# Dynactin 4 regulation of lung injury

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $466,844

## Abstract

Project Summary/Abstract
Acute respiratory distress syndrome (ARDS) continues to result in significant mortality (45% in severe ARDS).
To date, there are no direct therapies for ARDS, and clinical management is based on limiting lung damage with
protective ventilator strategies. We identified a single nucleotide variant (SNV) in the dynactin subunit 4 gene
(DCTN4; p62) that is significantly associated with ARDS secondary to sepsis. Heterozygosity of rs35772018
(henceforth called DCTN4-018) not only increased the risk of developing ARDS but has also been associated
with early and chronic P. aeruginosa infection and colonization with mucoid P. aeruginosa in individuals with
cystic fibrosis.
DCTN4 is an essential component of the multiprotein dynactin complex that binds cargo to cytoplasmic dynein,
which is a motor that moves along microtubules. We evaluated how DCTN4-018 is detrimental in lung injury and
P. aeruginosa infections and found that DCTN4-018 impaired β1-integrin recycling, focal adhesion turnover, and
cell migration. These data suggest DCTN4-018 impacts the regenerative potential of the lung epithelium after
injury. Moreover, lung epithelial expression of DCTN4-018 caused higher mortality and bacterial counts in a P.
aeruginosa pneumonia model. Leukocyte recruitment was identical between conditions indicating DCTN4-018
alters mucosal antimicrobial immunity. Accordingly, our central hypothesis is that dynactin is a critical regulator
of lung mucosal immunity and that DCTN4-018 alters membrane trafficking of integrins and other secreted
immunomodulatory factors to impair re-epithelialization and bacterial clearance after infection.
This proposal brings together a collaborative team of investigators each with unique strengths that will synergize
the research. Peter Chen, MD (contact PI) and William Parks, PhD (co-investigator) have research programs in
lung injury and repair with a particular focus on mucosal immunity. Trina Schroer, PhD (PI) discovered dynactin
and has been investigating its cellular function for more than 20 years. She is a well-established cell biologist,
and this proposal co-opts her unique knowledge and skill sets into pulmonary research. We have identified a
novel phenotype in the role of DCTN4-018 in regulating lung injury and repair, and our studies will provide an in-
depth evaluation of the molecular, cellular, and immunologic effects of this single nucleotide variant of dynactin
in augmenting lung injury after P. aeruginosa infection. These studies will provide a broader understanding of
how the dynactin complex controls the mucosal inflammatory response and identify therapeutic opportunities to
facilitate the resolution of the unrelenting lung inflammation in ARDS.

## Key facts

- **NIH application ID:** 9837486
- **Project number:** 5R01HL137076-03
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** PETER CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $466,844
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9837486

## Citation

> US National Institutes of Health, RePORTER application 9837486, Dynactin 4 regulation of lung injury (5R01HL137076-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9837486. Licensed CC0.

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