# Intracellular Collagen Sensing in Pulmonary Fibrosis

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $595,286

## Abstract

PROJECT SUMMARY
Despite decades of research, the pathogenesis of Idiopathic Pulmonary Fibrosis (IPF) is still not completely
understood. As a consequence, IPF causes significant morbidity and mortality and there are no therapies that
reverse existing fibrosis. IPF is characterized by accumulation of collagen and fibrotic extracellular matrix in the
lung that replace normal tissue and interfere with gas exchange, leading to dyspnea, respiratory failure, and
death. A key knowledge gap preventing our development of effective therapeutics is the understanding of how
collagen is degraded and turned over. If we were able to promote enhanced turnover and clearance of collagen
in fibrotic IPF, this could provide a viable strategy to reverse fibrosis in IPF. This grant proposes to address this
knowledge gap by delineating pathways of collagen clearance that we discovered by a recent unbiased CRISPR
screening approach. We have found a previously unappreciated mechanism of regulation of collagen clearance:
that collagen synthesis is sensed by cells internally and directly regulates clearance of collagen (i.e. cellular
uptake and degradation of extracellular collagen). The sensing mechanism is dependent on ER resident protein
SEL1L. This mechanism appears to be a homeostatic negative feedback loop to limit accumulation of collagen
in tissues. Importantly, we have also found that the induction of collagen turnover by collagen synthesis is
impaired in IPF, contributing to the excess and unmitigated buildup of collagen in lung tissue. The research
proposed in this grant will fully define the upstream and downstream mechanisms governing this pathway as
well as the cause of the impairment in this pathway in IPF. We will use mouse models, human lung organoids,
human IPF tissue and cells, and in vitro and in vivo functional experiments. If successful, the proposed research
has the potential to open the door to entirely new therapeutic avenues to try to reverse fibrosis in IPF and
ameliorate symptoms in patients.

## Key facts

- **NIH application ID:** 10980079
- **Project number:** 1R01HL169611-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Michael Podolsky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $595,286
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980079

## Citation

> US National Institutes of Health, RePORTER application 10980079, Intracellular Collagen Sensing in Pulmonary Fibrosis (1R01HL169611-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10980079. Licensed CC0.

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