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MtDNA repair: An isolated pharmacologic target in acute lung injury

Award Number: R01HL113614
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/16/2012
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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MtDNA repair: An isolated pharmacologic target in acute lung injury - PROJECT SUMMARY/ABSTRACT Mitochondrial (mt) dysfunction is common in the Acute Respiratory Distress Syndrome and its sequel, Multiple Organ System Failure, but the potential for mt-associated pathways to serve as pharmacologic targets in ARDS and MOSF has yet to be realized. Among the discoveries originating from this project, two lines of evidence may have paradigm-shifting implications. First, modulation of mtDNA repair coordinately regulates oxidative mtDNA damage and attendant cytotoxicity. And second, fragmentation of oxidatively damaged mtDNA into Damage Associated Molecular Patterns may disseminate injury to distant organs by activating a regenerative, feed-forward pathway in which mtDNA DAMPs, themselves, damage the mitochondrial genome and promote more mtDNA DAMP formation. These considerations provide the underpinnings for our long- term goal to develop pharmacologic strategies to treat ARDS and MOSF based on the concept that mitochondrial (mt) DNA acts as a molecular sentinel governing disease progression in response to critical illness or injury. Motivated by our finding that administration of transfusion products inadvertently containing variable amounts of mtDNA DAMPs increases circulating mtDNA DAMP levels and elevates the risk of ARDS-like Transfusion Related Acute Lung Injury in severely injured patients, Aim 1 will determine if a feed-forward pathway contributes to mtDNA DAMP accumulation in massively-transfused, critically injured human subjects at risk for TRALI. Here, we will test the hypothesis that the amount of exogenous mtDNA administered during massive transfusion dictates the amount of mtDNA DAMPs mobilized from endogenous, patient-derived sources. The second Aim is predicated on the fact that although oxidative mtDNA damage leads to DAMP release, only scant information is available concerning mechanisms of mtDNA fragmentation and sequence characteristics of the DAMPs so formed. Indeed, such deficiencies present serious obstacles to addressing fundamental questions pertaining to which mtDNA fragments are biologically active and how they are trafficked in the intra- and extracellular environments. Accordingly, Aim 2 will test the hypothesis that sites of oxidative damage to the mitochondrial genome promote its fracture into specific mtDNA DAMP sequences and predispose the mt-genome to somatic mutation. Collectively, the proposed research is significant because it will provide insight into the mechanisms of mtDNA DAMP formation, the importance of mtDNA DAMPs in the response to injury, and their utility as a pharmacologic target. It is innovative because the postulated operation of feedforward pathway involving mtDNA damage- induced DAMP formation is a fundamentally new concept to explain the progressive pathogenesis of ARDS and MOSF.


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: 2024 ( Subtotal = -$1,092 )
2024	2021	UNIVERSITY OF SOUTH ALABAMA	307 N UNIVERSITY BLVD	MOBILE	AL	36608	MOBILE	USA	Lung Diseases Research	000	9	1/26/2024	NON-COMPETING CONTINUATION	-$1,092
														Subtotal = -$1,092

Issue Date FY: 2021 ( Subtotal = $418,430 )
2021	2021	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	000	9	6/25/2021	NON-COMPETING CONTINUATION	$418,430
														Subtotal = $418,430

Issue Date FY: 2020 ( Subtotal = $418,430 )
2020	2020	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	000	8	6/30/2020	NON-COMPETING CONTINUATION	$418,430
														Subtotal = $418,430

Issue Date FY: 2019 ( Subtotal = $418,430 )
2019	2019	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	000	7	7/1/2019	NON-COMPETING CONTINUATION	$418,430
														Subtotal = $418,430

Issue Date FY: 2018 ( Subtotal = $454,751 )
2018	2018	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	001	6	6/21/2018	COMPETING CONTINUATION	$454,751
2018	2016	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	000	5	6/5/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $454,751

Issue Date FY: 2016 ( Subtotal = $371,250 )
2016	2016	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERSITY BOULEVARD	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	000	5	2/8/2016	EXTENSION WITH OR WITHOUT FUNDS	$371,250
														Subtotal = $371,250

Issue Date FY: 2015 ( Subtotal = $365,681 )
2015	2015	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERSITY BOULEVARD	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	000	4	2/20/2015	NON-COMPETING CONTINUATION	$365,681
														Subtotal = $365,681

Issue Date FY: 2014 ( Subtotal = $363,825 )
2014	2014	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERSITY BOULEVARD	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	000	3	3/18/2014	NON-COMPETING CONTINUATION	$363,825
														Subtotal = $363,825

Issue Date FY: 2013 ( Subtotal = $353,430 )
2013	2013	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERSITY BOULEVARD	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	001	2	6/25/2013	NON-COMPETING CONTINUATION	$19,305
2013	2013	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERSITY BOULEVARD	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	000	2	1/31/2013	NON-COMPETING CONTINUATION	$334,125
														Subtotal = $353,430

Issue Date FY: 2012 ( Subtotal = $371,250 )
2012	2012	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERSITY BOULEVARD	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	000	1	4/16/2012	NEW	$371,250
														Subtotal = $371,250

Grand Total All Awards = $3,534,385

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MtDNA repair: An isolated pharmacologic target in acute lung injury

Award Number: R01HL113614

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/16/2012

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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