# Role of Chaperone GRP78 and Mitochondrial Dysfunction in ER Stress-Mediated Pulmonary Fibrosis

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2023 · $558,938

## Abstract

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is an age-associated disease characterized by progressive
accumulation of scar tissue in the lungs. High morbidity rates in patients with IPF mandate more effective
treatments. A new paradigm implicates accumulation of alveolar epithelial cells (AECs) that are compromised
by loss of endoplasmic reticulum (ER) chaperone glucose-regulated protein 78 (GRP78), a master regulator of
proteostasis, in the pathogenesis of lung fibrosis. However, the molecular mechanisms and metabolic
landscapes characteristic of age-related PF have not been identified. Our goal in this project is to use alveolar
epithelial type II (AT2) cell-specific Grp78-KO mice, modeling the age-specific GRP78 reductions seen in AECs,
to establish how GRP78-loss impairs mitochondrial bioenergetics and biosynthesis, leading to development of
an aging phenotype in AT2 cells and subsequent lung fibrosis. Perturbed proteostasis and activation of ER
stress response signaling known as the unfolded protein response (UPRER) have been suggested as one
possible mechanism underlying observed AEC abnormalities. We found that GRP78 is downregulated
accompanied by activation of ER stress/UPRER in AT2 cells from IPF patients and aged mice/human
individuals. We further show that GRP78 undergoes reactive oxygen species (ROS)-induced carbonylation
(the most common form of oxidative stress-induced damage to proteins) in AT2 cells from IPF patients and
aged mice. In our model, AT2 cell-specific Grp78-KO mice develop aging-associated phenotypes including
disrupted proteostasis, mitochondrial dysfunction, abnormal mTOR signaling and metabolism, apoptosis and
senescence in AT2 cells with subsequent lung fibrosis. In this study, we highlight an emerging theme that
GRP78 loss-disrupted proteostasis leads to gradual decline of mitochondrial function and metabolic fitness,
which in turn is tightly linked with phenotypic changes of AECs (apoptosis and senescence) with the endpoint
of lung fibrosis. The use of Grp78-KO mice to model GRP78 loss in AECs allows us to rigorously examine how
impaired proteostasis promotes development of an aging phenotype in AT2 cells. Guided by our published and
unpublished results, we hypothesize that age-related AEC-specific downregulation of GRP78 induces
unresolved ER stress/UPRER, which in turn dysregulates metabolism and overactivates mTOR leading
to AEC dysfunction and subsequent lung fibrosis in IPF. We propose the following specific aims to
address this hypothesis: AIM 1: To identify mechanisms whereby disturbed GRP78-dependent mitochondrial
function and metabolism in AEC promote the development of PF. Aim 2: To characterize the role and
mechanisms of GRP78 reduction in mediating AEC aging phenotype and PF. Aim 3: To determine the
therapeutic potential of targeting GRP78 loss-mediated pathways in age-associated PF in vivo and in vitro. The
proposed studies will provide rationale for how therapeutics that target metabolism might a...

## Key facts

- **NIH application ID:** 10532246
- **Project number:** 5R01HL114959-07
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** David K. Ann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $558,938
- **Award type:** 5
- **Project period:** 2013-08-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10532246

## Citation

> US National Institutes of Health, RePORTER application 10532246, Role of Chaperone GRP78 and Mitochondrial Dysfunction in ER Stress-Mediated Pulmonary Fibrosis (5R01HL114959-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10532246. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*