canonical marker gene expression. We will then quantify the relative abundance of each cell type in these different disease states, and use innovative bioinformatic approaches to determine the gene expression programs that drive different phases of disease pathogenesis. Then, to determine the role of genetic variation in regulating these disease pathways, we will utilize the inter-individual genetic variation present in our sample to identify single nucleotide polymorphisms that are associated with gene expression changes (eQTLs) in each independent cell type. Next, to begin to interrogate the mechanisms underlying disease heterogeneity, we will determine cell-type specific gene expression changes that are associated with genetic predictors of disease outcome (MUC5B genotype, peripheral blood telomere length). Finally, we will define novel disease endotypes based on cell type specific gene expression patterns. The localization and spatial patterns of identified genes will be determined using matched FFPE samples, and key findings will be validated in primary cell/organoid culture systems. This work will generate the most comprehensive molecular characterization of healthy and IPF lungs, and promises to answer fundamental questions about cell types, genetic variants, and gene expression changes driving the idiopathic pulmonary fibrosis pathogenesis.

IC Name
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
  • Activity
    R01
  • Administering IC
    HL
  • Application Type
    5
  • Direct Cost Amount
    437133
  • Indirect Cost Amount
    194001
  • Total Cost
    631134
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    838
  • Ed Inst. Type
  • Funding ICs
    NHLBI:631134\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    GHD
  • Study Section Name
    Genetics of Health and Disease Study Section
  • Organization Name
    TRANSLATIONAL GENOMICS RESEARCH INST
  • Organization Department
  • Organization DUNS
    118069611
  • Organization City
    PHOENIX
  • Organization State
    AZ
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    850042274
  • Organization District
    UNITED STATES