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

> **NIH NIH R01** · TRANSLATIONAL GENOMICS RESEARCH INST · 2021 · $701,261

## Abstract

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 quest...

## Key facts

- **NIH application ID:** 10071087
- **Project number:** 5R01HL145372-03
- **Recipient organization:** TRANSLATIONAL GENOMICS RESEARCH INST
- **Principal Investigator:** Nicholas Eli Banovich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $701,261
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071087

## Citation

> US National Institutes of Health, RePORTER application 10071087, Combining genome, function, and phenotype to define the cell type specific gene regulatory architecture of idiopathic pulmonary fibrosis (5R01HL145372-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10071087. Licensed CC0.

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