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The mitochondrial genome in lung disease: a signaling hub linking the persistence and severity of inflammation to recovery

Award Number: R01HL169587
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2024
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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The mitochondrial genome in lung disease: a signaling hub linking the persistence and severity of inflammation to recovery - PROJECT SUMMARY/ABSTRACT The contribution of oxidative mitochondrial (mt) damage to inflammatory lung diseases is undisputed, but mechanisms underlying this association remain to be elucidated. Emerging evidence, however, points to the mitochondrial (mt) genome as a signaling hub integrating the initiation and resolution inflammatory responses. For example, one of the earliest events is reactive oxygen species (ROS) stress-induced oxidative mtDNA damage. Oxidized fragments of the mitochondrial genome (ox-mtDNA DAMPs) are then released into the cytosol where they stimulate the recognition receptor (PRR) NLRP3 to activate caspase-1 which triggers generation of proinflammatory cytokines. The mitochondrial base excision DNA repair (BER) pathway is important to this process since increasing or decreasing BER capacity suppressed or accentuated, respectively, mtDNA damage and ox-mDNA DAMP mobilization. BER also may be important in resolution of the inflammatory response. Full recovery requires restoration of mitochondrial function, accomplished in part by mitochondrial biogenesis. Mitochondrial DNA replication is a prerequisite for biogenesis, but replication must not take place until the mutagenic base damage initiating inflammation is repaired. Thus, BER and mtDNA replication must be faithfully coupled; if not, the resulting somatic mtDNA mutations would cripple recovery, potentially leading to acute and post-acute complications. Despite these advances, events underlying the transition between inflammation and its resolution are unclear. We now propose to test the hypothesis that a signaling axis involving mtDNA repair and caspase-1 integrates processes essential for initiation and resolution of NLRP3-dependent inflammation. Studies in cultured cells and intact rodents will: (1) Determine how BER coordinates initiation and resolution of ox-mtDNA DAMP formation with the intensity of inflammatory stress; and (2) Test the hypothesis that caspase-1 differentially regulates mtDNA repair and replication to ensure that NLRP3-induced inflammation is appropriate for the severity of the initiating stimulus while ensuring error-free, recovery-related mtDNA replication. This work is significant because it will test a new hypothesis to explain how the inflammatory response initiated by NLRP3 is titrated to the severity of the initiating stimulus and resolved without complications, including the potential introduction of somatic variants into mitochondrial genome during resolution of inflammation. These studies are also technically innovative; they will apply new mtDNA sequencing and isotopic labeling strategies to track the formation and fate of proinflammatory ox-mtDNA as it relates to lung cell inflammation and resolution.


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 = $724,530 )
2025	2025	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERSITY BLVD	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	001	2	8/26/2025	NON-COMPETING CONTINUATION	$72,452
2025	2025	UNIVERSITY OF SOUTH ALABAMA	307 N UNIVERSITY BLVD	MOBILE	AL	36608	MOBILE	USA	Lung Diseases Research	000	2	3/17/2025	NON-COMPETING CONTINUATION	$652,078
														Subtotal = $724,530

Issue Date FY: 2024 ( Subtotal = $724,530 )
2024	2024	UNIVERSITY OF SOUTH ALABAMA	307 N UNIVERSITY BLVD	MOBILE	AL	36608	MOBILE	USA	Lung Diseases Research	000	1	3/14/2024	NEW	$652,078
2024	2024	UNIVERSITY OF SOUTH ALABAMA	307 N UNIVERSITY BLVD	MOBILE	AL	36608	MOBILE	USA	Lung Diseases Research	001	1	6/13/2024	NEW	$72,452
														Subtotal = $724,530

Grand Total All Awards = $1,449,060

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The mitochondrial genome in lung disease: a signaling hub linking the persistence and severity of inflammation to recovery

Award Number: R01HL169587

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2024

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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