Saturday, July 5, 2025 7/5/2025

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

Award Number: R01HL114959
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2013
PERIOD OF PERFORMANCE END DATE: 12/31/2025

Group Awards By:

View Award Description

Role of Chaperone GRP78 and Mitochondrial Dysfunction in ER Stress-Mediated Pulmonary Fibrosis - 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 achieve specificity for pro-fibrotic cells as anti-IPF agents.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $488,387 )
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Lung Diseases Research	000	9	11/26/2024	NON-COMPETING CONTINUATION	$488,387
														Subtotal = $488,387

Issue Date FY: 2024 ( Subtotal = $551,228 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Lung Diseases Research	001	8	6/14/2024	NON-COMPETING CONTINUATION	$44,999
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Lung Diseases Research	000	8	12/6/2023	NON-COMPETING CONTINUATION	$506,229
														Subtotal = $551,228

Issue Date FY: 2023 ( Subtotal = $558,938 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Lung Diseases Research	001	7	2/17/2023	NON-COMPETING CONTINUATION	$55,894
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Lung Diseases Research	000	7	1/10/2023	NON-COMPETING CONTINUATION	$503,044
														Subtotal = $558,938

Issue Date FY: 2022 ( Subtotal = $568,218 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Lung Diseases Research	000	6	11/26/2021	COMPETING CONTINUATION	$568,218
														Subtotal = $568,218

Issue Date FY: 2020 ( Subtotal = -$26,068 )
2020	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Lung Diseases Research	000	5	1/6/2020	NON-COMPETING CONTINUATION	-$26,068
														Subtotal = -$26,068

Issue Date FY: 2017 ( Subtotal = $412,500 )
2017	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Lung Diseases Research	002	5	6/14/2017	NON-COMPETING CONTINUATION	$412,500
2017	2016	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Lung Diseases Research	001	4	10/27/2016	EXTENSION WITH OR WITHOUT FUNDS	$134,853
2017	2015	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Lung Diseases Research	000	3	10/27/2016	NON-COMPETING CONTINUATION	-$134,853
														Subtotal = $412,500

Issue Date FY: 2016 ( Subtotal = $412,500 )
2016	2016	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Lung Diseases Research	000	4	6/7/2016	EXTENSION WITH OR WITHOUT FUNDS	$412,500
														Subtotal = $412,500

Issue Date FY: 2015 ( Subtotal = $406,312 )
2015	2015	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Lung Diseases Research	000	3	6/16/2015	NON-COMPETING CONTINUATION	$406,312
														Subtotal = $406,312

Issue Date FY: 2014 ( Subtotal = $403,025 )
2014	2014	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Lung Diseases Research	000	2	6/17/2014	NON-COMPETING CONTINUATION	$403,025
														Subtotal = $403,025

Issue Date FY: 2013 ( Subtotal = $390,320 )
2013	2013	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Lung Diseases Research	000	1	8/1/2013	NEW	$390,320
														Subtotal = $390,320

Grand Total All Awards = $4,165,360

Top

All Categories

About

Search

Reports

Data Submission

Award Information

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

Award Number: R01HL114959

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2013

PERIOD OF PERFORMANCE END DATE: 12/31/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer