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Mitochondrial DNA Injury is a Key Contributor to the Development of Chemical Lung Injury

Award Number: R01HL031197
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/1987
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Mitochondrial DNA Injury is a Key Contributor to the Development of Chemical Lung Injury - Accidental exposure to chlorine (Cl2) causes potentially fatal lung injury accompanied, in survivors, by reactive airway disease and pulmonary fibrosis resembling symptoms typical of the acute respiratory distress syndrome (ARDS). Our preliminary data also document that the mitochondrial genome–the integrity of which is critical to maintenance of normal bioenergetics and mitochondrial signaling activities– displays oxidative damage after Cl2 gas exposure, similar to that detected in other models of acute and chronic lung injury. Against this background, here we propose to test the hypothesis that an early molecular target in Cl2 gas inhalation is the mitochondrial (mt) genome, in which oxidative damage functions as a molecular sentinel leading to activation of pro-inflammatory pathways that drive acute lung injury and progressive lung remodeling. To address this hypothesis we will perform the following in vivo and in vitro studies outlined in the following three aims: Aim 1. Define the kinetics of lung oxidative mtDNA damage in mice exposed to Cl2 gas and returned to room air and test whether a novel agent to augmenting mtDNA injury decreases mortality and the severity of acute and chronic lung injury. Exp. 1.1 will determine the time course of Cl2 gas-induced lung mtDNA damage and its relation to lung pathophysiology in global (mitochondrial and nuclear) OGG1 knockout mice (OGG1-/-) and their wild type (WT) controls (C57BL/6), along with OGG1 KO mice reconstituted with mito-targeted OGG1 (OGG1-/-+OGG1mt), while Exp. 1.2 will test if intranasal administration of mitoOGG1 at selected time points after termination of Cl2 exposure decreases lung injury pulmonary fibrosis and improves survival. Aim 2: Test the hypothesis that Cl2 gas-induced lung mtDNA damage triggers mobilization of mtDNA Damage Associated Molecular Patterns (DAMPs) that drive nucleic acid-dependent inflammation and serve as biomarkers and causative agents of pneumotoxicity. In Exp. 2.1 will use WT, OGG1-/-, and OGG1-/-+OGG1mt mice to test the hypothesis that OGG1 activity coordinately regulates Cl2 gas-induced mtDNA DAMP accumulation and activation of nucleic acid receptor-mediated pro-inflammatory pathways. Aim 3: Determine key cellular mechanisms by which Cl2 gas causes mtDNA damage-dependent lung cell death and dysfunction. In Exp. 3.1 we will isolate alveolar macrophages (AM) and lung epithelial type II cells (ATII) from WT, OGG1-/-, and OGG1-/-+OGG1mt mice, and measure oxygen consumption rate, reactive oxygen species, mitochondrial membrane potential, ion transport and key indices of cell injury prior to and following exposure to Cl2 gas. Additionally, Exp. 3.2 will define the mtDNA damage-dependent trafficking of mtDNA DAMPs to cytosolic and extracellular compartments and determine how these two mtDNA DAMP pools interact to dictate pro-inflammatory nucleic acid receptor activation. As part of this experiment, we also will determine if exogenous mtDNA DAMPs recapitulate nucleic acid receptor activation and inflammation evoked by Cl2 and use Dnase1 to degrade extracellular mtDNA DAMPs to define the specific effect of mtDNA DAMPs originating from this compartment.


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 = $577,859 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	30	4/18/2025	NON-COMPETING CONTINUATION	$577,859
														Subtotal = $577,859

Issue Date FY: 2024 ( Subtotal = $777,723 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	29	2/16/2024	NON-COMPETING CONTINUATION	$577,859
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	002	29	8/16/2024	SUPPLEMENT FOR EXPANSION	$148,499
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	001	29	6/22/2024	NON-COMPETING CONTINUATION	$51,365
														Subtotal = $777,723

Issue Date FY: 2023 ( Subtotal = $654,190 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	28	3/20/2023	COMPETING CONTINUATION	$654,190
														Subtotal = $654,190

Issue Date FY: 2012 ( Subtotal = $379,870 )
2012	2012	UNIVERSITY OF ALABAMA AT BIRMINGHAM	UAB STATION, CBB 990	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	27	5/31/2012	NON-COMPETING CONTINUATION	$379,870
														Subtotal = $379,870

Issue Date FY: 2011 ( Subtotal = $382,677 )
2011	2011	UNIVERSITY OF ALABAMA AT BIRMINGHAM	UAB STATION, CBB 990	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	26	6/17/2011	NON-COMPETING CONTINUATION	$382,677
														Subtotal = $382,677

Issue Date FY: 2010 ( Subtotal = $381,688 )
2010	2010	UNIVERSITY OF ALABAMA AT BIRMINGHAM	UAB STATION, CBB 990	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	25	5/31/2010	NON-COMPETING CONTINUATION	$381,688
														Subtotal = $381,688

Issue Date FY: 2009 ( Subtotal = $392,056 )
2009	2009	UNIVERSITY OF ALABAMA AT BIRMINGHAM	UAB STATION, CBB 990	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	001	24	9/18/2009	COMPETING CONTINUATION	-$392,056
2009	2009	UNIVERSITY OF ALABAMA AT BIRMINGHAM	UAB STATION, CBB 990	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	24	8/18/2009	COMPETING CONTINUATION	$392,056
2009	2009	UNIVERSITY OF ALABAMA AT BIRMINGHAM	UAB STATION, CBB 990	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	002	24	9/21/2009	COMPETING CONTINUATION	$392,056
														Subtotal = $392,056

Grand Total All Awards = $3,546,063

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Mitochondrial DNA Injury is a Key Contributor to the Development of Chemical Lung Injury

Award Number: R01HL031197

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/1987

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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