# Type I collagen signaling in lung injury and fibrosis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $374,565

## Abstract

Title: Type I collagen signaling in lung injury and fibrosis
Abstract/Project Summary
 Progressive fibrosis is a complication of many chronic diseases and collectively, organ fibrosis is the
leading cause of death in the US. Although many therapeutic strategies have dramatically attenuated fibrosis in
animal models translating these findings into successful therapies for IPF has proven disappointing with
several negative clinical trials and two new therapies only modestly slowing the progression of disease. Some
have suggested the need for multi-modality therapies targeting different parts of the pro-fibrotic pathway.
 The current paradigm is that injury initiates a dynamic repair process that ultimately leads to fibrillar
collagen deposition and scar formation. Progressive fibrosis is characterized by activation of self-amplifying
feed-forward/positive feedback signaling pathways leading to excessive scarring. However, the ubiquity of the
scar formation process after diverse injuries in nearly every tissue suggests that scarring may also be
protective in limiting ongoing cellular and tissue damage and may be necessary to resolve the initial injury.
Attempt at limiting collagen deposition may lead to persistence of the initial inciting stimuli. A more complete
understanding into the linked mechanisms involved in the balance between progressive fibrosis and resolution
of focal injurious stimuli is necessary.
 While matrix signaling during fibrosis has been studied, collagen I itself is often regarded as an end
product of fibrosis but we have found that collagen I is also a critical mediator of progressive fibrosis. We have
found that alveolar epithelial cell (AEC) apoptosis is a necessary and sufficient initiator of fibrosis and that a
rigid collagen I matrix blunts the AEC apoptotic response to TGFβ. In vivo, we found that collagen I expression
is induced early after injury and collagen I-deficient mice have sustained lung injury and greater death.
Collagen I signaling also enhances fibroblast recruitment and activation. Collagen can initiate signaling through
specific integrins as well as a family of receptor tyrosine kinsases, the discoidin domain receptors (DDR). Our
preliminary data support important and non-redundant roles for both α2β1 integrin and DDR2 in regulation of
this injury/fibrosis cycle. Thus, type I collagen is likely important in determining whether the response to injury
is limited scar formation versus progressive fibrosis and potentially establishes a dilemma in which failure of
fibrosis in the context of continued TGFβ-induced AEC apoptosis could lead to greater foci of injury and
suboptimal inhibition of profibrotic pathways. Our central hypothesis is type I collagen signaling promotes both
propagation of fibrosis and inhibition of AEC apoptosis but these processes are regulated by distinct pathways.
We will pursue studies aimed at understanding the mechanism of collagen I and its receptors in regulation of
AEC apoptosis an...

## Key facts

- **NIH application ID:** 9898421
- **Project number:** 5R01HL108904-09
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** KEVIN KEEWOUN KIM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $374,565
- **Award type:** 5
- **Project period:** 2012-05-15 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898421

## Citation

> US National Institutes of Health, RePORTER application 9898421, Type I collagen signaling in lung injury and fibrosis (5R01HL108904-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898421. Licensed CC0.

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