# Molecular Determinants of Usual Interstitial Pneumonia (UIP)

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2022 · $725,907

## Abstract

ABSTRACT: The overall goal of this proposal is to understand how the gain-of-function MUC5B promoter
variant affects transcriptional regulation and gene expression that are common to clinically distinct types of usual
interstitial pneumonia (UIP). UIP was initially described as a morphologic entity, however, recently has been
defined using specific pathologic and radiographic criteria. While UIP is characteristic of idiopathic pulmonary
fibrosis (IPF), these pathologic and radiographic patterns of chronic fibrosing interstitial pneumonia are also
typical of chronic hypersensitivity pneumonitis (CHP), rheumatoid arthritis-associated interstitial lung disease
(RA-ILD), asbestosis, and several drug-induced lung diseases. The gain-of-function promoter variant in MUC5B
(rs35705950) is the dominant risk factor for IPF, is present in >50% of affected patients, and has also been
reported to be the dominant genetic risk variant for the development of CHP and RA-ILD. However, while IPF is
by definition idiopathic, CHP develops following repeated exposure to organic antigens, and RA-ILD is a
complication of rheumatoid arthritis. We proposed by understanding the relationship between the MUC5B
promoter variant, transcriptional regulation, and gene expression in IPF, CHP, and RA-ILD, we will be able to
identify the common molecular elements that are critical to the development of UIP. The two critical questions
that we plan to address are: 1) what are the common molecular features of UIP, irrespective of clinical context,
and 2) does MUC5B promoter variant have a unique molecular signature common to UIP? The hypothesis we
plan to test is that the gain-of-function MUC5B promoter variant drives cell-specific chromatin
accessibility and gene expression that define UIP. In Aim 1, we will use single nucleus RNA sequencing
(snRNA-seq) to identify the cell-specific transcriptional profiles for IPF, CHP, and RA-ILD, and determine the
relationship of the common cell-specific transcriptional profiles of UIP to the MUC5B promoter variant. In Aim 2,
we will use a combinatorial indexing single nucleus assay for transposase-accessible chromatin (snATAC-seq)
to identify the cell-specific chromatin accessibility profiles for IPF, CHP, and RA-ILD, and determine the
relationship of the common cell-specific chromatin accessibility profiles of UIP to the MUC5B promoter variant.
In Aim 3, we will perform integrative analyses of the MUC5B promoter genotype, snRNA-seq, and snATAC-seq
data using single-cell expression QTL, multi-omic and network inference methods to identify UIP-specific gene
regulatory networks with key drivers of UIP in specific cell types. In Aim 4, we will validate the transcriptional
features that are common to MUC5B-associated UIP by determining the relationship of these key genes to the
pathogenic heterogeneity of UIP and relevant in vitro biology. In aggregate, we will characterize regulatory
effects of MUC5B on cell-specific transcriptional profiles and netw...

## Key facts

- **NIH application ID:** 10440715
- **Project number:** 1R01HL158668-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** David Albert Schwartz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $725,907
- **Award type:** 1
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440715

## Citation

> US National Institutes of Health, RePORTER application 10440715, Molecular Determinants of Usual Interstitial Pneumonia (UIP) (1R01HL158668-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10440715. Licensed CC0.

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